Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]1([C:10]([C:12]2[CH:22]=[CH:21][C:15]([CH:16]([CH3:20])[C:17](Cl)=[O:18])=[CH:14][CH:13]=2)=[O:11])[S:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[OH:4][CH2:3][CH2:2][NH:1][C:17](=[O:18])[CH:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:5]2[S:9][CH:8]=[CH:7][CH:6]=2)=[CH:22][CH:21]=1)[CH3:20]
Reactant: NCCO
Reactant: CC(C(=O)Cl)c1ccc(C(=O)c2cccs2)cc1
Solvent: ClC(Cl)Cl
Product: CC(C(=O)NCCO)c1ccc(C(=O)c2cccs2)cc1

Procedure:
To a stirred solution of 2.44 parts of 2-aminoethanol in 15 parts of chloroform is added dropwise a solution of 5.6 parts of p-(2-thenoyl)hydratropoyl chloride in 15 parts of chloroform at room temperature (highly exothermic reaction). Upon completion, the whole is stirred and refluxed for 1 hour. The reaction mixture is cooled and washed with a 1N hydrochloric acid solution. The organic layer is separated, washed twice with water, dried, filtered and evaporated. The oily residue solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from boiling ether, yielding N-(2-hydroxyethyl)-p-(2-thenoyl)hydratropamide; m.p. 87.1° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc2c(NC3CCCCC3)nc(Cl)nc12
Reaction time: 3 h
Yield: 96.1 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d]pyrimidine, and after 204 mg (2.1 mmol) of cyclohexylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 379 mg (yield: 98.2%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1
Reactant: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.1 %

Procedure:
In a flask were placed 2-amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid (15 mg, 0.12 mmol), pyridine (11 μL, 0.12 mmol) and N,N-dimethylformamide (1 mL), followed by stirring at room temperature for 24 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (8 mg).
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=2[CH3:29])=[C:16]([CH3:30])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:32]>C(OCC)(=O)C.O1CCOCC1.C(O)(C)C>[ClH:32].[CH3:29][C:21]1[CH:22]=[C:23]([C:26]([NH2:27])=[O:28])[CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:15][C:16]=1[CH3:30]
Reactant: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc(C(N)=O)cc1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(CNCCC(C)C)ccc1-c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4′-Carbamoyl-2′,2-dimethyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-2e: 12 g, 28.3 mmol) was dissolved in ethyl acetate and treated with 20 mL of 4.0 M hydrogen chloride in dioxane. After stirring overnight at room temperature, the volatiles were removed under reduced pressure and the resulting crude material dissolved in methanol and then ethyl acetate was added to precipitate a white solid that was isolated via filtration. This solid was suspended in iso-propanol (1 g: 20 mL), heated at reflux for 20 minutes and stirred overnight at room temperature. The resulting slurry was collect via filtration, rinsing with chilled iso-propanol, and dried under vacuum to provide the title compound (E2-01).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH2:8][CH2:7]1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C1(C)C=CC=CC=1>[O:16]1[CH:3]([CH2:4][O:5][C:6]2([CH3:15])[CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH2:8][CH2:7]2)[CH2:2]1
Reactant: CC(C)C1CCC(C)(OCC(O)CCl)CC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)C1CCC(C)(OCC2CO2)CC1
Yield: 82.8 %

Procedure:
Under a nitrogen atmosphere, into a reaction flask (volume: 200 ml) were added 1-chloro-3-1-menthoxypropan-2-ol (50 g, chemical purity: 97.8%, 0.1968 mol) obtained in Example 1, toluene (75 ml), a 50% aqueous sodium hydroxide solution (31.49 g, 0.3936 mol) and a 50% aqueous benzyltrimethylammonium chloride solution (1.46 g, 4.26 mmol), and they were reacted at 75° C. for 2 hours. After completion of the reaction, the organic layer was washed with water and then the solvent (toluene) was removed to obtain an oily substance. The oily substance was distilled under reduced pressure to obtain 1,2-epoxy-3-1-menthoxypropane (34.6 g, chemical purity: 98.25%) [boiling point: 75-80° C./10.7 Pa (0.08 mmHg)] as a colorless transparent oily substance (yield: 97.0% based on 1-chloro-3-1-menthoxypropan-2-ol).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:16]=[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:11]1([CH2:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:17]3=[O:16])[CH:9]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1F
Reactant: O=C1CCCCN1c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1Oc1ccccc1N1CCCCC1=O
Temperature: 50 °C

