Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].CS(C)=[O:17].Cl>O.C(OCC)(=O)C>[F:11][C:10]1[C:2]([OH:17])=[C:3]([CH:7]=[CH:8][C:9]=1[CH3:12])[C:4]([OH:6])=[O:5]
Reactant: CS(C)=O
Reactant: Cc1ccc(C(=O)O)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)O)c(O)c1F
Temperature: 140 °C
Reaction time: 12 h

Procedure:
A mixture of 2,3-difluoro-4-methylbenzoic acid (25.0 g), sodium hydroxide (23.2 g) and DMSO (250 mL) was stirred at 140° C. for 12 hr, and then overnight at room temperature, under argon atmosphere. To the reaction mixture was added 6M hydrochloric acid (100 mL) under ice-cooling. Ethyl acetate and water were added thereto at room temperature, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (24.3 g). This compound was used in the next step without an additional purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:22](=O)[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=1.[OH:26][NH:27]Cl.C([O-])(=O)C.[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:22](=[N:27][OH:26])[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=1
Reactant: CCC(=O)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Reactant: ONCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=NO)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.1 %

Procedure:
A mixture of 1-[-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-propan-1-one (0.598 g, 1.783 mmol), hydroxylamino hydrochloride (0.370 g, 5.35 mmol), sodium acetate (0.439 g, 5.35 mmol) in MeOH (30 ml) was stirred at room temperature for 24 hours. The mixture was concentrated to dryness. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 0.657 g of a white glassy foam. The glassy foam was purified through silica gel column chromatography to separated both E (white crystals, mp 162-164° C., confirmed by X-ray structural analysis) and Z (white crystals, mp 84-87° C.) isomers and a mixture of E and Z isomers (mp −150-190° C.).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[CH:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:22][CH:21]=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([NH:26][C:23]3[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=3)[CH:28]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: Oc1cccc(Nc2ccccc2)c1
Product: CO[C@@H](Cc1ccc(C#CCOc2cccc(Nc3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepare from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 3-hydroxydiphenylamine in a manner analogous to that described for Example 5, Step B. MS(ES) for CH23H23NO [M+H]+: 402.2.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18]C(=O)C)[CH:13]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C(O)C>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1cc(C(=O)Nc2nc(C(C)(C)C)cs2)ccn1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1csc(NC(=O)c2ccnc(N)c2)n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
N4-[4-(tert-Butyl)-1,3-thiazol-2-yl]-2-(acetylamino)isonicotinamide (546 mg) dissolved in ethanol (12 ml) was added dropwise with concentrated hydrochloric acid (1.2 ml) at room temperature and stirred at 80-90° C. for 1 hour. The reaction solution was returned to room temperature, concentrated under reduced pressure, neutralized with 1 N sodium hydroxide and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=60:1→20:1) to obtain 247.2 mg (52%) of the title compound as white crystals.
Reaction SMILES: O.[CH2:2]([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][S:8]([N:11]=C=O)(=[O:10])=[O:9])[CH3:3].C(=O)=O>ClC(Cl)(Cl)Cl>[S:8](=[O:9])(=[O:10])([O:7][C:6]1[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=1[O:4][CH2:2][CH3:3])[NH2:11]
Reactant: CCOc1ccccc1OS(=O)(=O)N=C=O
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOc1ccccc1OS(N)(=O)=O
Temperature: 0 °C
Yield: 93.3 %

Procedure:
2.2 g of water are added dropwise at 30° C. to 40° C. to a solution of 19.2 g of 2-ethoxyphenoxysulfonyl isocyanate in 150 ml of tetrachloromethane. The mixture is stirred at room temperature until the evolution of carbon dioxide has ceased and cooled to 0° C., the product is filtered off with suction, and the filter residue is washed with ice-cold tetrachloromethane. Drying in vacuo gives 16 g of 2-ethoxyphenyl sulfamate of melting point 62°-65° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[N:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]5[CH:35]=[CH:34][C:33]([C:30]6[N:29]=[C:28]([CH3:27])[O:32][N:31]=6)=[CH:41][CH:40]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)no1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: Cc1nc(-c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCC(c5cccc6c5CCO6)CC4)CC3)cc2)no1

