Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[OH-].[Na+].[CH3:9][N:10]1[C:18]([S:19]([O-:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N:11]1.[Li+]>O>[CH3:9][N:10]1[C:18]([S:19]([NH2:1])(=[O:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N:11]1
Reactant: NOS(=O)(=O)O
Reactant: Cn1nc2ccccc2c1S(=O)[O-]
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc2ccccc2c1S(N)(=O)=O
Temperature: 10 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
A solution containing 9.5 g (72 mmol) of 2-methyl-2H-indazole in 200 ml of ethyl ether, was cooled to -30° C., and 61.4 g (144 mmol) of n-butyl lithium (a 15% hexane solution) was dropwise added thereto. The mixture was stirred for one hour at the same temperature, and then an excess amount of sulfurous acid gas was blown thereinto for 3 hours at a temperature of not higher than -20° C. After completion of the reaction, the mixture was returned to room temperature, stirred for 12 hours and then diluted with ethyl ether. The product was subjected to filtration. The crystals were dried to obtain crude lithium 2-methyl-2H-indazole-3-sulfinate. This product was used for the subsequent reaction without purification. 48.8 g (430 mmol) of hydroxylamine-O-sulfonic acid was gradually added to a solution containing 17.2 g (430 mmol) of sodium hydroxide in water 300 ml) under cooling with ice (not higher than 10° C.). This solution was added all at once to a solution containing the crude lithium 2-methyl-2H-indazole-3-sulfinate previously prepared in water (100 ml), and then the mixture was stirred for 12 hours at room temperature. Formed crystals were collected by filtration to obtain 8.8 g (yield: 58%) of 2-methyl-2H-indazole-3-sulfonamide (slightly yellow granular crystals). Melting point: 181°-183° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:22])=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([O:26]CCC#N)=[O:25])=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2].[OH-].[Na+].C(OCC)C.O>COCCOC.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:22])=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([OH:26])=[O:25])=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2]
Reactant: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
642 mg (2.52 mmol) of the compound from Example 26A are dissolved in 40 ml of 1,2-dimethoxyethane/water (3:1 v/v), mixed with 5.04 ml (5.04 mmol) of 1 N sodium hydroxide solution and stirred at room temperature overnight. The mixture is then mixed with 30 ml of diethyl ether and 30 ml of water, the organic phase is separated off, and the aqueous phase is adjusted to pH 4-5 with 1 N hydrochloric acid. The resulting suspension is stirred for 1 h, and the precipitated solid is then removed by filtration. The precipitate is washed with water and a little diethyl ether. Drying at 40° C. in vacuo results in 642 mg (67% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][NH:5][C:6](=[O:38])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[C:20]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:19][N:18]=[C:17]([CH3:36])[CH:16]=2)=[CH:9][C:8]=1[Cl:37].O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:37][C:8]1[CH:9]=[C:10]([O:14][C:15]2[C:20]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:19][N:18]=[C:17]([CH3:36])[CH:16]=2)[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2cc(C)ncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(Oc2cc(Cl)c(C(=O)NCC(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.9 %

Procedure:
To a solution of 38 mg (0.067 mmol) {2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-acetic acid methyl ester (Example 69) in 2 mL dioxane was added 2 mL water and 4 mg (0.083 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred at room temperature for 4 hours and then poured on 20 mL 1N aqueous hydrochloric acid and 20 mL ethyl acetate. The layers were separated and the aqueous layer was extracted a second time with 20 mL ethyl acetate. The combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum to yield 10 mg (27%) of the desired compound as a light yellow solid. MS (ESI): m/z=555.119 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]([CH2:13][OH:14])([CH2:10][CH2:11][CH3:12])[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].C(=O)(OCC)OCC.[OH-].[K+]>C(O)C>[OH:9][CH:4]([C:3]1([CH2:10][CH2:11][CH3:12])[CH2:2][O:14][CH2:13]1)[C:5]([F:6])([F:7])[F:8]
Reactant: CCCC(CO)(CO)C(O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: CCCC1(C(O)C(F)(F)F)COC1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A mixture of 3,3-di-(hydroxymethyl)-1,1,1-trifluorohexan-2-ol (2.8 g.), diethyl carbonate (1.6 ml.), potassium hydroxide (0.1 g) and dry ethanol (4.0 mls) was refluxed gently (oil bath 110°), under a current of nitrogen, for 30 minutes. The ethanol was then removed by distillation. Distillation gave 3-(1-hydroxy-2,2,2-trifluoroethyl)-3-n-propyloxetane (1.7 g.), a colourless oil (b.p. 112°, 20-25 m.m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc(CN2CCN(c3ccc(Cl)cc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 41.2 %