Procedure:
2-Fluoro-4-imidazol-1-ylmethyl-benzonitrile (as described in Step E above) (0.080 g, 0.4 mmol), 2-(2-oxo-piperidin-1-yl)-phenol (as described in Step F above) (0.091 g, 0.5 mmol) and cesium carbonate (0.261 g, 0.8 mmol) were combined in DMF (2.0 mL) and heated at 50° C. for 18 hr. The reaction mixture was partitioned between EtOAc and a minimum volume of H2O. Additional product was salted out from the aqueous layer with solid NaCl, and extracted into EtOAc. The organic layers were combined, dried (Na2SO4), filtered and concentrated to give the title compound after RP HPLC on a Waters Prep Pak column eluting with a 0.1% TFA/H2O: 0.1% TFA/CH3CN gradient followed by conversion to the free base.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[C:19]([C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27])#[N:20].N12CCN(CC1)CC2>C(#N)C>[C:19]([C:21]1[CH:22]=[C:23]([S:28]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27])#[N:20]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Yield: 19.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (600 mg, 2.44 mmol) prepared in Example 14a, 3-cyano-4-fluorobenzenesulfonyl chloride (1.07 g, 4.87 mmol), 1,4-diazabicyclo[2.2.2]octane (549 mg, 4.89 mmol) and acetonitrile (12 mL), to yield the title compound (200 mg, 19%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[NH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[CH3:23][N:24]=[C:25]=[O:26]>O1CCCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([C:25](=[O:26])[NH:24][CH3:23])[N:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: CN=C=O
Reactant: Fc1ccccc1C1=NCc2cn[nH]c2-c2ccc(Cl)cc21
Solvent: C1CCOC1
Product: CNC(=O)n1cc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
The solution of 1.45 g of 8-chloro-6-(2-fluorophenyl)-1H,4H-pyrazolo[4,3-d](2)benzazepine and 1.4 ml of methylisocyanate in 20 ml of tetrahydrofuran is refluxed for 5 hours under nitrogen and evaporated under reduced pressure. The residue is taken up in chloroform, the solution filtered through a column of 15 g of silica gel, the first fractions collected, evaporated and the residue recrystallized from diethyl ether, to yield the 8-chloro-6-(2-fluorophenyl)-2-methylcarbamoyl-2H,4H-pyrazolo[4,3-d](2)benzazepine melting at 192°-193°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@H:3]([CH3:31])[CH2:2][NH:1][C:34](=[O:35])[C@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C1OCC[C@H]1O
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@H](CNC(=O)[C@H](O)CCO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 54 %

Procedure:
The procedure described in Example 63 was repeated using 5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 54% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 1.43-1.57 (m, 3H), 1.71-1.86 (m, 1H), 3.33-3.53 (m, 3H), 3.65-3.79 (m, 1H), 3.88-4.00 (m, 1H), 4.36 (t, 1H), 4.85-4.96 (m, 1H), 5.29 (s, 2H), 5.45 (d, 1H), 7.24 (d, 2H), 7.28-7.41 (m, 2H), 7.59 (t, 2H), 7.71 (t, 1H), 7.87 (t, 1H), 8.10-8.21 (m, 2H), 8.48 (s, 1H), 8.59 (d, 1H), 9.99 (s, 1H); Mass spectrum MH+ 537.9.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl>C(Cl)Cl>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:10]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Salicylic acid (4.3 g, 0.0312 mol) was taken up in 60 mL of CH2Cl2 along with tert-butyl 2-aminoethylcarbamate (5.0 g, 0.0312 mol) and EDC (6.6 g, 0.0343 mol). The resulting reaction mixture was stirred at room temperature for 8 h and then quenched with saturated aqueous NaHCO3. The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (1:1 pentane/EtOAc) afforded 5.7 g of tert-butyl 2-(2-hydroxybenzamido)ethylcarbamate (65%). tert-Butyl 2-(2-hydroxybenzamido)ethylcarbamate (650 mg, 2.31 mmol) was taken up in 4 mL of 4 N HCl in dioxane and allowed to stir at room temperature for 2 h. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure to afford the HCl salt of N-(2-aminoethyl)-2-hydroxybenzamide. This material was taken up in DMF (15 mL) along with (R)-α-lipoic acid (TCI, 478 mg, 2.31 mmol) along with EDC (443 mg, 2.54 mmol) and DIEA (1.2 mL, 6.93 mmol). The resulting reaction mixture was stirred at room temperature for 4 h and then diluted with EtOAc (60 mL). The organic layer was washed with water (4×5 mL), brine, dried (Na2SO4) and concentrated under reduced pressure to afford (S)—N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)-2-hydroxybenzamide (420 mg, 49%). Mass calculated for C17H24N2O3S2: 368.12. found: [M+H]+=369.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([CH2:36][CH3:37])[CH2:35][O:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH2:36][CH3:37])[CH2:33][O:34][CH2:35]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC1(CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 113b (2 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2 g, 91%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:14]3[N:13]=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[NH:11][C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:7]=2)=O)[CH2:3][CH2:2]1.C([O-])(=O)C.[K+].Cl.[O:33]([NH2:35])[CH3:34]>CCO.CCOC(C)=O.O>[CH:1]1([C:4](=[N:35][O:33][CH3:34])[C:6]2[C:14]3[N:13]=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[NH:11][C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCNC(=O)Nc1nc2c(C(=O)C3CC3)cc(-c3cccnc3)cc2[nH]1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2c(C(=NOC)C3CC3)cc(-c3cccnc3)cc2[nH]1
Temperature: 50 °C
Reaction time: 36 h
Yield: 27.4 %