Procedure:
The title compound, white solid (98 mg, 77%), MS (ISP) m/z=515.4 [(M+H)+], mp 256.5° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid.
Reaction SMILES: [N:1]([C@H:4]1[C:9]([F:11])([F:10])[CH2:8][CH2:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N+]=[N-].[H][H]>CO>[NH2:1][C@H:4]1[C:9]([F:11])([F:10])[CH2:8][CH2:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N=[N+]=[N-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Reaction time: 16 h
Yield: 91.7 %

Procedure:
A solution of tert-butyl [(1R,6R)-2-azido-3,3-difluorocyclohexyl]carbamate 36 (0.94 g, 3.40 mmol) in methanol (20 mL) was degassed with nitrogen and treated with 10% PdJC (72 mg). The resulting heterogenous solution was exposed to a hydrogen atmosphere and stirred vigorously for 16 hours. The reaction was filtered, washing with methanol, and evaporated in vacuo to give 0.78 g (91%) of tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate 37 as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 6.67 (1H, d, J=8.3 Hz), 3.55 (1H, bs), 3.07 (1H, bs), 2.03 (1H, m), 1.62 (3H, m), 1.45 (1H, m), 1.36 (12H, m).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)(=O)=O.[H-].[Na+].[F:19][C:20]([F:29])([F:28])[CH2:21][CH2:22][CH:23]([C:26]#[N:27])[C:24]#[N:25]>CN(C)C=O>[CH3:16][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14])[CH2:6][C:23]([CH2:22][CH2:21][C:20]([F:19])([F:28])[F:29])([C:24]#[N:25])[C:26]#[N:27]
Reactant: Cc1cc(COS(C)(=O)=O)ccc1[N+](=O)[O-]
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(C#N)(C#N)CCC(F)(F)F)ccc1[N+](=O)[O-]
Yield: 88.5 %

Procedure:
Using 0.49 g of 3-metyl-4-nitrobenzyl methanesulfonate, 5 ml of N,N-dimethylformamide, 0.10 g of sodium hydride (60% in oil), and 0.3 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.51 g of 2-(3-methyl-4-nitrobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (45)).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([CH:8]([CH2:37][CH2:38][C:39]([OH:42])([CH3:41])[CH3:40])[CH2:9][CH:10]([O:33][C:34](=[O:36])[CH3:35])[CH:11]([NH:20][C:21]([C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=O.C([O-])(=O)C.[NH4+:49].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:19][C:15]1[CH:14]=[C:13]([CH2:12][CH:11]([CH:10]([O:33][C:34](=[O:36])[CH3:35])[CH2:9][CH:8]([C:6]2[NH:5][CH:4]=[CH:3][N:49]=2)[CH2:37][CH2:38][C:39]([OH:42])([CH3:40])[CH3:41])[NH:20][C:21]([C:23]2[CH:32]=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(CNC(=O)C(CCC(C)(C)O)CC(OC(C)=O)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC(CC(CCC(C)(C)O)c1ncc[nH]1)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1
Temperature: 115 °C
Yield: 16.8 %

Procedure:
To a solution of acetic acid 3-(2,2-dimethoxy-ethylcarbamoyl)-1-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-6-hydroxy-6-methyl-heptyl ester (150 mg, 0.245 mmol) in acetic acid (2 mL) was added ammonium acetate (1.5 g 19.5 mmol). The resulting mixture was heated to 115° C. for 3 hours, cooled to ambient temperature and diluted with ethyl acetate. The solution was then neutralized with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel gave the title compound (22.5 mg, 17%).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:16]([C:18]1[S:19][C:20](=[NH:35])[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[C:22]=12)#[N:17]>O>[C:16]([C:18]1[S:19][C:20](=[N:35][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[C:22]=12)#[N:17]
Reactant: COc1cc2c(cc1OC)-c1c(C#N)sc(=N)n1CC2
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)-c1c(C#N)sc(=NC(=O)c3ccccc3)n1CC2

