Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:37])([Cl:36])[CH2:3][O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23]CC2C=CC(C(F)(F)F)=CC=2)=[O:22])[CH:15]=1.ClC(Cl)(Cl)COC(=O)C1C=CC=CC=1CSC1C=CC=C(CC(O)=O)C=1.[F:64][C:65]([F:76])([F:75])[C:66]1[CH:71]=[CH:70][C:69]([CH:72](O)[CH3:73])=[CH:68][CH:67]=1.Cl>CN(C1C=CN=CC=1)C.CCCCCCC.CCOC(C)=O.C(Cl)Cl.C(Cl)CCl>[Cl:1][C:2]([Cl:36])([Cl:37])[CH2:3][O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH2:73][CH2:72][C:69]2[CH:68]=[CH:67][C:66]([C:65]([F:64])([F:75])[F:76])=[CH:71][CH:70]=2)=[O:22])[CH:15]=1
Reactant: CC(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCCc1ccc(C(F)(F)F)cc1
Yield: 68 %

Procedure:
The titled compound was prepared according to the method described for 2-[3-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester above from 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (168 mg, 0.387 mmol), 1-(4-trifluoromethyl-phenyl)-ethanol (88 mg, 0.465 mmol), EDC×HCl (111 mg, 0.581 mmol), DMAP (4.7 mg, 0.039 mmol) and DCM (4 mL). The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (160 mg, 68%) as an oil; 1H NMR (400 MHz, CDCl3): δ 2.67 (dd, 2H), 3.23 (s, 2H), 4.03 (dd, 2H), 4.27 (s, 2H), 4.67 (s, 2H), 6.74 (br d, 1H), 6.85-6.99 (m, 6H), 7.06 (dd, 1H), 7.13 (dd, 1H), 7.22 (d, 2H), 7.79 (d, 1H); Mass spectrum: M−H+ 604.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1.[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](O)=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)Cl.CN1C(=O)CCC1.O>[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:5][CH2:6][CH2:7][CH2:8][S:9][C:10]4[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=4)=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1
Reactant: Cn1ccnc1SCCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCSc1nccn1C
Temperature: 5 °C
Reaction time: 1 h
Yield: 6.1 %

Procedure:
Thionyl chloride (0.80 ml, 11 mmol) was added to a solution of 2-(3-hydroxypropylthio)-1-methylimidazole (1.25 g, 7.3 mmol) in trichloromethane (25 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then at ambient temperature for 2 hours. The volatiles were removed by evaporation, the residue azeotroped with toluene and dried under vacuum to give crude 2-(3-chloropropylthio)-1-methylimidazole hydrochloride (1.0 g) which was used directly. Part of this product (226 mg, 1.0 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate.(303 mg 2.2 mmol) in NMP (20 ml) and the mixture was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1-methylimidazol-2-ylthio)propoxy)quinazoline (29 mg, 6%). m.p. 199-201° C. 1H NMR Spectrum: (DMSOd6) 2.22(m, 2H); 3.44(s, 3H); 3.94(s, 3H); 4.10(m, 4H); 7.10(d, 2H); 7.30(dd, 1H); 7.50-7.60(m, 2H); 7.79(s, 1H); 8.34(s, 1H); 9.50(s, 1H) MS-ESI: 474 [MH]+
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH3:21])[N:11]=2)[CH:5]=1)[CH3:2].[CH2:29](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([N:9]2[C:10]3=[N:11][C:12]([NH:19][C@H:20]([C:22]4[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])=[CH:13][CH:14]=[C:15]3[N:16]=[CH:29]2)[CH:5]=1)[CH3:2]
Reactant: CCO
Reactant: CCOc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(-n2cnc3ccc(N[C@@H](C)c4ncc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
N2-(5-Ethoxy-1H-pyrazol-3-yl)-N6-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 28, 0.3 g) was dissolved into ethanol (20 mL) with Pd—C (90 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.034 g of the title compound. MS (electrospray): 369 (M+1) for C17H17FN8O. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.30 (s, 1H) 7.80 (d, 1H) 6.80 (d, 1H) 6.30 (s, 1H) 5.40 (m, 1H) 4.30 (q, 2H) 1.70 (d, 3H) 1.55 (t, 3H).