Procedure:
To a solution of 1-(4-cyclopropanecarbonyl-6-pyridin-3-yl-1H-benzoimidazol-2-yl)-3-ethyl-urea (37.2 g, 0.106 mmol) in dry EtOH (3 mL) were added potassium acetate (84 mg, 0.848 mmol, 8 eq.), methoxylamine hydrochloride (70.8 mg, 0.848 mmol, 8 eq.), molecular sieves (4 Å, powdered) in succession. The resulting suspension was stirred at 50° C. for 36 hours. The reaction mixture was then cooled to ambient temperature, diluted with EtOAc and water. The phases were separated, the aqueous layer was extracted with EtOAc (1×) and the combined organic extracts were dried (MgSO4), filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC, converted to the bis-HCl salt to afford the title compound as a tan solid (11.0 mg): HPLC (10 to 90% CH3CN, 8 min.): tR=4.05 minutes; 1H NMR (CD3OD, 500 MHz) δ 9.30 (s, 1H), 8.99 (d, 1H), 8.90 (d, 1H), 8.22 (dd, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 4.14 (s, 3H), 3.36 (q, 2H), 2.04 (m, 1H), 1.23 (t, 3H), 1.15 (m, 2H), 0.92 (m, 2H); MS (ES+) m/z (M++1) 379.2.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[Cl:11][CH2:12][CH2:13][C:14]#[N:15]>C(Cl)Cl.CC(C)=O>[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[S:1]([NH:5][C:14](=[NH:15])[CH2:13][CH2:12][Cl:11])(=[O:3])(=[O:2])[NH2:4]
Reactant: N#CCCCl
Reactant: NS(N)(=O)=O
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: ClCCl
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C
Yield: 47.2 %

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a solution of methanesulfonic acid anhydrous (48.0 g, 0.5 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the reacting period, the mixture was diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml), and the suspension filtered and the product dried, to yield 13.3 g of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:35])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].C(N(CC)CC)C.Br[CH2:44][C:45]([O:47]C)=[O:46].C(O)(=O)C>C1COCC1.[OH-].[Na+].CO>[CH:27]1([NH:26][C:24]([C:23]2[CH:30]=[C:31]([F:34])[C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][CH2:44][C:45]([OH:47])=[O:46])([CH3:12])[CH3:13])[C:16]3=[O:35])[CH:22]=2)=[O:25])[CH2:28][CH2:29]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN)c1=O
Reactant: COC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCNCC(=O)O)c1=O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 3-(3-(2-(2-(2-aminoethoxy)phenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 311, 0.17 g) dissolved in THF (10 mL) was treated with triethylamine (0.049 mL) and methyl bromoacetate (0.034 mL) under nitrogen. The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture was diluted with 2M aqueous NaOH (2 mL) and methanol (2 mL). The solution was stirred at room temperature for 1 h, acidified with acetic acid and extracted with ethyl acetate (50 mL).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](OCC)([O:19]CC)[C:14](OCC)=O)[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[O:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[N:1]=1)=[O:19])[CH3:11]
Reactant: Cc1cccc(O)c1N
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Product: CCOC(=O)c1nc2c(C)cccc2o1
Temperature: 110 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To 2-amino-3-methylphenol (1 g, 8.1 mmol) was added ethyl triethoxyacetate (5.4 g, 3 eq). The mixture was stirred at 110° C. overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 1.36 g of 4-methyl-benzooxazole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH2:24])[CH2:17][CH2:16][CH2:15][C:14]2=1>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH:24][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)=[O:9])[CH2:17][CH2:16][CH2:15][C:14]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Cn1nccc1C(=O)O
Product: Cn1nccc1C(=O)NC1CCCc2c1[nH]c1ccc(Cl)cc21