Procedure:
A solution of 0.97 g (0.00493 mol) of 1-(4-chloro-phenyl)-piperazine in 35 ml of dimethylformamide was treated with 1.37 ml (0.00986 mol) of triethylamine and 0.60 g (0.0016 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 60 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent, digested in dichloromethane/water 1:1 and subsequently filtered off under suction. 0.21 g (40%) of 5-[4-(4-chloro-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 296°-298°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[C:41]1[NH:42][C:43]([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[C:48]([C:61]([O:63][CH3:64])=[O:62])[CH:47]=2)=[CH:44][N:45]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)(O)[O-].[Na+]>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:27][C:25]([C:20]1[C:21]([C:49]2[C:48]([C:61]([O:63][CH3:64])=[O:62])=[CH:47][C:46]([C:43]3[NH:42][C:41]([CH:37]4[CH2:38][CH2:39][CH2:40][N:36]4[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[N:45][CH:44]=3)=[CH:51][CH:50]=2)=[CH:22][CH:23]=[C:18]([C:15]2[NH:14][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=2)[CH:19]=1)=[O:26]
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1-c1ccc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)cc1C(=O)OC
Temperature: 80 °C
Yield: 34.8 %

Procedure:
To the solution of 2-[5-(4-bromo-3-methoxycarbonyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (158 mg, 0.35 mmol) and 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (166 mg, 0.33 mmol) in 1,2-dimethoxyether (3 ml) and water (1 ml) was added sodium bicarbonate (91 mg, 1.1 mmol), followed by Pd(PPh3)4 (15 mg) and PdCl2(dppf)CH2Cl2 (15 mg). The mixture was heated at 80° C. for 7 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 4,4′-Bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2,2′-dicarboxylic acid dimethyl ester (85 mg). m/z: 741.0 (M+H)+, 370.9 (M+2H)+/2.
Reaction SMILES: IC.[F:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.N12CCCN=C1CCCC[CH2:18]2>CN(C=O)C.C(OCC)(=O)C>[F:3][C:4]1[C:9]2[N:10]([CH3:18])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)oc2cc([N+](=O)[O-])cc(F)c21
Temperature: 65 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Iodomethane (0.393 ml, 6.31 mmol) is added in portions to crude 4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (Step 5, 1.00 g, 5.05 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.94 ml, 6.31 mmol) in DMF (10 ml). The reaction is stirred at 65° C. overnight, diluted with ethyl acetate, washed with 2N HCl and saline, dried (MgSO4), and evaporated to give crude product containing trace amounts of undesired 5-nitro isomer. Purification by flash column chromatography (20% ethyl acetate/hexane) gives pure product as a white solid (0.89 g, 83%); mp 118-9° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1[OH:23].[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][C@@H:4]([OH:23])[C@H:3]([CH2:2][NH:1][CH2:35][C:32]3[CH:33]=[CH:34][C:28]4[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=4[N:31]=3)[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@@H](CN)[C@H](O)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](O)C3)c2n1
Reaction time: 24 h
Yield: 62 %

