Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]([CH3:20])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[CH3:23])#[N:2].[BH4-].[Na+].[NH4+].[Cl-]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:2][CH2:1][C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]([CH3:20])[C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]=1[CH3:23]
Reactant: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1C#N
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1CN
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A solution of 4-cyano-3,N-dimethyl-N-(4-trifluoromethyl-phenyl)-benzamide from Example E118.2 (1.08 g, 3.4 mmol) in methanol (40 ml) at room temperature was treated with cobalt(II) chloride hexahydrate (1.61 g, 6.8 mmol). The mixture was stirred for 10 min then sodium borohydride (1.28 g, 34 mmol) was added portionwise. The mixture was stirred for 20 h then saturated NH4Cl solution (10 ml) was added. The mixture was stirred for 30 min, filtered through glass-fibre paper and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% dichloro-methane) to yield the title compound (863 mg, 79%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([OH:15])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:16][CH2:17]O>>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([OH:15])[C:12]([O:14][CH2:16][CH3:17])=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)[C@H](O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 mL ethanolic HCl were added to a solution of 3.5 g (14.9 mmol) of (R)-3-(3,4-dichloro-phenyl)-2-hydroxy-propionic acid in 50 mL EtOH and the reaction mixture was stirred for 4 h at RT. The reaction solution was evaporated down i. vac., the residue was combined with DCM, extracted with 15% K2CO3 solution and the organic phase was dried over Na2SO4. After the desiccant and solvent had been eliminated the product was obtained as an oil, which was further reacted without purification.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]>C(O)C.O.O>[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][C:1]#[N:2])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
Sodium cyanide (1.07 g, 22 mmol) was added to a stirred solution of 4-t-butylbenzylbromide (5 g, 22 mmol) in a mixture of EtOH-H2O (6:1) (70 mL). The reaction mixture was allowed to stir under reflux conditions for 4 hours. After cooling the mixture to room temperature, the solvent was evaporated under reduced pressure to afford a yellow oil. The oil was suspended in water (20 mL) and extracted with ether (3×25 mL). The solvent was removed under reduced pressure to give a yellow oil which was purified by distillation (Kugelrohr, bp 120-125° C., 0.2 mm Hg) to afford 3.37 g (89%) of the title compound as a colorless oil.
Reaction SMILES: C(OC([N:11]1[C@@H:16]([CH3:17])[C:15](=[O:18])[N:14]2[C@@H:19]([CH2:22][CH2:23][CH2:24][N:25]3[CH2:32][CH2:31][C:28]4([CH2:30][CH2:29]4)[C@H:27]([OH:33])[CH2:26]3)[CH2:20][O:21][C:13]2([CH3:34])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:33][C@@H:27]1[CH2:26][N:25]([CH2:24][CH2:23][CH2:22][C@@H:19]2[N:14]3[C:15](=[O:18])[C@H:16]([CH3:17])[NH:11][CH2:12][C:13]3([CH3:34])[O:21][CH2:20]2)[CH2:32][CH2:31][C:28]21[CH2:30][CH2:29]2
Reactant: C[C@H]1C(=O)N2[C@@H](CCCN3CCC4(CC4)[C@H](O)C3)COC2(C)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1NCC2(C)OC[C@H](CCCN3CCC4(CC4)[C@H](O)C3)N2C1=O
Yield: 97.8 %

Procedure:
A solution of (3S,6S)-3-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-6,8a-dimethyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid benzyl ester (295 mg, 0.63 mmol) in MeOH (3 mL) was stirred for 1½ h at room temperature under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 133 mg), then insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated to afford the title compound (208 mg, 99%) Colourless gum, MS (ISP)=338.3 (M+H)+.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[CH:12]1([C:17]2[C:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:38]([CH3:40])[CH3:39])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:43])[CH2:20][C:21]([CH3:42])([CH3:41])[O:22]3)[CH2:16][CH2:15][CH2:14][CH2:13]1.CO>O1CCCC1>[CH:12]1([C:17]2[C:26]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[C:25]([CH:38]([CH3:39])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C@@H:19]([OH:43])[CH2:20][C:21]([CH3:41])([CH3:42])[O:22]3)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)c1cc2c(c(C3CCCC3)c1Cc1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C3CCCC3)c1Cc1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