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-5-carboxamide was prepared from 2-methyl-2H-pyrazole-3-carboxylic acid and 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid (30% yield). 1H-NMR (CDCl3): δ 8.69 (s, 1H), 7.45 (m, 2H), 7.22 (d, 1H), 7.10 (dd, 1H), 6.48 (d, 1H), 6.26 (d, 1H), 5.28 (m, 1H), 4.22 (s, 3H), 2.71 (m, 2H), 2.28 (m, 1H), 1.95 (m, 3H); MS m/z 327 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][C:23](=O)[CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:23]([CH3:24])[CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-phenyl-butan-2-one. After the reaction the crude material was purified via preparatory chiral HPLC (Chiralcel-AD column, 2% EtOH in hexanes, 25 minutes) to afford two separate enantiomers. The first enantiomer eluted from the column is the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:25][CH:24]3[CH:19]([N:20](C(OC(C)(C)C)=O)[CH2:21][CH2:22][CH2:23]3)[CH2:18]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH2:22][CH2:23][CH:24]2[CH2:25][N:17]([C:4]3[C:5]4[CH2:12][CH2:11][CH2:10][C:9]5[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=5[C:6]=4[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:18][CH:19]12
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCCc3ccccc3-4)CC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(c(N3CC4CCCNC4C3)n1)CCCc1ccccc1-2
Reaction time: 2 h

Procedure:
A solution of Example 59D in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.5 mL), stirred for 2 hours, concentrated and partitioned between 1M NaOH solution and CH2Cl2. The organic layer was isolated, dried over MgSO4 and concentrated to yield the title product. 1H NMR (CDCl3) δ 0.86 (m, 1H), 1.77 (m, 5H), 2.16 (m, 2H), 2.30 (m, 1H), 2.64 (m, 3H), 3.03 (m, 1H), 3.43 (m, 3H), 3.87 (m, 2H), 4.73 (bs, 2H), 7.19 (m, 1H), 7.33, (m, 2H), 7.75 (m, 1H). MS (M+H)+ m/z 336.
Reaction SMILES: [F:1][C:2]1([F:26])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20](N(OC)C)=[O:21])=[N:12]3)[C:4]=2[O:3]1.[CH3:27][Mg+].[Br-]>C1COCC1>[C:20]([C:13]1[C:14](=[O:19])[C:15]([O:17][CH3:18])=[CH:16][N:11]([C:10]2[C:4]3[O:3][C:2]([F:26])([F:1])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)[N:12]=1)(=[O:21])[CH3:27]
Reactant: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 1-(2,2-difluoro-1,3-benzodioxol-4-yl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (2.7 g, 7.2 mmol) in THF (70 mL) was added dropwise 1 M MeMgBr in THF (14 mL, 14 mmol) at −78° C. for 15 min. After stirring at −78° C. for 1 h, the mixture was quenched with 1 M HCl aqueous solution (30 mL). The mixture was warmed to room temperature and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.3 g, 99% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.95 (3H, s), 7.17 (1H, dd, J=7.9, 1.1 Hz), 7.26-7.32 (1H, m), 7.55 (1H, dd, J=8.7, 1.1 Hz), 8.00 (1H, s).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH2:15][CH:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=O)=[C:8]([CH3:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>CC(O)(C)C>[CH3:24][O:23][C:7]1[C:8]([CH3:22])=[C:9]2[C:4]([C:1]([OH:3])=[CH:2][C:11]([C:13]3[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=3)=[N:10]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)C2=NC(C(F)(F)F)CS2)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Temperature: 70 °C
Yield: 89 %

Procedure:
To a solution of compound 202b (70 g, 1 eq.) in tBuOH (1.2 L) was added potassium t-butoxide (46 g, 2.1 eq.) under nitrogen. The mixture was heated to 70° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure and then acidified to pH 5. The precipitate was filtered, washed with water, and triturated in a diisopropylether/pentane mixture to yield compound 203b as a beige solid in 89% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.43 (s, 3H), 3.98 (s, 3H), 6.76 (d, J=1.76 Hz, 1H), 7.04 (d, J=9.10 Hz, 1H), 7.96 (s, 1H), 8.24 (d, J=9.10 Hz, 1H), 9.31 (brs, 1H).