Procedure:
To a stirred solution of (±)-trans-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.62 g, 1.94 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.38 g, 1.94 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.61 g, 2.91 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.60 g, 62%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 4.11 (s, 3H), 4.05 (m, 4H), 3.52 (m, 4H), 3.42 (s, 2H), 3.19 (m, 2H), 2.98 (m, 2H), 2.70 (m, 2H). LC-MS (ES) m/e 499 (M+H)+.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[NH2:4][C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1.[CH2:15]([O:17][CH2:18][CH3:19])[CH3:16]>>[O:3]=[C:1]([N:9]1[CH2:8][CH2:7][CH:15]([O:17][C:18]2[CH:13]=[CH:14][CH:5]=[CH:6][CH:19]=2)[CH2:16][CH2:10]1)[CH2:2][NH:4][C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1
Reactant: CCOCC
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: CC=O
Product: O=C(CNc1ccc2[nH]c(=O)oc2c1)N1CCC(Oc2ccccc2)CC1

Procedure:
The title compound is prepared from 2-chloro-1-(4-phenoxy)-piperidin-1-yl]-ethanone and 6-amino-3H-benzoxazol-2-one according to the method described in Example 206. Melting Point:220-223° C. (diethylether)
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]1[CH3:23])(=[O:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]([Cl:1])=[O:4])[CH2:19][C@@H:18]1[CH3:23])(=[O:15])=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H]1CNCCN1S(C)(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)Cl)CCN1S(C)(=O)=O
Temperature: 25 °C
Yield: 154.7 %

Procedure:
Second step: To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (560 mg, 1.88 mmol) in CH2Cl2 (10 mL) at −78° C., was added a solution of (S)-1-methanesulfonyl-2-methyl-piperazine (838 mg, 4.70 mmol) and pyridine (0.74 mL, 9.4 mmol) in CH2Cl2 (10 mL) over 1 hour. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo and flash chromatography (SiO2, EtOAc/H, 1:1) yielded 0.70 g (62%) of (S)-4-methanesulfonyl-3-methyl-piperazine-1-carbonylchloride as a light yellow solid.
Reaction SMILES: CN(C)CCCN=C=NCC.[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.[N:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=[C:25]=S.C(OCC)(=O)C>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=[C:25]1[NH:24][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1
Reactant: COCCNc1ccccc1N
Reactant: COC(=O)c1ccc(N=C=S)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCn1c(Nc2ccc(C(=O)OC)cc2)nc2ccccc21
Temperature: 25 °C
Yield: 68.9 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 791 mg) is added to a solution of N1-(2-methoxyethyl)benzene-1,2-diamine (311 mg, 1.87 mmol) and methyl 4-isothiocyanatobenzoate (328 mg, 1.70 mmol) in tetrahydrofuran. The reaction may be heated to reflux for 2 hr and cooled to room temperature. The mixture may be diluted in an appropriate solvent such as ethyl acetate, filtered and concentrated. The residue may be purified by any appropriate method, including Biotage column chromatography to give methyl 4-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-ylamino)benzoate (381 mg).
Reaction SMILES: [CH:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([NH:14][CH:15]=[O:16])[CH2:4]1)=[O:2].[N+:17]([O-])([O-:19])=[O:18].[Na+]>FC(F)(F)C(O)=O>[CH:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][C:11]=2[N+:17]([O-:19])=[O:18])[CH2:6][CH:5]([NH:14][CH:15]=[O:16])[CH2:4]1)=[O:2]
Reactant: O=CNC1Cc2cc(Br)ccc2N(C=O)C1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=CNC1Cc2cc(Br)cc([N+](=O)[O-])c2N(C=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
A mixture of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-3-quinolyl)formamide (12.8 g, 45.2 mmol) and sodium nitrate (12.8 g, 150 mmol) in trifluoracetic acid (100 mL) was stirred at room temperature for 18 hours. The bulk of the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate was washed with sodium hydroxide and water, and the ethyl acetate was removed to give 14.2 g of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolyl)formamide (compound XXVIII) as a solid. This was dissolved in ethanolic hydrogen chloride (100 mL of 4.0 N), the mixture was refluxed for 1 hour, ether (200 mL) was added, and the precipitate was filtered off, washed with ether and dried to give 12.8 g (82% of 6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolinamine dihydrochloride, mp >300° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[C:9](O)(=[O:11])[CH3:10].C(C=O)=O.C(=O)([O-])O.[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7]/[N:8]=[CH:10]/[CH:9]=[O:11]
Reactant: CC(=O)O
Reactant: NNc1ccccn1
Agent: O=C([O-])O
Agent: O=CC=O
Agent: [Na+]
Solvent: O
Product: O=C/C=N/Nc1ccccn1
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A mixture of the 1-(pyridin-2-yl)hydrazine (2.00 g, 18.33 mmol), water (13 mL), and acetic acid (10.49 ml, 183.3 mmol) was added with stirring into a 40% aqueous solution of glyoxal (10.51 ml, 91.63 mmol) over 20 minutes. Stirring was continued for 18 hours and then the aqueous was extracted with EtOAc. The diluted aqueous layer was slowly basified with sodium hydrogen carbonate (15.40 g, 183.3 mmol). The resulting solids were collected by filtration and washed with water to afford 1.65 g (85%) of the desired product and dimer. LRMS (apci pos): 150 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N:18]([CH2:19][CH3:20])[C:17]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:16]=3[N:15]=2)=[O:13])=[C:4]([N:26]2[C:30](=[O:31])[C:29]3=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]3[C:27]2=[O:36])[CH:3]=1.[NH2:37][NH2:38]>>[Cl:25][C:23]1[CH:22]=[CH:21][C:17]2[N:18]([CH2:19][CH3:20])[C:14]([S:12]([CH2:11][C:5]3[C:6]([CH3:10])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[CH:3][C:4]=3[NH:26][C:27]([C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[C:30]([NH:37][NH2:38])=[O:31])=[O:36])=[O:13])=[N:15][C:16]=2[CH:24]=1
Reactant: NN
Reactant: CCn1c(S(=O)Cc2c(N3C(=O)c4ccccc4C3=O)cc(C)c(OC)c2C)nc2cc(Cl)ccc21
Product: CCn1c(S(=O)Cc2c(NC(=O)c3ccccc3C(=O)NN)cc(C)c(OC)c2C)nc2cc(Cl)ccc21
Yield: 57 %

