Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:13](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 900.2 %

Procedure:
To a solution of 2-chloro-5-fluoronicotinic acid 6 (50 g, 285 mmol) and DMF (2 mL, 28 mmol) in DCM (400 mL) at 0° C. was added oxalyl chloride (64 mL, 741 mmol) dropwise. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The resulting yellow liquid was dissolved in 1,4-dioxane (600 mL), cooled at 0° C. and NH3(g) was bubbled through the solution for 30 minutes. The mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filtrate was concentrated to give compound 3 (44 g, 89%) as a beige solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.84 (s, 1H), 7.96 (dd, 1H), 8.09 (s, 1H), 8.49 (d, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]1([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21]1)=[O:18])=[CH:10][CH:9]=2)#[CH:4].[CH2:28](Br)[C:29]#[CH:30].O>C1COCC1>[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]1([CH2:24][O:25][CH2:30][C:29]#[CH:28])[CH2:23][CH2:22][CH2:21]1)=[O:18])=[CH:10][CH:9]=2)#[CH:4]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(CO)CCC3)cc2c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCC1(NC(=O)C(Oc2ccc3ncc(C#C)cc3c2)SC)CCC1
Temperature: 25 °C
Yield: 15.5 %

Procedure:
NaH (172 mg, 60% in oil) was added to a solution of 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-cyclobutyl)-2-methylsulfanyl-acetamide (850 mg) in THF (50 ml), at room temperature, under nitrogen atmosphere. The mixture was stirred until gas evolution ceased (30 min). Propargyl bromide (638 mg, 80% toluene solution) was added and the mixture was stirred at 40° C. during 3 hours, and then after cooling to room temperature poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/CH2Cl2, 1/1/1) to give 2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-N-(1-prop-2-ynyloxymethyl-cyclobutyl)-acet-amide (146 mg) as slightly brown oil. 1H NMR (CDCl3) δ ppm: 8.82 (1H, d); 8.18 (1H, d); 8.03 (1H, d); 7.44 (1H, dd); 7.21 (1H, d); 6.88 (1H, br s); 5.62 (1H, s); 4.14 (2H, s); 3.84-3.74 (2H, dd, AB system); 3.28 (1H, s); 2.49-2.13 (4H, m); 2.42 (1H, s); 2.19 (3H, s); 2.01-1.79 (2H, m).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:18][CH:19]([C:21]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32]O)[CH2:28][CH2:27]2)[O:23][N:22]=1)[CH3:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:20][CH:19]([C:21]1[N:25]=[C:24]([N:26]2[CH2:27][CH2:28][CH:29]([CH2:32][O:17][C:14]3[CH:15]=[N:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[N:12][CH:13]=3)[CH2:30][CH2:31]2)[O:23][N:22]=1)[CH3:18]
Reactant: CS(=O)(=O)c1ccc(-c2ncc(O)cn2)cc1
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3cnc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Yield: 75.5 %

Procedure:
The title compound (0.145 g, 75%) was prepared as a white solid from 2-[4-(methylsulfonyl)phenyl]-5-pyrimidinol (0.106 g, 0.42 mmol), 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Step 3, 0.10 g, 0.42 mmol) and Ph3P (0.12 g, 0.42 mmol) in THF (3 mL) followed by diisopropyl azodicarboxylate (92 mg, 94%, 0.42 mmol) in THF (1 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CD3OD): δ 8.61 (s, 2H), 8.58 (d, 2H, J=8.6 Hz), 8.04 (d, 2H, J=8.3 Hz), 4.25-4.10 (m, 2H), 4.12 (d, 2H, J=6.2 Hz), 3.25-3.10 (m, 5H), 2.85 (septet, 1H, J=7.0 Hz), 2.25-2.10 (m, 1H), 2.05-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.26 (d, 6H, J=7.1 Hz); LRMS (ESI), m/z 458 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[N:32](C(OC(C)(C)C)=O)[N:31]=[CH:30]5)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([C:12]4[CH:11]=[C:10]([NH:9][C:7]([CH:4]5[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]5)=[O:8])[CH:15]=[CH:14][CH:13]=4)[N:25]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)C5CCNCC5)c4)nc4ccccc34)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)C1CCNCC1

