Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[C:12]1(=[O:26])[N:16]([CH2:17][C:18](Cl)=[O:19])[C:15](=[O:21])[C:14]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:13]12>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:18](=[O:19])[CH2:17][N:16]3[C:15](=[O:21])[C:14]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:13]4[C:12]3=[O:26])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11]
Reactant: CN1C(=O)Cc2ccccc21
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Product: CN1C(=O)Cc2cc(C(=O)CN3C(=O)c4ccccc4C3=O)ccc21
Yield: 65.3 %

Procedure:
1-Methyl-2-indolinone (34.0 g) and 2-phthalimidoacetyl chloride (37.3 g) was reacted according to a similar manner to that of Example 8-(1). The object compound was purified by column chromatography on silica gel (300 g) using chloroform as an eluent to give 36.41 g of 1-methyl-5-phthalimidoacetyl-2-indolinone.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1.C(N(CC)C(C)C)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[C:20]3[CH:21]=[N:22][CH:23]=[C:18]([C:16]([NH:15][C@H:4]([C:5]4[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:12])=[O:13])[CH:6]=4)[CH2:3][CH2:2][O:1][S:44]([CH3:43])(=[O:46])=[O:45])=[O:17])[C:19]=3[CH:26]=[N:25]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1cc([C@H](CCO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Reaction time: 0.08 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-3-hydroxy-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide (0.10 g, 0.21 mmol) and N,N-diisopropylethylamine (167 μL, 0.957 mmol) in dichloromethane (20 mL) was cooled in an ice water-brine bath. After 5 minutes, methanesulfonyl chloride (25 μL, 0.32 mmol) was added and the cold bath was removed until the mixture became homogeneous. The mixture was again cooled in an ice bath. After 30 minutes, the mixture was quenched with saturated aqueous ammonium chloride (10 mL), washed with brine (10 mL), dried over magnesium sulfate and concentrated to afford methanesulfonic acid(S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propyl ester which was used without further purification.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:31]1([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2.[N:31]1([CH2:37][CH2:38][CH2:39][NH-:40])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: NCCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [NH-]CCCN1CCOCC1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (73.9 mg, 0.18 mmol) and 3-morpholine-4-yl-propylamine (0.053 ml, 0.37 mmol) in DMF 4.0 mL was added HATU (54.8 mg, 0.37 mmol) and DIPEA (0.064 ml, 0.37 mmol). After stirring at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=10:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (3-morpholine-4-yl-propylamide as a white foam (11.9 mg, 13% yield).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Cl:25][C:26]1[CH:27]=[C:28]([C@@H:36]([CH2:40][C@H:41]2[CH2:45][CH2:44][C:43](=[O:46])[CH2:42]2)[C:37](Cl)=[O:38])[CH:29]=[CH:30][C:31]=1[S:32]([CH3:35])(=[O:34])=[O:33]>C(Cl)Cl>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:37](=[O:38])[C@@H:36]([C:28]2[CH:29]=[CH:30][C:31]([S:32]([CH3:35])(=[O:33])=[O:34])=[C:26]([Cl:25])[CH:27]=2)[CH2:40][C@H:41]2[CH2:45][CH2:44][C:43](=[O:46])[CH2:42]2)=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
In a round bottom flask was placed 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 54 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (88 mg, 77%) as a yellow foam: [α]30589=−74.3° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C26H38N3O5SSiCl (M+H)+ 568.2063, observed 568.2063; 1H NMR (300 MHz, DMSO-d6) δ −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.51 (m, 1H, CH), 1.79-2.29 (m, 8 H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.84 (m, 2H, OCH2), 3.96 (m, 1H, ArCHCO), 3.96 (m, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.61 (dd, Jo=8.2 Hz, Jm=1.4 Hz, 1H, Ar), 7.73 (d, Jm=1.4 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (s, 1H, NH).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][NH2:28])[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[CH3:29][C:30](OC(C)=O)=[O:31]>N1C=CC=CC=1>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][NH:28][C:30](=[O:31])[CH3:29])[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To the solution of 2-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)ethanamine hydrochloride (Intermediate 19; 260 mg; 0.62 mmol) in pyridine (3 mL), was added Ac2O (2.00 mL; 2.13 mmol) under nitrogen. The reaction mixture was stirred overnight. The reaction mixture was concentrated and the residue was trituated with a small amount of EtOAc to afford 150 mg (52%) of the title compound as a red solid, which was used directly without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH:19][C:20]([NH2:22])=[S:21].CC1N=C(NC2C=NC=CN=2)SC=1C1C=CC(S(N)(=O)=O)=CC=1>>[CH3:11][C:10]1[N:22]=[C:20]([NH:19][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][N:13]=2)[S:21][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CC(C)=O)cc1
Reactant: NC(=S)Nc1cnccn1
Agent: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(N)(=O)=O)cc1
Product: CSc1ccc(-c2sc(Nc3cnccn3)nc2C)cc1

