Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:11]1)=[O:5].[CH3:35][O-:36].[Na+]>CO>[CH3:35][O:36][C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:11][N:12]([CH:14]2[CH2:15][CH2:16][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)[CH2:13]1)=[O:5]
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1F)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
2-Fluoro-N-{[1-(4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide (as prepared in Example 66, 50 mg, 0.11 mmol) was treated with NaOMe (0.5 M in MeOH, 600 μL, 0.30 mmol) in MeOH (1 mL) at room temperature overnight. The solvent was removed and the residue was purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]>C(#N)C>[CH3:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[CH3:49]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1C
Yield: 36.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3,4-dimethylbenzenesulfonyl chloride (0.0400 g, 0.195 mmol) to obtain 4-(3,4-dimethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0149 g. yield 36%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[Br:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:31])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:17]=[CH:18][CH:19]=1>C(O)C>[Br:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:31][C:4]4[C:5](=[O:12])[C:6](=[O:11])[C:7]=4[O:8][CH2:9][CH3:10])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: CCO
Product: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A solution of 1.08 g of 3,4-diethoxy-3-cyclobutene-1,2-dione and 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 mL of ethanol was refluxed for 3 hr. The mixture was cooled to room temperature. The solid was collected by filtration and washed with ethanol to give 0.9 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 441.1.
Reaction SMILES: C[N+]([O-:5])(C)C.Br[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]#[N:13]>CS(C)=O>[CH3:14][C:11]([CH3:15])([CH2:10][CH2:9][CH2:8][CH:7]=[O:5])[C:12]#[N:13]
Reactant: C[N+](C)(C)[O-]
Reactant: CC(C)(C#N)CCCCBr
Solvent: CS(C)=O
Product: CC(C)(C#N)CCCC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of trimethylamine oxide (1.5 g, 19.6 mmol, Aldrich) in DMSO (10 mL) was added 6-bromo-2,2-dimethylhexanenitrile (0.84 mL, 4.9 mmol, Aldrich). After stirring at room temperature overnight, the reaction mixture was quenched with water (10 mL) and extracted with hexanes (4×10 mL). The combined organic extracts were washed with brine (20 mL), dried (NaSO4), filtered and concentrated to afford 0.65 g (80% pure) of the title compound. MS (ESI+) m/z 157 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2.Cl[C:35]([O:37][CH3:38])=[O:36]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:35]([O:37][CH3:38])=[O:36])[C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2
Reactant: COC(=O)Cl
Reactant: Cc1c(N2CCN[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: COC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)C[C@@H]1C

Procedure:
Essentially prepared according to Procedure N using (S)-5,7-difluoro-3-methyl-2-(3-methylpiperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (50 mg, 0.11 mmol) and methyl chloroformate to give (S)-methyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-2-methylpiperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.94 (1H, d, J=2.3 Hz), 7.69 (1H, d, J=2.2 Hz), 7.30 (1H, ddd, J=10.0, 2.6, 1.3 Hz), 6.89 (1H, d, J=12.9 Hz), 6.81 (1H, ddd, J=13.9, 8.8, 2.5 Hz), 6.58 (1H, t, J=2.4 Hz), 4.43 (1H, br. s.), 4.03 (1H, d, J=13.5 Hz), 3.86 (4H, dd, J=5.7, 3.9 Hz), 3.76 (3H, s), 3.71 (1H, d, J=9.8 Hz), 3.52-3.64 (1H, m), 3.38 (1H, td, J=12.8, 3.2 Hz), 3.17 (4H, dd, J=5.7, 4.1 Hz), 3.12 (1H, dd, J=12.8, 3.8 Hz), 2.93 (1H, td, J=12.6, 3.4 Hz), 2.10 (3H, s), 1.32 (3H, d, J=6.8 Hz). Mass Spectrum (ESI) m/e=513.3 (M+1).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].[CH2:8]([O:10][CH2:11][CH2:12]Br)[CH3:9]>>[CH2:8]([O:10][CH2:11][CH2:12][O:7][CH:3]([CH2:4][CH2:5][CH3:6])[C:2]#[CH:1])[CH3:9]
Reactant: C#CC(O)CCC
Reactant: CCOCCBr
Product: C#CC(CCC)OCCOCC
Yield: 44.7 %