40 μl (210 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 1.2 mg (10 μmol) of (1R,2S)-1-aminoindan-2-ol in 1.5 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 23 mg (50 μmol) of 5-cyclopentyl-7-isopropyl-2,2-dimethyl-6-[4-(trifluoromethyl)benzyl]-2,3-dihydro-4H-chromen-4-one (Example 39A) in 1.5 ml of tetrahydrofuran is then added very slowly dropwise, and the mixture is stirred for 2 h. Methanol is then added, and the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) gives the target product.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O(C(O)C)C>[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: COC(C)O
Product: c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
N1-phenylbenzene-1,2-diamine (4.15 g, 22 mmol) and benzaldehyde (2.1 g, 20 mmol) were mixed with methoxylethanol (60 ml) in a three-neck flask. The mixture was heated up to reflux for 48 hours. After cooled to room temperature, the solvent was evaporated. The residue was purified by column chromatography using dichloromethane to 5% of ethyl acetate in dichloromethane as eluent. 2 g of desired product was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.3 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 105 mg, 0.33 mmol) in pyridine (5 mL) was treated with dimethylsulfamoyl chloride (0.04 mL, 0.38 mmol). The reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in methylene chloride, and the organic phase was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 60/40 heptane/ethyl acetate) afforded the N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-dimethylsulfamide (21.3%) as a white solid: mp 110-112° C.; FAB-HRMS m/e calcd for C19H26N4O3S2 (M+H)+ 423.1524, found 423.1524.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[NH:17]2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2ccc(N)cc2[nH]1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COC(=O)c1cc2ccc(Nc3nc(Cl)ncc3F)cc2[nH]1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2-(methoxycarbonyl)-(1H)-indole were reacted to provide 2-chloro-5-fluoro-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-4-pyrimidineamine which was used without further purification. LCMS: purity: 65%; MS (m/e): 322 (MH+).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH2:6][O:7][P:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])([OH:10])=[O:9])([CH3:4])[CH3:3].FC(F)(F)C(O[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=O.N1C(C)=CC=CC=1C.C(OCC)C>CN(C)C=O>[CH3:1][N+:2]([CH2:5][CH2:6][O:7][P:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:18])([O-:10])=[O:9])([CH3:4])[CH3:3]
Reactant: C[N+](C)(C)CCOP(=O)(O)OCCCCCC(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Product: C[N+](C)(C)CCOP(=O)([O-])OCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A sample of 6-phosphocholinehexanoic acid in dimethylformamide is stirred at room temperature for 5 min. To this mixture, approximately a three fold molar excess of p-nitrophenyl trifluoroacetate is added. While stirring the resulting mixture, approximately a 2 fold molar excess of 2,6-lutidine is added and the mixture is stirred until the 6-phosphocholinehexanoate completely dissolves. The reaction mixture is stirred at room temperature for an additional 6 hours. Afterwards, an aliquot of ethyl ether is added to the reaction mixture to precipitate p-nitrophenyl 6-(O-phosphocholine)hydroxyhexanoate from solution. The supernatant is decanted and the oily product is dissolved in acetonitrile and is precipitated again with ether. After the removal of solvent traces, p-nitrophenyl 6-(O-phosphocholine)hydroxyhexanoate is obtained.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:13]3[N:17]4[CH:18]=[C:19]([C@@H:22]([N:27]5[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]5)[C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][C:16]4=[N:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:40][N:41]1[C:45]([CH3:55])(B2OC(C)(C)C(C)(C)O2)[CH:44]=[CH:43][NH:42]1>>[CH3:40][N:41]1[C:45]([C:2]2[C:11]([CH3:12])=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:13]4[N:17]5[CH:18]=[C:19]([C@@H:22]([N:27]6[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:28]6)[C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:21][C:16]5=[N:15][N:14]=4)=[N:9]3)=[CH:4][CH:3]=2)([CH3:55])[CH:44]=[CH:43][NH:42]1