Procedure:
To tert-butyl 5-(2-(3-(piperidine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (mg, mmol) was added a solution of 1:1 TFA:CH2Cl2 (4 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether to afford N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)piperidine-4-carboxamide. (97 mg, 0.21 mmol, 75% over two steps)
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH2:23][NH:28][CH2:27][CH2:25][OH:26])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Reactant: NCCO
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(CNCCO)ccc1-2
Yield: 27 %

Procedure:
Following the procedure for 119, 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde and ethanolamine were reacted. After aqueous work-up the resulting gum was triturated with DCM/ether/pentane to give a solid that was filtered off and dried to give 131 as an off-white solid (55 mg, 27%). LCMS: RT=5.54 min, [M+H]+=386. 1H NMR δ (ppm) (CDCl3): 8.37 (1H, s), 8.30 (1H, d, J=8.11 Hz), 7.13 (1H, dd, J=8.15, 1.72 Hz), 7.05 (1H, d, J=1.68 Hz), 5.70-5.63 (1H, m), 4.41 (2H, t, J=5.06 Hz), 3.84 (2H, s), 3.68 (2H, t, J=5.17 Hz), 3.42 (2H, t, J=5.07 Hz), 2.85 (2H, t, J=5.16 Hz), 1.65 (6H, d, J=6.74 Hz). 2 Exchangeable protons not seen
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:22]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:23]([C:39]([NH:41][C@H:42]([C:44](O)=[O:45])[CH3:43])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:22]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[C@H:23]([C:39]([NH:41][C@H:42]([C:44]([NH:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:45])[CH3:43])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
compound SP303r2. To a solution of Trp-NHPh (202 mg, 0.723 mmol) in CH2C12/DMF (3 mL, 1/1) at 0° C. were successively added N-Boc-Tyr(Bn)-Ala-OH (320 mg, 0.723 mmol), EDC (153.6 mg, 0.8 mmol) and HOBt (108 mg, 0.8 mmol). The resulting mixture was allowed to warm up to room temperature overnight. The solvent was evaporated and the crude was triturated with water. After filtration, the solid was collected and purified by precipitation in CH2Cl2/MeOH to give a white amorphous solid (160.3 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, J=7 Hz, 3H, CH3), 1.28 (s, 9H, (CH3)3), 2.63 (m, 1H, CH2), 2.89 (m, 1H, CH2), 3.06 (dd, J=14.5 Hz, 7.5 Hz, 1H, CH2), 3.2 (dd, J=14.5 Hz, 6.1 Hz, 1H, CH2), 4.1 (m, 1H, CHα), 4.34 (m, 1H, CHα), 4.69 (m, 1H, CHα), 5.02 (s, 2H, CH2 (Bn)), 6.88 (d, J=8.5 Hz, 2 aromatic H Tyr), 6.94 (m, 2 aromatic H Trp), 7.03 (t, J=7.4 Hz, 2 aromatic H Trp), 7.16 (m, 3 aromatic H), 7.25-7.42 (m, 8H), 7.58 (m, 3H), 8.02 (d, J=7.2 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H), 10 (s, 1H, NH), 10.8 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6) δ 18.2 (CH3), 27.7 (CH2 Trp), 28.1 ((CH3)3), 36.3 (CH2 Tyr), 48.1, 54.2, 55.7 (CHα Ala, Tyr, Trp), 69 (CH2 (Bn)), 78 (C(CH3)3), 109.5, 111.2, 114.2, 118.2, 118.4, 119.4, 120.8, 123.3, 123.5, 127.3, 127.5, 127.7, 128.3, 128.6, 130.1, 130.3, 135.9, 137.2, 138.8 (25 aromatic C), 155.2, 156.8 (Car-O, CO carbamate), 170, 171.5, 172.1 (3 CO amide). Anal. Calcd. for C41H45N5O6, 0.5H2O: C, 69.08; H, 6.5; N, 9.82. Found: C, 68.82; H, 6.34; N, 9.79.