Procedure:
In accordance with the procedure of the step 1 of Example 10, 21.8 g of 1-hexyn-3-ol was allowed to react with 37.2 g of 2-bromoethyl ethyl ether to obtain 16.9 g of 3-(2-ethoxyethoxy)-1-hexyne.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.[NH2:15][C:16]1[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=1)=[O:19].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:15][C:16]2[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([C:28]([F:31])([F:29])[F:30])[CH:22]=2)=[O:19])=[CH:9][CH:8]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: COc1ccc(C=O)cn1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNc2ccccc2C(=O)Nc2ccc(Br)c(C(F)(F)F)c2)cn1
Reaction time: 16 h

Procedure:
Sodium cyanoborohydride (8.80 g of 95%, 133 mmol) is added in portions over 30 minutes to a stirred mixture of acetic acid (3.8 mL), 6-methoxy-3-pyridinecarboxaldehyde (Fluka, Buchs, Switzerland; 7.80 g, 57 mmol) and 2-amino-N-(4-bromo-3-trifluoromethylphenyl)-benzamide (step 1.2; 13.65 g, 38 mmol) in methanol (380 mL) at 25° C. The mixture is stirred for 16 hours. The solvent is evaporated under reduced pressure to give a residue which is treated with a saturated aqueous solution of sodium hydrogen carbonate (500 mL) and extracted with dichloromethane (3×150 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product that is purified by column chromatography on silica gel, eluent 5% ethyl acetate in dichloromethane and recrystallised from diethylether-hexane to give the title compound as a beige crystalline solid, m.p. 101–103° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30]C1C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][CH3:30])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCCc2cc(CO)ccc2OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COCc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)OC)cc2)c1
Yield: 66.2 %

Procedure:
To a solution of methyl 4-[3-(2-benzyloxy-5-hydroxymethylphenyl) propyl]benzoate (5.31 g) in methanol (100 ml) was added 4-methylbenzenesulphonic acid (3.11 g). The reaction was heated at reflux for 18 hours, the solvent evaporated, the residue dissolved in EtOAc, washed with brine and the solvent evaporated to give methyl 4-[3-(2-benzyloxy-5-methoxymethylphenyl)propyl]benzoate (3.64 g).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:11])=O.[OH-].[NH4+:13]>C1(C)C=CC=CC=1>[NH2:11][C@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]1[C:3]([NH2:13])=[O:2]
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NC(=O)[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-2-Aminocyclohexanecarboxylic acid methyl ester (2.20 g, 14.0 mmol) was treated with aqueous ammonium hydroxide (40 mL) in toluene (40 mL) and stirred vigorously at room temperature for 16 h. The reaction was concentrated to dryness in vacuo and azeotroped with toluene (50 mL). The crude product, cis-2-aminocyclohexanecarboxylic acid amide, was used in the next reaction without purification: 1H NMR (400 MHz, DMSO-d6) δ 7.78 (2 H, s br), 7.67 (s, 1 H), 7.25 (s, 1 H), 1.87 (m, 2 H), 1.60 (m, 4 H), 1.41 (m, 4 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][C:11]([NH:13][C:14]3[S:15][C:16]([C:20]([NH:22][C@@H:23]([CH2:27][NH:28][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[O:30])[C:24]([OH:26])=[O:25])=[O:21])=[C:17]([CH3:19])[N:18]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39][O:25][C:24](=[O:26])[C@@H:23]([NH:22][C:20]([C:16]1[S:15][C:14]([NH:13][C:11](=[O:12])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[N:2][NH:1]3)=[N:18][C:17]=1[CH3:19])=[O:21])[CH2:27][NH:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30]
Reactant: CC(C)(C)CCO
Reactant: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OCCC(C)(C)C
Temperature: 100 °C
Yield: 35.9 %

Procedure:
A mixture of the (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (75.3 mg, 0.147 mmole), 3,3-dimethyl-1-butanol (1 mL, 8.054 mmol) and p-toluenesulfonic acid monohydrate (14.1 mg, 0.0741 mmol) was heated at 100° C. for 2½ hours. The reaction is cooled, neutralized and extracted with ethyl acetate (3×15 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (80% EtOAc in hexanes) to give (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]propionic acid 3,3-dimethyl-butyl ester (31.5 mg, 35.9%) as a white solid. MS m/e 597.7 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6]Br)=[C:4]([F:11])[CH:3]=1.[C-:12]#[N:13].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][C:12]#[N:13])=[C:4]([F:11])[CH:3]=1
Reactant: Fc1cc(Cl)cc(F)c1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(F)cc(Cl)cc1F
Temperature: 100 °C
Yield: 58.6 %