Reactant: CN1NC=CC1(C)B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Br)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Product: Cc1c(C2(C)C=CNN2C)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 191, using tert-butyl (S)-1-((R)-1-(3-(7-bromo-8-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate in place of 7-bromo-2,8-dimethylquinoline and using 1,5-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step A. LCMS APCI (+) m/z 621 (M+H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[CH:10][C:9]=2[CH:14]=1)=[NH:4].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21](O)=O)[CH3:16].ONC(=N)C1C=CC(OC(C)C)=C(I)C=1.ClC1C=C(C=CC=1OCCC)C(O)=O>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:12][C:11]([CH3:13])=[CH:10][C:9]=4[CH:14]=3)[N:4]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: Cc1cc2cc(C(=N)NO)ccc2o1
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Agent: CC(C)Oc1ccc(C(=N)NO)cc1I
Agent: CCCOc1ccc(C(=O)O)cc1Cl
Product: CCOc1ccc(-c2nc(-c3ccc4oc(C)cc4c3)no2)cc1OCC
Yield: 6 %

Procedure:
The product Step A was converted to N-hydroxy-2-methylbenzofuran-5-carboximidamide by method described for Example 36, Step A. When N-hydroxy-2-methylbenzofuran-5-carboximidamide and 3,4-diethoxybenzoic acid were substituted for N-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro-4-propoxybenzoic acid, respectively, in Example 36, Step B, the similar procedure afforded the title compound in 6% yield, as colourless solid. 1H-NMR (CDCl3) 8.28 (bs, 1H); 8.00 (dd, 1H, J=8.55, 1.68 Hz); 7.8 (dd, 1H, J=8.4, 1.98 Hz); 7.68 (d, 1H, J=1.92 Hz); 7.47 (d, 1H, J=8.58 Hz); 6.97 (d, 1H, J=8.46 Hz); 6.45 (s, 1H); 4.23-4.16 (m, 4H); 2.48 (3H); 1.52-1.47 (m, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=[C:4]([F:23])[C:3]=1[C:24]([NH2:26])=[O:25].O>C(Cl)Cl>[F:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=[C:4]([F:23])[C:3]=1[C:24]([NH2:26])=[O:25]
Reactant: COc1ccc(-c2noc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(O)cc3)no2)c1F
Yield: 65 %

Procedure:
Bororn tribromide solution (1.0 M in CH2Cl2, 1.5 ml, 1.5 mmol, 2 equiv.) was added slowly, dropwise to stirred suspension of 2,6-difluoro-3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]methoxybenzenecarboxamide (272 mg, 0.75 mmol, 1 equiv.) in CH2Cl2 (5 ml), at r.t., under N2. The reaction mixture was stirred at r.t. for 4 h and poured into water (20 ml). CH2Cl2 (10 ml) was added and the biphasic mixture was stirred for 30 min. at r.t. The white un-dissolved solid was filtered, washed with water and Et2O, to give 170 mg (65% yield), mp 209-210° C., HPLC-MS (method 1): m/z 348 [M+H]+, Rt=3.00 min.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:12]=2)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:12]=2)=[O:9])[CH2:3][CH2:4][N:5]([C:22]2[C:23]3[C:30]([CH3:31])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:6][CH2:7]1
Reactant: CC1(C(=O)Nc2cccc(S(N)(=O)=O)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(S(N)(=O)=O)c4)CC3)c12
Temperature: 105 °C
Yield: 21 %

Procedure:
4-Methyl-N-(3-sulfamoylphenyl)piperidine-4-carboxamide from step B (33 mg, 0.098 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (16 mg, 0.098 mmol), N,N-diisopropylethylamine (51 mg, 0.39 mmol), and isopropanol (1.0 mL) were combined in a pressure rated sealed tube and heated at 105° C. for 18 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound in 21% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2].[Br-:20].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Br:20][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1cccc(C(=O)OCc2ccccc2)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
To a solution of compound prepared in Example 103 (8.40 g, 0.33 mol) in THF (160 mL) was added Phenyl Trimethylammonium Tribromide (12.40 g, 0.33 mol) and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by combiflash chromatography (silica gel, 40 g, 2-3% ethyl acetate/hexanes) to afford the title compound (7.99 g, 55%) as a white solid.