Procedure:
5 ml. of pyridine and 0.3 ml. of benzoyl chloride are added to 0.5 g. of 1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline, and the mixture is refluxed for 0.5 hours. After cooling, the mixture is diluted with water. 0.6 g. of 1-cyano-3-benzoylimino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a] isoquinoline is obtained in crystalline state; m.p.: 274°-276°C (after recrystallization from a mixture of dimethylformamide and butanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[C:13]2=[O:18])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11].[CH:19]1([O:22][C:23]2[N:28]=[CH:27][C:26](O)=[CH:25][CH:24]=2)[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:19]1([O:22][C:23]2[N:28]=[CH:27][C:26]([O:17][C@@H:14]3[CH2:15][CH2:16][N:12]([C:4]4[CH:5]=[C:6]5[C:10](=[C:2]([F:1])[CH:3]=4)[CH2:9][CH2:8][C:7]5=[O:11])[C:13]3=[O:18])=[CH:25][CH:24]=2)[CH2:21][CH2:20]1
Reactant: O=C1CCc2c(F)cc(N3CC[C@H](O)C3=O)cc21
Reactant: Oc1ccc(OC2CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(OC5CC5)nc4)C3=O)cc21
Reaction time: 2 h

Procedure:
To a mixture of (S)-1-(7-fluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)-3-hydroxy-pyrrolidin-2-one (80 mg), 6-cyclopropoxy-pyridine-3-ol (53.4 mg), triphenylphosphine (polymer, 126 mg) and THF (1.5 mL) was added DIAD (97 mg). The mixture was shaken for 2 hours and filtered. The filtrate was concentrated and the residue purified by preparative HPLC to provide Example 3-13. 1H-NMR (400 MHz, DMSO) δ 8.02 (1H, d, J=3.1 Hz), 7.99 (1H, d, J=11.1 Hz), 7.78 (1H, s), 7.55 (1H, dd, J=9.0, 3.1 Hz), 6.83 (1H, d, J=9.0 Hz), 5.25 (1H, dd, J=8.3, 8.3 Hz), 4.13 (1H, m), 3.97 (1H, m), 3.86 (1H, m), 3.10 (2H, m), 2.72 (2H, m), 2.70 (1H, m), 2.14 (1H, m), 0.74 (2H, m), 0.64 (2H, m).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:32][C:33](=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)[CH2:30]C>>[CH2:29]([O:32][C:33](=[O:43])[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:39][CH:40]=1)[CH3:30]
Reactant: CCCOC(=O)Cc1ccc(CBr)cc1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOC(=O)Cc1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and (4-Bromomethyl-phenyl)-acetic acid propyl ester as in the procedure of Example 43. MS (ESI) m/z 556;
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[I:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[I:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1ccccc1I
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1I

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-iodobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29](C(OC(C)(C)C)=O)[N:28]=[CH:27]4)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]([O:2][CH3:1])=[O:40])[CH:12]=[CH:11][CH:10]=4)[N:22]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: COC(=O)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (18 mg, 0.033 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ethyl ether to get a yellow solid to afford methyl 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenylamino)-2-oxoacetate. (15 mg, 100%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[C:13]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])([F:15])[F:14]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]([P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])([F:15])[F:14])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(I)c([N+](=O)[O-])c1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1[N+](=O)[O-]