Procedure:
Using 1-(4-methylsulfanyl-phenyl)-propan-2-one (27b) and pyrazin-2-yl-thiourea (1a) in an analogous procedure described for the preparation of 4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide (Example 1b) affords the title compound.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:59])[N:46]([C:52]1C=CC=[C:54](N)[CH:53]=1)CCOCC)([CH3:43])([CH3:42])[CH3:41].C(OC(=O)N(C1C=CC=C(N)C=1)C)(C)(C)C.BrCCOCC.IC.COC(=O)C1C=CC=C(N)C=1>>[C:40]([O:44][C:45](=[O:59])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:33])[CH3:34])[C:14]2=[O:37])[CH:5]=1)[CH2:52][CH2:53][CH3:54])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOCCN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CCOCCBr
Agent: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Solvent: CI
Product: CCCN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained as the hydrochloride salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that (3-amino-phenyl)-2-ethoxyethyl-carbamic acid tert-butyl ester (obtained using the method employed in the preparation of (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) except that 2-bromoethyl-ethyl ether was used in step b instead of iodomethane) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-propyl-carbamic acid tert-butyl ester (Example 41, step a) according to the method of Example 41 step b. 1H NMR (CDCl3) 8.45 (1H, s), 7.61 (1H, s), 7.56-7.47 (2H, m), 7.36 (4H, m), 7.03 (1H, d), 4.70 (2H, dd), 4.26 (2H, dd), 3.73 (2H, br s), 3.51 (4H, m), 2.82 (1H, br s), 2.05-1.65 (6H, m), 1.30-1.17 (16H, m). Found: C, 63.90; H, 7.66; N, 11.58%; C32H43N5O4.HCl.0.25H2O requires: C, 63.77; H, 7.44; N, 11.62%.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:31][C:9]2[C:10]3[S:15][CH:14]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:11]=3[S:12][C:8]=2[C:7]=1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:5])C.[OH-].[Na+].O.Cl>CCO>[CH2:32]([C:7]1[C:8]2[S:12][C:11]3[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][S:15][C:10]=3[C:9]=2[S:31][C:6]=1[C:4]([OH:5])=[O:3])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCc1csc2c1sc1c(CCCCCCCCCCCCCCC)c(C(=O)OCC)sc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCc1csc2c1sc1c(CCCCCCCCCCCCCCC)c(C(=O)O)sc12
Yield: 98 %

