Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][C:6](=O)[NH:5][C:4]=2[CH:3]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:6]1[NH:5][C:4]2[CH:3]=[C:2]([Cl:1])[S:10][C:9]=2[S:8](=[O:12])(=[O:11])[N:7]=1
Reactant: O=C1Nc2cc(Cl)sc2S(=O)(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A suspension of 6-chloro-2,3-dihydro-3-oxo-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (10.75 g, 0.045 mol) in phosphorus oxychloride (100 ml) was cooled on an ice bath and dry pyridine (7.3 ml, 0.09 mol) was added dropwise at such a rate that the temperature did not exceed 10° C. The mixture was then heated at 95°-100° C. for 16 h, and cooled to room temperature. A yellow precipitate was removed by filtration, and the filtrate was concentrated in vacuo. To the residue was added 200 g of ice, and the resulting mixture was stirred for 1 h, and filtered. The isolated solid was dissolved in saturated aqueous sodium hydrogen carbonate (100 ml), and filtered to remove a small amount of insoluble material. After treatment with decolorising charcoal the filtrate was adjusted to pH 2 with 4M hydrochloric acid and the precipitate that formed was filtered, washed with water and dried to yield 5.55 g (48%) of the title compound; mp >240° C. decomp.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:10]=[C:9]([NH:8][C:6]([C@H:2]5[CH2:3][CH2:4][CH2:5][NH:1]5)=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)[C@H]5CCCN5)c4)nc4ccccc34)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)[C@H]1CCCN1

Procedure:
To tert-butyl 5-(2-(3-((R)-pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (65 mg, 0.12 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. Product was purified using prep HPLC (method 25-50—70 mins) to afford (2R)—N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)pyrrolidine-2-carboxamide. (64 mg, 100%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:19][C:20]1[N:21]([CH2:25][CH2:26][CH3:27])[CH:22]=[CH:23][N:24]=1.O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:19][C:20]2[N:21]([CH2:25][CH2:26][CH3:27])[CH:22]=[CH:23][N:24]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCCn1ccnc1CCl
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccnc1CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
2-mercapto-5-nitropyridine (3.2 g) was dissolved in DMF (64 ml), potassium carbonate (8.5 g) and 2-chloromethyl-1-propylimidazole hydrochloride (4.8 g) were added to the mixture, and the mixture was stirred for 1 hour at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[[(1-propylimidazol-2-yl)methyl]sulfanyl]pyridine (4.8 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].[Br:14]Br>>[Br:14][CH:3]([CH:2]([CH3:13])[CH3:1])[C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: BrBr
Reactant: Cc1ccncc1C(=O)CC(C)C
Product: Cc1ccncc1C(=O)C(Br)C(C)C
Yield: 85.9 %

Procedure:
By the reaction in the same manner as in Example 53-ii) using 3-methyl-1-(4-methylpyridin-3-yl)butan-1-one (3.10 g) and bromine (2.68 g), the title compound (3.69 g) was obtained as a pale-yellow powder.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12]Br>>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:11]1)(=[O:4])[CH3:5]
Reactant: BrCCBr
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C1(C(C)=O)CC1

Procedure:
Ethyl acetoacetate is allowed to react with 1,2-dibromoethane to obtain ethyl 1-acetylcyclopropanecarboxylate. Next, ethyl 1-acetylcyclopropanecarboxylate is allowed to react with zinc powder and ethylbromoacetate to give ethyl 1-ethoxycarbonyl-β-hydroxy-β-methyl-cyclopropanoate.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.Cl>C(Cl)Cl>[CH3:3][CH:2]1[CH2:4][C:17]2[C:16](=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][C:19]=3[CH:18]=2)[C:1]1=[O:5]
Reactant: c1ccc2c(c1)CCC2
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1=O)CCC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.3 %