Procedure:
2-[(4,6-Dimethyl-5-methoxy-2-phthalimidylphenyl)methylsulfinyl]-5-chloro-1-ethyl-1H-benzimidazole (Example 121) (66 mg, 0.13 mmol) was treated with hydrazine according to the procedure of Example 39 to give the crude acyl hydrazide as an oil which was triturated with ether to give the partially deprotected amine as the title compound (28 mg, 57%). 1H NMR δ1.29, (t, 3H), 2.26 (s, 3H), 2.34 (s, 3H), 3.66 (s, 3H), 4.16 (s, 2H), 4.29 (m, 2H), 4.95 (q, 2H), 7.24 (s, 2H), 7.37 (s, 1H), 7.48 (s, 1H), 7.55 (m, 2H), 7.69 (m, 1H), 7.82 (m, 1H), 7.87 (s, 1H).
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.CN(C)P(N(C)C)(N(C)C)=O.Cl[CH2:25][C:26]([NH2:28])=[O:27]>CS(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:25][C:26](=[O:27])[NH2:28])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: NC(=O)CCl
Agent: [K]
Solvent: CS(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: NC(=O)COC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
The potassium salt of 4-hydroxyphenylacetic acid (9.5 g, 0.1 mol) was taken up in a mixture of dimethylsulfoxide (80 mL) and hexamethylphosphoramide (5.37 g, 0.1 mol). 2-Chloroacetamide (13.5 g, 0.3 mol) was added and the reaction mixture was first stirred at room temperature for 24 hours, then heated for 1 hour. The reaction mixture was evaporated, then cooled. The product which separated was taken up in ethyl acetate (150 mL), stirred, filtered and evaporated. The oily residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated to give the desired ester, carbamoylmethyl 4-hydroxyphenylacetate, melting at 85°-87° C., in 48.8% yield.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:6]1[C:10]2=[C:11]([N:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[N:12]=[C:13]([C:15]#[N:16])[CH:14]=[C:9]2[C:8]([CH:27]=[O:28])=[C:7]1[CH3:29])[CH:4]=[CH2:5].O>CO>[CH2:3]([N:6]1[C:10]2=[C:11]([N:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[N:12]=[C:13]([C:15]#[N:16])[CH:14]=[C:9]2[C:8]([CH2:27][OH:28])=[C:7]1[CH3:29])[CH:4]=[CH2:5]
Reactant: C=CCn1c(C)c(C=O)c2cc(C#N)nc(N3CCc4ccccc4C3)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCn1c(C)c(CO)c2cc(C#N)nc(N3CCc4ccccc4C3)c21
Reaction time: 1 h
Yield: 28.5 %