Reaction SMILES: N[C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[ClH:18].O1CCOCC1.N([O-])=O.[Na+]>C(OCC)(=O)C.[Cu]Cl.ClCCl>[Cl:18][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)c(Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine methyl 2-amino-3,4,5-trimethoxybenzoate (4.8 g, 20 mmol) and dichloromethane (20 mL). Cool in an ice bath. Add a solution of hydrochloric acid in dioxane (10 mL, 4 M, 40 mmol). Add polyethylene glycol 200 (20 mL) followed by sodium nitrite (2.76 g, 40 mmol). After 10 minutes add copper(I) chloride (3.96 g, 40 mmol). Warm to ambient temperature. After 18 hours, dilute the reaction mixture with ethyl acetate and extract with a 1 M aqueous solution of sodium hydroxide an then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. the title compound. Chromatograph the residue on silica gel eluting sequentially with hexane and then 5% ethyl acetate/hexane to give methyl 2-chloro-3,4,5-trimethoxybenzoate: Rf=0.7 (silica gel, 20% ethyl acetate/toluene).
Reaction SMILES: [Na].CS(C)=O.[OH:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[CH2:27]([O:26][C:24]([CH:23]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[N:8]=1)[CH3:29])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 0.54 g portion of sodium was dissolved in 15 ml of absolute ethanol, and was added to 50 ml of dimethylsulfoxide containing 5.4 g of 3-hydroxy-1-(4-trifluoromethylphenyl)-1,2,4-1H-triazole. An additional 25 ml of dimethylsulfoxide was added, and the mixture was heated on the steam bath for 15 minutes. Then 4.3 g of ethyl 2-bromopropionate was added and heating was continued for 1 hour. The mixture was then cooled and poured over ice-water, and the product was collected, dried, and purified by high-performance liquid chromatography, eluting with 1:1 hexane:ethyl acetate. The product-containing fractions were combined and evaporated under vacuum to obtain 3.5 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:37])([CH2:35][OH:36])[CH2:33][OH:34]>C1COCC1>[OH:34][CH2:33][C:32]([NH:31][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1)([CH3:37])[CH2:35][OH:36]
Reactant: CC(N)(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(CO)CO)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 72 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and 2-amino-2-methyl-1,3-propanediol (105 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 0-25% EtOAc/CH2Cl2 Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 160-162°, LC MS m/z=453 (MH+) Retention time=1.75 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]1)=[O:19])=[N:5]2
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 80 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 80%). 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 2.95-3.02 (m, 4H), 3.74-3.77 (m, 3H), 4.08-4.14 (m, 4H), 7.01-7.57 (m, 7H), 7.64-7.85 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:34]=2[N:35]=1>>[Cl:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH:16]([CH2:21][CH2:22][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:32][C:33]=2[CH:39]=1
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Product: O=C(CC(CCc1ccccc1)C(=O)O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Yield: 24.7 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (78 mg, 0.20 mmol), 2,6-dichloro-1,3-benzothiazole (61.6 mg, 0.30 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenylyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 26.7 mg (25%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (br s, 1H), 7.75-8.05 (m, 9H), 7.60 (d, 1H), 7.10-7.40 (m, 6H), 3.50 (q, 1H), 3.10 (m, 1H), 2.85 (m, 1H), 2.65 (m, 2H), 1.80 (m, 2H). LC-MS m/z 541.3 (MH+), ret. time 4.07 min.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[O-].[Na+].CO.C(O[CH:22]=[C:23]([C:26]#[N:27])[C:24]#[N:25])C>CCOC(C)=O.O>[NH2:27][C:26]1[N:12]([C:9]2[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=2)[N:13]=[CH:22][C:23]=1[C:24]#[N:25]
Reactant: CCOC=C(C#N)C#N
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2N)cc1
Reaction time: 0.29 h
Yield: 26.5 %

Procedure:
A round-bottomed flask (100 mL), equipped with a reflux condenser and N2 inlet septum, was charged with 4-(methylsulfonyl)phenylhydrazine hydrochloride (2 g, 9 mmol), and sodium methoxide (0.49 g, 9 mmol). Methanol (20 mL) was added under a stream of nitrogen at room temperature. The reaction mixture was stirred for 15-20 minutes until the purple color disappeared and a white precipitate was formed. This was followed by the addition of ethoxymethylenemalononitrile (1.1 g, 9 mmol) and stirring at room temperature for an additional 10 mins, subsequently the reaction mixture was brought to reflux for 150 mins. The cooled reaction mixture was filtered and concentrated under reduced pressure to afford the crude product. The solid residue was dissolved in EtOAc/H2O. The EtOAc layer was collected, washed with saturated aqueous NaCl, dried over NaSO4 and concentrated to give second portion of the crude product. The crude product was purified by flash chromatography (10% CH3OH/CH2Cl2) and recrystallized from methanol to give a yellow crystalline product (625 mg, 26%). 1H NMR (DMSO-d6, 400 MHz) δ 3.27 (s, 3H), 6.98 (s, 2H), 7.81 (d, 2H), 7.88 (s, 1H), 8.06 (s, 2H). LCMS: calculated for C11H10N4O2S 262.05, observed 262.9 (MH+)
Reaction SMILES: [N:1]1([C@H:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:16][CH2:15][C:14]4[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=4[CH2:8]3)[CH2:6][CH2:5]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: N#Cc1ccc2c(c1)CC[C@H](N1CCNCC1)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CC[C@H](N1CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)C2

Procedure:
A mixture (6S)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.31 mg, 0.13 mmol), 1-(2-bromoethyl)-4-nitrobenzene (80 mg, 0.35 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DMF was heated to 60° C. for 30 hours. LC showed formation of the desired product. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, and purified by MPLC to deliver 13 mg of (65)-6-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 391 [M+1]+. (0.083 μM)
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:34]=[C:35]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: CC(=O)c1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)c1
Yield: 79 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-acetylphenyl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 79%. Melting point: 209-210° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[C:13]([OH:15])=O.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[C:13]([NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(O)nc2ccc(Br)cc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(O)nc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-bromo-2-hydroxyquinoline-4-carboxylic acid (9.0 g) was dissolved in dichloromethane and cooled to 0° C. 3-aminopyridine (1 eq), T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide, 50% solution in ethyl acetate, 1.2 eq.), and DIPEA (diisopropylethylamine, 2.0 eq) were added. The solution was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature overnight. The solution was washed with water, sat. sodium chloride, dried, and concentrated. Purification by silica gel column chromatography provided 6-bromo-2-hydroxy-N-(pyridin-3-yl)quinoline-4-carboxamide (9.0 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][C@@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O.Br>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][C@@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1c(F)cccc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3c(F)cccc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
(2S,4R)-Methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (344 mg, 0.98 mmol) (from example 127, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 8 mL, 45.68 mmol) and the mixture stirred at room temperature for 24 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(2,6-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (222 mg, 77%). 1H NMR (600 MHz, cd3od) δ 1.47 (q, 1H), 1.68 (dq, 1H), 1.96-2.07 (m, 2H), 2.79-3.02 (m, 4H), 3.18-3.25 (m, 1H), 3.27-3.34 (m, 1H), 5.49 (s, 1H), 6.95-7.01 (m, 2H), 7.28-7.36 (m, 1H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1240