Procedure:
Step A To the solution of 4-chloro-2,6-difluorobenzyl bromide (Alfa) (2.5 g, 10 mmol) in ethanol (13 mL) and H2O (10 mL) was added KCN (1.75 g, 27 mmol). The reaction mixture was heated at 100° C. for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4) to give (4-chloro-2,6-difluoro-phenyl)-acetonitrile as a yellow oil (1.1 g, 57%).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:62])[CH:24]([NH:25][C:26](=[O:61])[C:27]([C:36]4[N:37]=[C:38]([NH:41]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:39][CH:40]=4)=[CH:28][C:29]([O:31]C(C)(C)C)=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:63][S:64][C:65]2[S:66][C:67]([CH3:70])=[N:68][N:69]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[F:71][C:72]([F:77])([F:76])[C:73]([O-:75])=[O:74].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[NH2:41][C:38]1[S:39][CH:40]=[C:36]([C:27](=[CH:28][C:29]([OH:31])=[O:30])[C:26]([NH:25][CH:24]2[C:23](=[O:62])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([CH2:63][S:64][C:65]4[S:66][C:67]([CH3:70])=[N:68][N:69]=4)[CH2:19][S:20][C@H:21]23)=[O:61])[N:37]=1.[F:71][C:72]([F:77])([F:76])[C:73]([O-:75])=[O:74]
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=CC(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)s1
Agent: O=C([O-])C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=CC(=O)O)c4csc(N)n4)[C@H]3SC2)s1
Reaction time: 4 h

Procedure:
7-[2-(2-tritylaminothiazol-4-yl)-2-t-butoxycarbonylmethylene-acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethylester (Z-isomer) (60 mg) was dissolved in anisole (0.5 ml), and the resultant solution was ice-cooled. The cooled solution was admixed with trifluoroacetate acid (2 ml), and the admixture obtained was stirred for 4 hours at 0° to 5° C. The resulting reaction solution was poured into isopropylether (50 ml), to precipitate the titled compound. The precipitate was removed by filtration to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethylene-acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (Z-isomer) trifluoroacetate (20 mg) as powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[N:9]O)=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.S(Cl)(Cl)=O>>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C=NO)c(Cl)n1
Solvent: O=S(Cl)Cl
Product: CSc1nc(Cl)c(C#N)c(Cl)n1

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde oxime (7.20 g, 30.38 mmol) was added to neat thionyl chloride (29.63 g, 245 mmol), then the mixture was heated to reflux for 4 hours. The reaction mixture was poured onto ice-water. The precipitate of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile was collected and dried (Yield=6.15 g, 92%). 1H-NMR (300 MHz, CDCl3) δ 2.75(s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:26])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:34]([CH3:36])[CH3:35]>CN(C)C=O.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH:20]4[CH2:21][CH2:22][N:23]([CH:34]([CH3:36])[CH3:35])[CH2:24][CH2:25]4)=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:26])=[CH:5][CH:4]=1
Reactant: CC(C)I
Reactant: O=C1CCc2cc(OC3CCNCC3)ccc2N1c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)CCC(=O)N3c2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A suspension of 1-(4-fluorophenyl)-6-(piperidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one hydrochloride prepared in Example 7-(3) (0.30 g), potassium carbonate (0.55 g) and 2-iodopropane (0.68 g) in N,N-dimethylformamide (10 mL) was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1) to give the titled compound (0.16 g, 52%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1.[CH3:28][C@@H:29](O)[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:28][C@@H:29]([O:26][C:25]([C:22]1([C:20]2[N:21]=[C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[C:14](=[O:18])[O:13][CH2:12]5)[N:5]3[N:19]=2)[CH2:23][CH2:24]1)=[O:27])[CH2:30][CH3:31]
Reactant: CC[C@@H](C)O
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@@H](C)OC(=O)C1(c2nc3c(OC)ccc(-c4ccc5c(c4)COC5=O)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A mixture of 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (400 mg, 1.095 mmol), (2R)-butan-2-ol (122 mg, 1.64 mmol), DMAP (147 mg, 1.20 mmol) and EDCI.HCl (231 mg, 1.20 mmol) in DCM (10 mL) was stirred at RT overnight before it was evaporated to dryness. Column chromatography (gradient MeOH 0 to 5% in DCM) followed by recrystallization in EtOH and freeze drying afforded the title compound as colorless powder (138 mg, 30%). HPLC-Retention time (XE Metode 7 CM): 2.33 minutes. Detected “M+1”-mass: 422.15. Calculated “M+1”-mass: 422.17. 1H NMR (DMSO, 400 MHz): δ=8.23 (br s, 1H), 8.14 (dd, 1H, J=8.0, 1.6 Hz), 7.99 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.2 Hz), 7.24 (d, 1H, J=8.2 Hz), 5.51 (s, 2H), 4.78 (h, 1H, J=6.3 Hz), 4.04 (s, 3H), 1.62-1.38 (m, 6H), 1.13 (d, 3H, J=6.3 Hz), 0.78 (t, 3H, J=7.4 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl-].[C:20](#[N:22])[CH3:21]>CN(C)C=O>[C:20]([CH2:21][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:22]
Reactant: CCOC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: CC#N
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(OC)cc2n1CC#N