Procedure:
Methacryloyl chloride (50 ml, 0.5 mol) was added to a suspension of 133.5 g (1 mol) AlCl3 in 500 ml CH2Cl2 at −78° C. and stirred for 20 min. Then 59 g (0.5 mol) indane was added at the same temperature. The mixture was allowed to warm to room temperature and then was stirred overnight. Next day the mixture obtained was poured carefully into a mixture of ice (1000 g) and HCl (200 ml). The organic phase was separated, washed with water and 5% NaHCO3, and dried over MgSO4. Solvent was evaporated and residue was distilled in vacuum giving 77.6 g of product (83%), b.p. 118-120° C./0.5 torr.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:8])[OH:7].[CH3:23]O>>[ClH:1].[CH3:23][O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH2:3]
Reactant: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
L-Phenylalanine (7.4 g, 0.045 mole) was stirred in 90 ml of water. The pH of this solution was adjusted to 10.2 (0°-2° C.) with 50% NaOH. Then a solution of pure NCA (8.3 g, 0.048 mole) in 8 ml of THF was added in 15 min. with vigorous stirring. The pH was maintained at 10.0-10.2 by the addition of 7N NaOH solution. The reaction mixture was then stirred at 0°-2° C. for 2 hr (pH 10.0-10.2). Sufficient 37% hydrochloric acid (9.7 g) was added at the end of the hold period to neutralize the NaOH. The solution was then warmed to 25° C. Liquid chromatography indicated an 80-82% yield of aspartyl ester based on L-phenylalanine. This clear solution was extracted twice with 50 ml portions of ethyl acetate. To the aqueous solution, 4.2 g of 37% HCl (0.043 mole) was added. The solution was concentrated under vacuum to a total weight of 31.1 g. Another 8.4 g (0.085 mole) of 37% HCl was added and the reaction slurry was held at 40° C. for 6 h to convert the aspartyl ester to α-L-aspartyl-L-phenylalanine hydrochloride. Solid (NaCl) was collected at 40° C. and washed with 2.6 g (0.026 mole) of 37% HCl and 7.5 g of methanol. Seed crystals were added to the combined filtrate and washings. The resulting solution was stirred at ambient temperature for 68 hours. The thick slurry was cooled to 0°-2° C. and the solid was collected by filtration and washed with 7 ml of cold water. The dry weight of α-APM.HCl was 9 g (55% yield based on L-phenylalanine). Product identity was confirmed by LC analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[SH2:13].[Na]>CN(C=O)C>[SH:13][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: S
Reactant: NS(=O)(=O)c1cc(Cl)ccc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(Cl)ccc1S
Yield: 30.1 %

Procedure:
To 34.0 g (0.15 mol) of 2,5-dichloro-benzene sulfonamide in 200 mL of DMF was added 16.0 g (0.28 mol) of sodium hydrogensulfide. The mixture was refluxed for 18 hours, then cooled, concentrated, and the solids collected by filtration. The solids were dissolved in hot water, the pH adjusted to 4.0 and the precipitate filtered. This material was dried to yield 10.1 g of the title compound, mp 142°-144° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([OH:9])=[C:7]([CH2:10]O)[C:6]([CH:12]=[CH2:13])=[CH:5][N:4]=1.S(Cl)([Cl:16])=O>O1CCCC1>[ClH:16].[CH3:2][C:3]1[C:8]([OH:9])=[C:7]([CH2:10][Cl:1])[C:6]([CH:12]=[CH2:13])=[CH:5][N:4]=1
Reactant: C=Cc1cnc(C)c(O)c1CO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: C=Cc1cnc(C)c(O)c1CCl

Procedure:
A mixture of 1.65 g. of 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine hydrochloride, 1 ml. of thionyl chloride and 20 ml. of tetrahydrofuran is refluxed 6 hours. After cooling, the precipitate is collected on a filter, washed with ether and dried to give 2-methyl-3-hydroxy-4-chloromethyl-5-vinyl pyridine hydrochloride.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([CH3:24])[N:6]=1)=[O:4].[NH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:12]1[C:13]2[C:8](=[C:7]([CH3:24])[N:6]=[C:5]([C:3]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C)c2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCCC(=O)O)c(O)c2c1ccc(=O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-5-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (18 mg, 0.056 mmol), β-alanine (494 mg, 5.6 mmol) and NaOMe solution (8.9 mL, 4.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., mixture was concentrated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 11.4 mg of the title compound. MS: (+) m/z 382.28 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15](=[O:27])[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1)[CH:9]=2)=[O:4].CO.[Li+].[OH-]>C1COCC1>[C:23]([CH:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:15]([C:10]2[CH:9]=[C:8]3[C:13]([CH:14]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[C:7]3[CH2:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:12][CH:11]=2)=[O:27])[CH2:22][CH2:21]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1cc2ccc(C(=O)NC3CCC(C(C)(C)C)CC3)cc2c(CC2CCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C1CCC(NC(=O)c2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)CC1
Yield: 118.2 %