Procedure:
Commercially available 4-iodo-3-nitrotoluene was reacted with diethyl bromodifluoromethylphosphonate under Cd coupling conditions using Example 25 to yield diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate (500 mg, 1.55 mmol) was dissolved in EtOAc (10 mL) and EtOH (10 mL). Five percent Pd-C (approximately 20 mg) was added and the mixture placed under H2 (1 atm.) and stirred at room temperature overnight. The mixture was then filtered and concentrated in vacuo to give diethyl(4-methyl-2-aminophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-amino-phenyl)difluoromethylphosphonate was converted to diethyl (2-iodo-4-methylphenyl)-difluoromethylphosphonate using Example 86. Compound 95 was synthesized from this corresponding diethyl phosphonate using procedures similar to those of Example 40. MS (ES-): m/z 347.1 (M−H). 1H NMR: (CD3OD, 400 MHz) δ 7.90 (s, 1H), 7.49 (dd, J=0.8, 8.2, 1H), 7.27 (d, J=8.2, 1H), 2.31 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:10]=[CH:11][C:12]=1[F:13].N1C=CC=CC=1>ClCCl>[CH2:18]([S:15]([NH:14][C:9]1[CH:10]=[CH:11][C:12]([F:13])=[C:7]([CH:8]=1)[NH:6][C:2](=[O:3])[O:4][CH3:5])(=[O:17])=[O:16])[CH3:19]
Reactant: CCS(=O)(=O)Nc1ccc(F)c(N)c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(F)c(NC(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
22.1 g (229 mmol) of methyl chloroformate was added dropwise to a mixture of 50.0 g (229 mmol) of N-(3-amino-4-fluorophenyl)ethanesulfonamide, 18.1 g (229 mmol) of pyridine and 500 ml of dichloromethane at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for 5 hours. After the dichloromethane layer was separated out by adding water to the resultant mixture, the dichloromethane layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. Thereafter the dichloromethane was distilled off to obtain the crude product (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 61.0 g of the objective product (yield: 96%) in the form of light brown crystals.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]2[CH:16]=[CH:17][NH:18][C:14]=2[CH:13]=[CH:12][N:11]=1>CN(C)C=O>[Cl:9][C:10]1[C:15]2[C:16]([I:1])=[CH:17][NH:18][C:14]=2[CH:13]=[CH:12][N:11]=1
Reactant: Clc1nccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Clc1nccc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Iodosuccinimide (1.3 g, 5.8 mmol) was added to a 0° C. solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (0.60 g, 3.9 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 18 hours, whereupon it was concentrated in vacuo. Purification via silica gel chromatography (0% to 50% ethyl acetate in petroleum ether) afforded the product as a yellow solid. Yield: 900 mg, 3.2 mmol, 82%. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=5.5 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.34 (d, J=5.8 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:24]1)(=O)=O>CCCCCC.CS(C)=O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][C@@H:23]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:24]2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc(CCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
60% sodium hydride (240 mg, 6.0 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (20 ml). After stirring at room temperature for 50 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (1.20 g, 6.0 mmol) was added to the obtained suspension. They were stirred at room temperature for 60 minutes and then at 50° C. for 60 minutes. A solution of (S)-3-methanesulfonyloxy-1-(4-methoxyphenethyl)pyrrolidine (734 mg, 2.45 mmol) in dimethyl sulfoxide (10 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction liquid was poured into ice/water. After the extraction with a solvent mixture of hexane and ethyl acetate (1:1), the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1), then with a mixture of the same solvents (3:1) and finally with a mixture of them (2:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-methoxyphenethyl) pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (0.36 g, 36%).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4](OCC)=[O:5].O.[NH2:22][NH2:23]>C(O)(C)C>[NH2:1][C:2]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4]([NH:22][NH2:23])=[O:5]
Reactant: NN
Reactant: CCOC(=O)c1c(C(F)(F)F)cc(C(F)(F)F)nc1N
Solvent: O
Solvent: CC(C)O
Product: NNC(=O)c1c(C(F)(F)F)cc(C(F)(F)F)nc1N
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-amino-4,6-di(trifluoromethyl)-nicotinate (2.55 g., 8.45 mmole), 85% hydrazine hydrate (5 ml.) and isopropanol (5 ml.) is stirred in an oil-bath at 110° C. for 3 hours. On cooling, the dark red solution deposits colorless crystals which are filtered off and washed with a little isopropanol. A second crop of solid is obtained by evaporation of the mother liquors giving a total yield of 1.45 g. (59.6%) of product, m.p. 240°- 243° C. (dec.). Upon recrystallization from isopropanol (25 ml.) there is obtained 1.05 g. (42.8%) of product, m.p. 244°-245° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2cc3ccccc3o2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2cc3ccccc3o2)S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-(3-{[(benzofuran-2-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12u, and 4-fluorobenzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.46 (m, 1H), 7.28-7.03 (m, 9H), 6.42 (s, 1H), 4.45 (s, 2H), 4.38 (s, 2H), 3.67 (s, 3H), 2.90 (t, 2H), 2.58 (t, 2H).
Reaction SMILES: [C:1]1([C:7](=[O:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC(Cl)[Cl:15]>>[C:1]1([C:7](=[O:11])[C:8]([Cl:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(Cl)Cl
Reactant: O=C(O)C(=O)c1ccccc1
Product: O=C(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
In a 50 mL-volume flask, 12.2 g of phenyl glyoxylic acid was placed, and then 9.26 g of dichloromethyl methyl ether was dropwise added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was placed under reduced pressure (62° C./2 torr) to give 13.4 g of phenylglyoxylic acid chloride. The obtained phenylglyoxylic acid chloride was dropwise added to a mixture of 7.86 g of phenol, 7.26 g of pyridine and 10 mL of toluene. The resulting mixture was stirred at 50° C. for 2 hours.