Procedure:
A mixture of 5 (4.2 g, 6.1 mmol) and NaOH (0.49 g, 12.2 mmol) in EtOH (80 mL) was refluxed for 6 h. The mixture was poured into water (400 mL). The pH was adjusted to 1 with aqueous 10 M HCl solution. The precipitated solid was collected by filtration and dried under vacuum. The crude product was used for the next step without any purification (3.9 g, 98% yield).
Reaction SMILES: [CH3:1][C:2]([OH:18])([CH3:17])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:16]=[CH:15][NH:14][N:13]=2)[CH2:7][CH2:6]1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([C:40](=O)[CH2:41][CH2:42][CH3:43])[C:35](OCC)=[O:36])=[CH:29][CH:28]=1)#[N:20]>ClC1C=CC(Cl)=CC=1Cl>[OH:18][C:2]([CH3:1])([CH3:17])[CH2:3][O:4][C@@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:35](=[O:36])[C:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([C:22]4[C:21]([C:19]#[N:20])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:28][CH:29]=3)=[C:40]([CH2:41][CH2:42][CH3:43])[N:13]3[N:14]=[CH:15][N:16]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CC(C)(O)COC1CCC(Nc2nc[nH]n2)CC1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 25 °C

Procedure:
A solution of 2-methyl-1-{[4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol (2.80 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (7.69 g) in 1,2,4-trichlorobenzene (15 mL) was stirred at 195° C. for 2 days. The reaction mixture was cooled to room temperature, and purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→50/50 (volume ratio)] to give the title compound as a brown amorphous compound (620 mg, 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][C:29]([CH2:32]O)=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(Cl)([Cl:36])=O.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:36][CH2:32][C:29]1[N:28]=[CH:27][C:26]([S:23]([NH:22][C:13]2[C:12]([NH:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CO)nc2)cc(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CCl)nc2)cc(OC)c1
Yield: 108.3 %

Procedure:
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(hydroxymethyl)pyridine-3-sulfonamide (90 mg; 0.19 mmol; 1 eq.) is dissolved in CHCl3 (10 ml) at rt. Thionyl chloride (0.05 ml; 0.39 mmol; 2 eq.) is added and reaction mixture is stirred for 1 h30. Water and aqueous NaHCO3 are added and the product is extracted with DCM. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to afford 100 mg (108%) of the title compound as a powder. It was used as such in the next step. HPLC (max plot) 35%; Rt 4.78 min, LC/MS: (ES+) 486.22, (ES−) 484.22.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:22][OH:23])[C@@H:15]([C:18]([F:19])([F:20])[F:21])[O:16][CH2:17]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl isothiocyanate (19.0 mL) was added to a solution containing ((2S,3R,4S)-4-amino-4-(2-fluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (28.72 g) in DCM (150 mL), and the mixture was stirred at RT for 18 h. Sodium bicarbonate (sat., aq., 200 mL) was then added, the mixture extracted with EtOAc (3×300 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% to 30% EtOAc in hexanes) to obtain the title compound (37.07 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.22 (dd, J=8.1, 4.5 Hz, 1H), 3.31 (td, J=8.0, 3.0 Hz, 1H), 3.94-4.07 (m, 1H), 4.31-4.46 (m, 1H), 4.53 (d, J=9.9 Hz, 1H), 4.83 (d, J=9.9 Hz, 1H), 6.97-7.14 (m, 1H), 7.22 (td, J=7.7, 1.3 Hz, 1H), 7.31-7.45 (m, 1H), 7.49-7.61 (m, 2H), 7.61-7.70 (m, 1H), 7.75 (td, J=8.1, 1.5 Hz, 1H), 7.79-7.93 (m, 2H), 8.90 (s, 1H), 11.85 (s, 1H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](O)=[O:7])#[N:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)C(C)C)(C)C.CCOC(OC(OCC)=O)=O>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:18]([O:19][CH3:20])[CH3:17])=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNOC
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(C#N)cc(C(F)(F)F)c1
Yield: 81.6 %