Procedure:
A solution of 7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid methyl ester (57 mg, 0.126 mmol) in THF:MeOH was treated with an aq. solution of LiOH (26 mg, 0.632 mmol) via the general procedure I to give 65 mg of 7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid. This was used directly for the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1.[C:39](O)(=[O:41])[CH3:40]>>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[C:21]([F:38])=[C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:13][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:39](=[O:41])[CH3:40])[N:8]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:29]
Reactant: CC(=O)O
Reactant: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Product: CC(=O)NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 275 using N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.1 g, 0.178 mmol) and acetic acid (0.053 g, 0.889 mmol), the title compound was obtained as a solid (30 mg, 27% yield). MS (ESI): 605 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[N:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]5[CH:30]=[CH:29][O:28][CH:27]=5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:6]=1)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>[O:28]1[CH:29]=[CH:30][C:26]([C:22]2[CH:21]=[C:20]([C:17]3[N:14]4[N:15]=[CH:16][C:11]([C:7]5[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][CH:8]=5)=[CH:12][C:13]4=[N:19][CH:18]=3)[CH:25]=[CH:24][N:23]=2)=[CH:27]1
Reactant: CCOC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccoc5)c4)cnc3c2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCc1cccc(-c2cnn3c(-c4ccnc(-c5ccoc5)c4)cnc3c2)c1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
3-[3-(2-Furan-3-yl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex. 41) (1 eq, 0.122 mmol, 50 mg) is dissolved in DCM (1 ml) and the reaction mixture is cooled to −70° C. DIBAL-H (1.5 M in THF, 10 eq, 1.22 mmol, 1.74 ml) is then added and the reaction is stirred at this temperature for 3 h. The reaction mixture is then poured in NaHCO3/EtOAc. The organic phase is separated and the aqueous phase is extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and the solvent is removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to afford {3-[3-(2-Furan-3-yl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-phenyl}-methanol as a light brown solid; [M+H]+=369
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:30]([C:36](O)=[O:37])=[C:29]([F:39])[CH:28]=[CH:27][C:26]=4[NH:25]3)[CH:19]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:30]([C:36]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:37])=[C:29]([F:39])[CH:28]=[CH:27][C:26]=4[NH:25]3)[CH:19]=2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(F)c(C(=O)O)c4CC3(C)C)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(F)c(C(=O)NS(C)(=O)=O)c4CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a suspension of 60% sodium hydride (75 mg, 1.86 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (181 mg, 1.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (80 mg, 0.19 mmol) and 1,1′-carbonyldiimidazole (65 mg, 0.38 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-methanesulfonamide (19 mg, 20%) as a white solid: LC/MS m/e calcd for C29H33FN2O3S (M+H)+: 509.66, observed: 509.1.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[C:5]=1[NH2:18])([O-])=O.Cl[Sn]Cl.O>CO.Cl>[F:11][C:10]([F:12])([F:13])[C:9]1[CH:8]=[CH:7][C:6]([C:14]([F:17])([F:16])[F:15])=[C:5]([NH2:18])[C:4]=1[NH2:1]
Reactant: Nc1c(C(F)(F)F)ccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1c(C(F)(F)F)ccc(C(F)(F)F)c1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of 2-nitro-3,6-bis(trifluoromethyl)benzenamine (2.3 g, 8.4 mmol) in methanol (10 mL) was added a solution of SnCl2.H2O (7.56 g, 33.6 mmol) in concentrated HCl (15 mL). The mixture was heated to 50° C. and stirred for 2 hours. Methanol was removed in vacuum and the aqueous solution was basified with sodium hydroxide solution. The suspension was diluted with EtOAc (150 mL), and the mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was washed with brine (100 mL), dried over sodium sulfate, and filtered. The solution was concentrated to give a crude product of 3,6-bis(trifluoromethyl)benzene-1,2-diamine (1.5 g). MS (ESI): m/z 245 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18](Cl)=[O:19])[CH2:13][CH2:12][CH2:11][CH2:10]1>N1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:16]=1
Reactant: Nc1cnccc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cnccc2Cl)cc1OC1CCCC1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A stirred solution of 4-chloropyrid-3-ylamine (1.94 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.85 g) in pyridine (50 mL) is heated at 80° C. for 7 hours and then it is allowed to stand overnight. The reaction mixture is evaporated, to give a brown oil, which is subjected to mplc on silica gel, using diethyl ether as eluent, to give N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.1 g), m.p. 130°-132° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9](I)[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Cu][C:20]#[N:21]>CN1C(=O)CCC1>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:20]#[N:21])[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCn1ccc2c(I)cc(C(=O)OC)cc21
Solvent: CN1CCCC1=O
Product: CCCCn1ccc2c(C#N)cc(C(=O)OC)cc21
Temperature: 150 °C
Yield: 47.4 %