Procedure:
Sodium borohydride (111.2 mg, 2.94 mmol) was added to a solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-formyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (350 mg, 0.98 mmol) prepared in Step 4 in methanol (10 ml). The reaction mixture was stirred for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 100 mg of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([CH3:64])=[C:46]([CH:63]=1)[O:47][C:48]1[N:53]=[C:52]2[S:54][C:55]([NH:57][C:58]([CH:60]3[CH2:62][CH2:61]3)=[O:59])=[N:56][C:51]2=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[CH:60]1([C:58]([NH:57][C:55]2[S:54][C:52]3[C:51]([N:56]=2)=[CH:50][CH:49]=[C:48]([O:47][C:46]2[CH:63]=[C:42]([NH:41][C:10](=[O:12])[C:9]4[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=4)[CH:43]=[CH:44][C:45]=2[CH3:64])[N:53]=3)=[O:59])[CH2:61][CH2:62]1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(OC(F)(F)C(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (44 mg, 0.185 mmol) in pyridine (2.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.185 mmol), and the mixture was stirred at room temperature for 10 min. N-[5-(5-Amino-2-methylphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (60 mg, 0.176 mmol) produced in Example C47(i) was added to the obtained solution, and the mixture was stirred at 70° C. for 20 hr. After the reaction mixture was cooled to room temperature, water (2 mL) was added, and the obtained precipitate was collected by filtration, washed with water and ethyl acetate, and dried to give the title compound (55 mg, 56%) as a colorless powder.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C@@H:6]([C@H:10]([OH:12])[CH3:11])[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:16])=O>>[Br:5][C@@H:6]([C@H:10]([O:12][C:1](=[O:3])[CH3:2])[CH3:11])[C:7]([Cl:16])=[O:9]
Reactant: CC(=O)Cl
Reactant: C[C@@H](O)[C@H](Br)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CC(=O)O[C@H](C)[C@H](Br)C(=O)Cl
Temperature: 5 °C

Procedure:
Acetyl chloride (6.82 g, 86.88 mmole) was added dropwise to (2S, 3R)-2-bromo-3-hydroxybutyric acid (neat) with stirring. The reaction mixture was cooled in a bath at 5° C. as exotherm began. After completion of addition, the cooling bath was removed. After 45 minutes the mixture was heated at 45°-50° C. for 1.5 hours. Heating was discontinued and 10 mL toluene was added. The mixture was cooled in an ice bath and oxalyl chloride (11.4 80 g, 90.44 mmole) was added dropwise. After completion of addition, the mixture was allowed to warm to room temperature then heated at reflux for 30 minutes. Toluene and excess of reagents were removed by fractional distillation. The residue was subjected to bulb-to-bulb distillation at 80°-90° C. under high vacuum (1mm/Hg) to yield the title compound. 1H NMR (200 MHz, CDC/3) w 1.44 (d, J=6.0Hz, 3H), 2.11 (s, 3H), 4.67 (d, J=6.0 Hz, 1H), 5.41 (m, 1H); 1R (neat) 1810, 1790, 1740 cm-1.