Procedure:
A solution of 3-cyano-5-(trifluoromethyl)benzoic acid (200 mg, 0.93 mmol) in tetrahydrofuran (2 mL) was added with N,O-dimethylhydroxyamine hydrochloride (145 mg, 1.49 mmol), N,N-diisopropylethylamine (470 mg, 3.64 mmol) and DEPC (227 mg, 1.39 mmol) with stirring on an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the resulting residue was added with 1 M hydrochloric acid (0.5 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 3-cyano-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (196 mg, 82%) as pale yellow solid.
Reaction SMILES: C(O)=O.[F:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17].Br[CH2:19][C:20](=[O:36])[CH2:21][C@H:22]1[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]1[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31]>>[F:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:19][C:20](=[O:36])[CH2:21][C@H:22]3[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]3[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17]
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: CSc1cc2c(=O)[nH]cnc2cc1F
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(F)c(SC)cc2c1=O

Procedure:
In the manner of Example 4, 0.462 g (0.0018 mol) of 7-fluoro-6-methylthioquinazolin-4(3H)-one formic acid salt and 0.750 g (0.00224 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.50 g (60%). 1H--NMR(CDCl3) 1.4-2.1 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.6 (singlet, 3H, SCH3), 2.8-3.4 (multiplet, 4H, NCH2, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.3 (doublet, 1H, aromatic H), 7.9 (singlet, 1H, N=CH--N), 8.0 (doublet, 1H, aromatic H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][NH:7][C:6]1=[S:13].[CH3:19]I.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[S:13][CH3:19]
Reactant: CI
Reactant: Cc1n[nH]c(=S)n(Cc2cc(F)ccc2Cl)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 4-(2-chloro-5-fluorobenzyl)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (29, 3.06 g, 10.72 mmol) in ethanol (50 mL) was added MeI (2.44 g, 17.1 mmol) followed by NaOH (429 mg, 10.72 mmol). The mixture was stirred at RT for 40 min to produce a clear yellow solution. The reaction was diluted with water (200 mL), and extracted with EtOAc (100 mL×3). The extracts were washed with brine, dried over MgSO4, and concentrated to give the crude product (3.195 g). This was crystallized from ethyl acetate-petroleum ether to give 4-(2-chloro-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (30). MS: m/z, 300 (100%, M+1), 302 (35%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[C:12](/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[CH:2]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[C:12](/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:1]
Reactant: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(CO)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(C=O)c1
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a stirred solution of (E)-methyl 2-[2-(3-hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.250 g) in dichloromethane (5 ml) at room temperature was added pyridinium dichromate (0.414 g). After stirring for 3 hours, GC analysis of an aliquot indicated the absence of starting material. Water was added and stirring continued for 10 minutes. The reaction mixture was filtered (filter washed through with water (5 ml) and dichloromethane (5 ml)) and then further diluted with dichloromethane (5 ml). The organic layer was separated and the aqueous phase further extracted with dichloromethane (×3). The combined organic layers were dried, filtered and evaporated to give a dark yellow oil. Chromatography on silica gel (eluent ether-petroleum ether, 7:3) afforded (E)-methyl 2-[2-(3-formylphenoxy)pyridin-3yl]-3-methoxypropenoate (0.136 g, 55%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[NH:3]1.[NH:17]1[CH:21]=[N:20][C:19]([S:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH2:32][NH2:33])[CH:29]=[CH:30][CH:31]=2)=[N:18]1.C(N(C(C)C)CC)(C)C>C(O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:33][CH2:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH2:24][CH2:23][S:22][C:19]3[N:20]=[CH:21][NH:17][N:18]=3)[CH:27]=2)=[O:14])[NH:3]1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Reactant: NCc1cccc(OCCSc2nc[nH]n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(NCc1cccc(OCCSc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 15 h
Yield: 8 %

Procedure:
A suspension of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (200 mg, 0.917 mmol), 1-(3-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}phenyl)methanamine obtained in Reference Example 3 (298 mg, 1.19 mmol) and diisopropylethylamine (237 mg, 1.83 mmol) in ethanol (10 mL) was stirred at 90° C. for 15 hr. The reaction solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile-90/10→0/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and the obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (29.2 mg, 8%).