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[C:19](OCC)(=O)C.O>CO.S(=O)(=O)(O)O>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Commercially available 4-bromo-3-nitro-benzoic acid (1.17 g, 4.76 mmol) was dissolved in methanol (5 mL) containing five drops of concentrated sulfuric acid. The mixture was heated in air at 90° C. for six hours and more MeOH (7 mL) followed by concentrated sulfuric acid (0.6 mL) was added. Heating was continued another 24 hours. Extractive work up (ethyl acetate-water) followed by drying over MgSO4, filtered and concentrated under vacuum giving the title compound in quantitative yield.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:9][N:8]([O:11][CH2:12][CH3:13])[CH2:7][CH2:6]1)=O.C[O-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:12]([O:11][N:8]1[CH2:9][CH2:10][C:5]2([NH:14][C:15](=[O:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:3]2[OH:2])[CH2:6][CH2:7]1)[CH3:13]
Reactant: CCON1CCC(NC(=O)Cc2c(C)cc(C)cc2C)(C(=O)OC)CC1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Temperature: 65 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a solution of 2.3 g of 1-ethoxy-4-[2-(2,4,6-trimethyl-phenyl)-acetylamino]-piperidine-4-carboxylic acid methyl ester in 26 ml of dimethylformamide was added 3 g of sodium methoxide. The reaction mixture was heated to 65° C. and stirred for 5 hours. The reaction mixture was poured into brine, neutralized and extracted with ethyl acetate. The organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (heptane/ethyl acetate 2:1) to yield 510 mg of 8-ethoxy-4-hydroxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound C8) as a solid, mp: >250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([O:23]CC)=O)[N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:28]=1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([N:37]3[CH2:38][CH2:39][N:34]([CH2:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[CH2:35][CH2:36]3)=[O:23])[N:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)c1noc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)n1
Reactant: c1cncc(CN2CCNCC2)c1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(Cc4cccnc4)CC3)no2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-3-carboxylate (27 mg, 0.07 mmol), 1-(pyridin-3-ylmethyl)piperazine (40 mg, 0.23 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (2 mL). A portion of the crude product was purified using prep method D.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[C:35]([C:36]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)OCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 558.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][CH2:10][C:11](=[O:14])[N:12]([CH3:26])[N:13]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NN(C)C(=O)CS3)c(F)c2)C(=O)O1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A mixture of N-{3-[3-fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-acetamide (0.100 g, 0.273 mmol), potassium carbonate (0.075 g, 0.546 mmol), and iodomethane (0.0187 ml, 0.300 mmol) in DMF (3 ml) is heated at 80° C. overnight. The reaction mixture is filtered and evaporated to dryness. The residue is purified by PTLC (10% MeOH/DCM) to give product as a white solid (0.104 g, 90%); 1HNMR (300 MHz, DMSO-d6) δ 1.82 (s, 3H), 3.39 (s, 3H), 3.42 (t, J=5.5, 2H), 3.66 (s, 2H), 3.76 (dd, J=6.6, 9.3 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.71-4.80 (m, 1H), 7.43 (dd, J=2.2, 8.8 Hz, 1H), 7.59 (dd, J=1.9, 14 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 8.25 (t, J=5.8 Hz, 1H); mp 179-80; MS (m/z): [M+H]+=381.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:22][NH:23]C(OCC2C=CC=CC=2)=O)([C:13](=[O:21])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.C(Cl)Cl.