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.CO[C:24](OC)([CH3:26])[CH3:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C@H:3]2[CH2:2][O:1][C:24]([CH3:26])([CH3:25])[N:14]2[C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc([N+](=O)[O-])cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl N-[(1S)-2-hydroxy-1-(4-nitrobenzyl)ethyl]carbamate (22.3 g), 2,2-dimethoxypropane (46.3 ml), p-toluenesulfonic acid monohydrate (1.43 g) and dichloromethane (200 ml) was stirred at room temperature for 15 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with isopropyl ether to give tert-butyl (S)-4-(4-nitrobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (16.9 g) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([Si](C)(C)C)[N:17]=[N:16]3)[O:11][C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[I:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: C[Si](C)(C)c1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
A solution of the crude (5R)-3-(3-fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one (1024, 14.72 g, 32.0 mmol) in an 1 M solution of tetrabutylammonium fluoride in THF (TBAF, 128 mL, 128 mmol, 4.0 equiv) was treated with acetic acid (HOAc, 5 mL) at room temperature, and the resulting reaction mixture was stirred at room temperature for 24 h. When TLC and HPLC/MS showed that the reaction was complete, the solvents were removed in vacuo. The residue was treated with H2O (300 mL) at room temperature and the resulting mixture was stirred at room temperature for 1 h. The solids were collected by filtration, washed with H2O (2×100 mL) and 20% EtOAc/hexane (2×100 mL), dried in vacuo. The crude, (5R)-3-(3-fluoro-4-iodo-phenyl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one (1025, 11.65 g, 12.416 g theoretical, 93.8%) was obtained as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For 1025: 1H NMR (300 MHz, DMSO-d6) 3.89 (dd, 1H, J=6.4, 9.2 Hz), 4.23 (t, 1H, J=5.4 Hz), 4.84 (d, 211, J=4.9 Hz), 5.12-5.18 (m, 1H), 7.14 (dd, 1H, J=2.4, 8.7 Hz), 7.49 (dd, 1H, J=2.4, 8.7 Hz), 7.76 (d, 1H, J=1.0 Hz, triazole-H), 7.82 (dd, 1H, J=7.5, 8.7 Hz), 8.17 (d, 1H, J=1.0 Hz, triazole-H); C12H10FIN4O2, LCMS (EI) m/e 389 (M++H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:25]=[CH:24][C:11]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.[NH:26]1[C:34]2[C:29](=[CH:30][C:31]([CH2:35]O)=[CH:32][CH:33]=2)[CH:28]=[N:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH:26]1[C:34]2[C:29](=[CH:30][C:31]([CH2:35][N:7]3[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:8]4[CH:25]=[CH:24][C:11]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[O:13])=[CH:10][CH:9]=4)=[N:6]3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1
Reactant: OCc1ccc2[nH]ncc2c1
Reactant: O=C(NCCCN1CCCCC1)c1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCCN1CCCCC1)c1ccc(-c2ccc(=O)n(Cc3ccc4[nH]ncc4c3)n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere, 38 mg (0.11 mmol) of 4-(6-oxo-1,6-dihydropyridazin-3-yl)-N-(3-piperidin-1-ylpropyl)benzamide are suspended in 1 ml of THF, and 27 mg (0.18 mmol) of (1H-indazol-5-yl)methanol and 88 mg (0.34 mmol) of triphenyphosphine are added. 53 μl (0.34 mmol) of diethyl azodicarboxylate was added dropwise to this suspension at 2-10° C. with ice-cooling. The suspension was stirred at room temperature for 15 h. The reaction mixture was evaporated and purified by means of preparative HPLC.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][OH:11])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].S(=O)(=O)(O)O>C(#N)C>[C:12]([O:11][CH2:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC(CO)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CC(=O)OCC(C#N)c1ccccc1
Reaction time: 0.42 h
Yield: 98 %

Procedure:
A sample of this 2-phenyl-3-hydroxypropanenitrile (127 mg, 0.863 mmol) and acetic anhydride (106 μL, 1.1 mmol) in acetonitrile (250 μL) was treated with sulfuric acid (˜0.5 μL). After 25 min at ambient temperature, work-up as described above in Example 5 gave 160 mg (98%) product as a colorless oil.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[N:6]1([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C1CCNCC1
Product: O=S(=O)(Cl)N1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
A solution of sulfuryl chloride (1N in dichloromethane, 75 mL, 75 mmol) at −20° C. was treated dropwise with piperidine (12.6 g, 150 mmol), stirred at 0° C. for 2 hours, and partitioned between dichloromethane and water (50 mL). The organic layer was washed with aqueous 1N HCl, brine and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was distilled under reduced pressure (1 mm Hg) at 105° C. to give the title compound (5 grams).