Procedure:
Under nitrogen, dissolve 2.15 g of ethyl 6-methoxy-1H-indole-2-carboxylate in 10 ml of dimethylformamide. Add 0.59 g of sodium hydride in small portions at 0° C. and stir the reaction at 0° C. for 30 minutes. Add 0.93 ml of acetonitrile chloride at 0° C. and stir the reaction at ambient temperature for 24 hours. Add water and extract with ethyl acetate. Wash the organic phase with saturated aqueous sodium hydrogen carbonate solution and with saturated aqueous sodium chloride solution. Dry the organic phase over sodium sulfate, filter and evaporate. Purify the compound by column chromatography on silica gel using dichloromethane as eluant. The title compound is obtained in the form of a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=3)=[CH:17][CH:16]=2)[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH:2]=1.[OH:44]O>C(O)(=O)C>[O-:44][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=3)=[CH:17][CH:16]=2)[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH:2]=1
Reactant: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)O)NC(=O)c3cccnc3)cc2)ccc1NC(=O)Nc1ccccc1C
Reactant: OO
Solvent: CC(=O)O
Product: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)O)NC(=O)c3ccc[n+]([O-])c3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of (R)-3-[(pyridine-3-carbonyl)amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propanoic acid [0.4 g, Example 5(e)], acetic acid (2.5 ml) and hydrogen peroxide (0.5 ml) was stirred at 80° C. for 6 hours. The reaction mixture was evaporated and the residue was triturated with water. The resulting solid was subjected to flash chromatography on silica gel eluting with a mixture of dichloromethane, methanol and acetic acid (9:1:0.5, v/v/v) to give the title compound as a light brown solid (50 mg), m.p. 190° C. (with decomposition). MS: MH+ 598.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[CH3:17]
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: CCOC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure AA above and using 3,5-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared.
Reaction SMILES: [O:1]1[CH:8]2[CH:2]1[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12.C[Si](C)(C)[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:20]=[C:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C@@H:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH2:3][C@H:2]1[OH:1]
Reactant: c1ccc2c(c1)OCCC1OC21
Reactant: C[Si](C)(C)N1CCCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCN1[C@@H]1c2ccccc2OCC[C@H]1O
Temperature: 100 °C

Procedure:
3.24 g (20 mmol) of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepin and 9.60 g (61 mmol) of N-trimethylsilyl-2-oxo-pyrrolidine are dissolved in 8 ml of dry THF and, while cooling, 6.31 g (20 mmol) of tetrabutylammonium fluoride trihydrate are added in one portion, and the mixture is heated at 100° C. for several hours (TLC check). The mixture is hydrolyzed with ice-water and extracted several times with diethyl ether. The combined diethyl ether extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation of the solvent in vacuo, the residue is crystallized in diisopropyl ether/ethyl acetate. Crystals of melting point 151°-153° C. are obtained.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].N1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19]>ClCCl>[CH:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][C:18](=[O:19])[CH2:17][Br:16])=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1ccccc1OC(=O)CBr
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of Salicylaldehyde (50 grams) and pyridine (48.5 grams) in dichloromethane (500 ml) maintained at 0-5° C. under nitrogen atmosphere was added dropwise bromoacetyl bromide (210.6 grams). The reaction mixture was stirred for one hour at the same temperature. The reaction mixture was washed with 1000 ml of water and 1500 ml of 5% sodium bicarbonate solution, dried over sodium sulphate followed by distillation of solvent under reduced pressure to get 60.0 grams of bromo-acetic acid 2-formyl-phenyl ester.