[Pd]>[NH2:23][CH2:22][C:10]1([C:13](=[O:21])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)(C(=O)Nc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN)(C(=O)Nc2ccccc2)C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To 3-(benzyloxycarbonylamino-methyl)-3-phenylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1200.00 mg; 2.65 mmol; 1.00 eq.) in 30 ml of methanol was added of ammonium formate (1668.40 mg; 26.46 mmol; 10.00 eq.) and 10% Pd/C (wet) 1.2 g. The mixture was stirred at 65° C. for 1 hr and then filtered. The filtrate was concentrated to give the crude, which was dissolved in DCM and washed with 5% NaHCO3, brine, dried and concentrated to afford the title compound (820 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:4]([C@@H:11]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C@H:12]2[C:23]([O:25]C)=[O:24])[CH:5]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[C:19]([O:18][C:16]([N:14]1[CH2:15][C@@H:11]([C:4]2[CH:5]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:7]=[C:2]([Cl:1])[C:3]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@H:12]([C:23]([OH:25])=[O:24])[CH2:13]1)=[O:17])([CH3:20])([CH3:22])[CH3:21]
Reactant: CCCc1cc(Cl)c(C(=O)OCC)c([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(Cl)c(C(=O)OCC)c([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of (±)-trans-1-tert-butyl 3-methyl 4-(3-chloro-2-(ethoxycarbonyl)-5-propylphenyl)pyrrolidine-1,3-dicarboxylate (0.78 g, 1.72 mmol) in 20 mL of THF and 10 mL of water was added lithium hydroxide (0.051 g, 2.15 mmol). The reaction was stirred at ambient temperature for 3 h and then was acidified with 1N HCl. The reaction mixture was extracted with EtOAc and the organics were washed with brine, dried (MgSO4) and concentrated to afford 0.75 g (98%) of the title compound as a white foam. LRMS (ES)+: 340.17/342.16 (M+H—BOC)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Product: C#Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 2(4-chlorophenyl)-1-trimethylsilylethyne Prepared in Stage 1 (30.90g:0.02 mole) in methanol was added potassium carbonate (0.276g:002 mole). The mixture was stirred at room temperature until starting material disappeared as monitored by gas liquid chromatography. After this time, solvent was removed in vacuo and the residue taken up in dichloromethane. The solution was dried and declourised over charcoal. Filtration, followed by removal of solvent gave a brown solid which was passed through silica in hexane. This gave pale yellow crystals (1.511g:55.3%)
Reaction SMILES: [CH:1]1([CH:6]([N:28]2[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=2[F:27])[CH2:13][C:14]2([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH:1]1([CH:6]([N:28]2[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=2[F:27])[CH2:13][C:14]2([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1CCN(C(C(=O)Nc2cc(CC3(C(=O)OC(C)(C)C)CC3)ccc2F)C2CCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1CCN(C(C(=O)Nc2cc(CC3(C(=O)O)CC3)ccc2F)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
20.1 mg (0.04 mmol) of rac-tert-butyl 1-(3-{[cyclopentyl(4-methoxypiperidin-1-yl)acetyl]amino}-4-fluorobenzyl)cyclopropanecarboxylate (Example 95A) were dissolved in 2.4 ml of 20% strength trifluoroacetic acid in dichloromethane and stirred at RT for 5 h. The mixture was then concentrated on a rotary evaporator and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA, 10:90→95:5; run time 38 min). This gave 6.8 mg (30% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH2:10][OH:11].[C:12]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.[OH-].[Na+].Cl>O.C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]2=[O:21])=[CH:4][C:3]=1[CH2:10][OH:11]