Procedure:
To a mixture of methyl 1-butyl-4-iodo-1H-indole-6-carboxylate (EXAMPLE SP-218, Step 4) (1.47 g) in N-methyl pyrrolidinone (15 mL) was added copper (I) cyanide (1.1 g). The mixture was heated to 150° C. for 6 h, removed from heat and cooled to room temperature. The mixture was partitioned between water and ethyl acetate and the layers were separated. The organic layer was washed three times with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 20% ethyl acetate as eluent to give 0.5 g of the title compound: 1H NMR (CDCl3) δ 0.955, 1.32, 1.85, 3.98, 4.23, 6.76, 7.43, 8.16, 8.30.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][C@H:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]3=[O:22])=[CH:8][C:7]=2[F:23])[CH2:2]1.Cl[C:25]1[N:34]=[C:33]2[C:28]([C:29](=[O:41])[C:30]([C:38]([OH:40])=[O:39])=[CH:31][N:32]2[CH:35]2[CH2:37][CH2:36]2)=[CH:27][C:26]=1[F:42].C[Si](C)(C)Cl.C(N(CC)CC)C>CN1CCCC1=O>[C:19]([NH:18][CH2:17][CH:15]1[O:14][C:13](=[O:22])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH:3]3[CH2:4][N:1]([C:25]4[N:34]=[C:33]5[C:28]([C:29](=[O:41])[C:30]([C:38]([OH:40])=[O:39])=[CH:31][N:32]5[CH:35]5[CH2:37][CH2:36]5)=[CH:27][C:26]=4[F:42])[CH2:2]3)=[C:7]([F:23])[CH:8]=2)[CH2:16]1)(=[O:21])[CH3:20]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OC3CNC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)NCC1CN(c2ccc(OC3CN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.12 h

Procedure:
A suspension of 100 mg N-{(5S)-3-[4-(Azetidin-3-yloxy)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (MW: 323.32, 0.31 mmol), 73 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-Naphthyridine-3-carboxylic acid (MW: 282.66, 0.25 mmol), 0.066 ml trimethylchlorosilane (MW: 108.64, d=0.859, 0.51 mmol) and 0.108 ml triethylamine (MW: 101.19, d=0.726, 0.77 mmol) in 2 ml N-methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150° C. for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography. Yield: 55 mg, 30%. MS: 570.5 (M+H)+, Method ESI+. Molecular Weight=570
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: NCc1ccncc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCc1ccncc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z=537.98 (M+H+); retention time=0.54 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:30][C:29]#[CH:28])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
First, 70 mg of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61) was dissolved in 0.25 ml of N,N-dimethylformamide, to which 36 mg of potassium carbonate and 27 mg of propargyl bromide were added, and the mixture was stirred at 50° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 76 mg (yield, 96%) of 3-[4-chloro-2-fluoro-5-(propargyloxy)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-156; m.p., 106.9-107.1° C.).