Reaction SMILES: [CH2:1]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([NH2:22])=O)[CH2:16][CH2:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:22][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]1
Reactant: CCCCCCCCCCCCCN1CCC(C(N)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCCN1CCC(CN)CC1
Yield: 80.4 %

Procedure:
Prepared from 1-tridecylpiperidine-4-carboxamide (4.7 g, 15.1 mmol) and LAH (1.14 g, 30.0 mmol) according to general procedure used for Example 8 (Step B) to give 3.6 g of title compound as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]
Reactant: O=C(O)c1ccccn1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2ccccn2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from picolinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 12.54 (s, 1H), 8.92 (d, J=9.3, 1H), 8.73 (d, J=3.9, 1H), 8.28 (d, J=6.9, 1H), 7.95-7.90 (m, 1H), 7.74 (d, J=3.0, 1H), 7.54-7.50 (m, 1H), 7.31-7.27 (m, 1H), 4.11 (q, J=6.9, 2H), 1.46 (t, J=6.9, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=[O:2].S(=O)(=O)(O)O.[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=3[Cl:35])=[C:22]([C:36]#[N:37])[CH:21]=2)[CH:17]=[CH:16][N:15]=1.N>O>[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][C:26]=3[Cl:35])=[C:22]([C:36]([NH2:37])=[O:2])[CH:21]=2)[CH:17]=[CH:16][N:15]=1
Reactant: N#Cc1cc(-c2ccnc(N)n2)[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of TFA (2.0 mL), water (0.480 mL) and 98% sulfuric acid (0.240 mL) was added to 5-(2-amino-pyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbonitrile (137 mg, 0.415 mmol). The mixture was allowed to stir for 8 h at 70° C. and then was diluted by drop wise addition of water (6 mL). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia under stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50° C. affording the title compound as a white solid (133 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:20][C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4-Chlorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([N:19]=1)=[N:8][C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:10]([OH:12])[N:11]=2)[NH2:2].CCN(C(C)C)C(C)C.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>CN1C(=O)CCC1.CCOCC>[O:12]=[C:10]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]2[N:19]=[C:3]([NH:1][NH:2][C:35]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:36])[CH:4]=[CH:5][C:6]=2[NH:11]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: O
Product: O=C(NNc1ccc2[nH]c(=O)c(-c3ccccc3)nc2n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-hydrazino-3-phenylpyrido[2,3-b]pyrazin-2-ol (3-3) (200 mg, 0.79 mmol) and DIEA (0.55 mL, 3.16 mmol) in NMP (8 mL) was added morpholine-4-carbonyl chloride (354 mg, 2.37 mmol), and stirred at room temperature for 1 hour. To the mixture was added water and Et2O, and the precipitate was collected by filtration to yield N′-(2-oxo-3-phenyl-1,2-dihydropyrido[2,3-b]pyrazin-6-yl)morpholine-4-carbohydrazide (8-1) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][C:8](=O)[CH2:7][CH2:6][C:5]=2[N:4]=1.C([O-])(=O)C.[Na+].Cl.[NH2:20][OH:21]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][C:8](=[N:20][OH:21])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1ccc2c(n1)CCC(=O)C2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(n1)CCC(=NO)C2

Procedure:
2-Methoxy-7,8-dihydro-5H-quinolin-6-one (246 mg, synthesized according to J. Org. Chem. 1991, 56 (15), 4636) was dissolved in ethanol/water 1:1 (14 ml) and sodium acetate (600 mg) and hydroxylamine hydrochloride (482 mg) was added. The resulting suspension was heated to reflux for 4 hours until TLC analysis confirmed complete consumption of the starting tetrahydroquinolinone. The reaction mixture was poured into a mixture of ice, water and 1N NaOH (pH>10) and the aqueous layer was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried and evaporated to give a crude product. This was purified by flash chromatography (gradient of ethyl acetate in hexanes, 20% to 50%) to give the desired product as a mixture of (E/Z)-isomers (232 mg) as a yellow solid. Mp: 124-126° C. MS (ISP): 193.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[N:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:44]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:45])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: O=C(Cl)N1CCOCC1
Product: COc1ccc(CC2c3cc(OC(=O)N4CCOCC4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 4-morpholinecarbonyl chloride