Reactant: O=Cc1ccc(O)c(CO)c1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C(=Cc2ccc(O)c(CO)c2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-hydroxy-3-(hydroxymethyl)benzaldehyde (1.08 g), indan-1-one (0.94 g), ethanol (30 ml) and 5M aqueous sodium hydroxide solution (1.6 ml) was boiled under reflux for 6.5 hours. The mixture was cooled to ambient temperature and allowed to stand at that temperature for 16 hours. The mixture was diluted with water (45 ml) and then with 5M hydrochloric acid (1.6 ml) which was added with cooling. The precipitate formed was collected by filtration, washed with water and dried to give 2-(4-hydroxy-3-(hydroxymethyl)benzylidene)-1-indan-one, m.p. 194-195° C.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].Cl[CH:15]([CH:18]=O)[CH:16]=[O:17].C(=O)([O-])[O-].[Mg+2]>O1CCOCC1>[CH:16]([C:15]1[S:13][C:2]([CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH3:4])=[N:1][CH:18]=1)=[O:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=S
Reactant: O=CC(Cl)C=O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: CC(NC(=O)OC(C)(C)C)c1ncc(C=O)s1
Temperature: 60 °C
Yield: 71.5 %

Procedure:
A mixture of (S)-tert-butyl 1-amino-1-thioxopropan-2-ylcarbamate (6.9 g, 0.03 mol), 2-chloromalonaldehyde (5.2 g, 0.049 mol) and magnesium carbonate (2.76 g, 0.03 mol) in 1,4-dioxane (400 mL) was heated at 60° C. for 3 hours and further at room temperature overnight. The reaction mixture was concentrated and the residue purified by column chromatography (50-80% EtOAc/hexane) to afford tert-butyl 1-(5-formylthiazol-2-yl)ethylcarbamate (5.5 g, 64%). LC-MS: (FA) ES+ 257.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].CCCCCC.C([Li])CCC.[CH:18]([CH:20]=[CH2:21])=[O:19]>O1CCCC1>[OH:19][CH:18]([C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:20]=[CH2:21]
Reactant: C#CC(C)(C)C
Reactant: C=CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(O)C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 741.3 %

Procedure:
Ten grams (0.122 mole) of 3,3-dimethyl-1-butyne was dissolved in 100 ml of anhydrous tetrahydrofuran and the resulting solution was cooled to -40° C. or less in a dry ice-acetone bath. Under the stream of a nitrogen gas, 81.13 ml (0.122 mole) of a 1.5M hexane solution of n-butyllithium was added dropwise at -40° C. or less with stirring. After ageing the reaction solution at -50° C. for 30 minutes, 6.84 g (0.122 mole) of acrolein was added dropwise at -50° C. or less. After the reaction solution was allowed to stand overnight at room temperature, it was poured into 200 ml of ice water and extracted with two 100-ml portions of ethyl acetate. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 125 g of 3-hydroxy-6,6-dimethylhept-1 -ene-4-yne (bp20, 80° C.).
Reaction SMILES: BrC1C=C([C@@H]2[C@@H](C3C=C(F)C=CC=3F)[O:11][C:10](=O)N2)C=NC=1.Cl.Cl.[NH2:24][C@H:25]([C:35]1[CH:40]=[C:39]([Cl:41])[N:38]=[CH:37][N:36]=1)[C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[OH:27]>>[Cl:41][C:39]1[N:38]=[CH:37][N:36]=[C:35]([C@@H:25]2[C@@H:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[O:27][C:10](=[O:11])[NH:24]2)[CH:40]=1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Reactant: N[C@H](c1cc(Cl)ncn1)[C@H](O)c1cccc(F)c1
Agent: Cl
Product: O=C1N[C@H](c2cc(Cl)ncn2)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared according to the same procedure as (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one, starting with (1R,2R)-2-amino-2-(6-chloropyrimidin-4-yl)-1-(3-fluorophenyl)ethanol 2HCl. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.55 (s, 1H), 7.86 (s, 1H), 7.52 (td, J=7.9, 6.1 Hz, 1H), 7.42-7.17 (m, 3H), 5.62 (d, J=4.9 Hz, 1H), 4.93 (d, J=5.2 Hz, 1H), Mass spec.: 294.1 (MH)+.