Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:18](=[O:20])[CH3:19])[CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[C:3]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:18](=[O:20])[CH2:19][Br:1])[CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)OCc1cc(C(C)=O)ccc1OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1cc(C(=O)CBr)ccc1OC(C)=O
Yield: 69.1 %

Procedure:
A solution of bromine (7.1 g.) in chloroform (20 ml.) was added dropwise to a stirred solution of 3'-acetoxymethyl-4'-acetoxyacetophenone (11.0 g.) in chloroform (150 ml.) at room temperature. After completion of the addition, the solution was washed with water (2×150 ml.) and brine (100 ml.). The organic phase was dried (MgSO4), filtered and evaporated to give 3'-acetoxymethyl-4'-acetoxy-2-bromoacetophenone (10.0 g.) which was judged to be sufficiently pure by IR and TLC [SiO2 ; 1:1 v/v EtOAc/petrol (60°-80° C.)] for use without further purification or characterisation. A solution of 3'-acetoxymethyl-4'-acetoxy-2-bromoacetophenone (10.0 g.) in dimethylsulphoxide (150 ml.) was stirred at room temperature for 48 hours. The solution was then poured into ice-water (500 ml.) and extracted with ethyl acetate (3×200 ml.). The organic layers were combined, dried (MgSO4) filtered. The solvent was removed by evaporation to give 3'-acetoxymethyl- 4'-acetoxy-phenylglyoxal hydrate as a yellow oil (6.5 g. 81%). The glyoxal derivative had a satisfactory IR spectrum and was judged pure by TLC (SiO2 : EtOAc) and was therefore used without full characterisation or isolation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]1.N1C=CC=CC=1.[C:30](Cl)(=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:22][C:30](=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH:18]([O:20][CH3:21])[CH2:19]1
Reactant: COC1CN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)C1
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1CN(CCOc2ccc(NC(=O)CC(C)C)cc2-c2c(Br)cnn2C)C1
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzenamine (40.3 mg, 0.107 mmol) and pyridine (35 μL) in CH2Cl2 (2 mL) was added isovaleryl chloride (15 μL, 0.122) and stirred for two hours. The resulting material was purified by HPLC. The product was dried in vacuo to afford the title compound as a white solid (36.0 mg, 73%). LCMS m/z (%)=465 (M+H 79Br, 75), 467 (M+H 81Br, 90). 1H NMR (400 MHz, DMSO-d6) δ: 10.00 (bs, 1H), 7.69 (dd, J=8.99, 2.65 Hz, 1H), 7.60 (s, 1H), 7.48 (d, J=2.63 Hz, 1H), 7.09 (d, J=9.06 Hz, 1H), 4.03-3.86 (m, 2H), 3.82 (quint, J=5.76 Hz, 1H), 3.65 (s, 3H), 3.35-3.28 (m, 1H), 3.24-3.17 (m, 1H), 3.08 (s, 3H), 2.73-2.55 (m, 41H), 2.16 (d, J=6.96 Hz, 2H), 2.12-2.00 (m, 1H), 0.92 (d, J=6.55 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[NH:6][CH3:7].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[N:6]([CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CNc1cccc(OC)c1
Solvent: CCO
Product: CCOC(=O)C(=CN(C)c1cccc(OC)c1)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of 3-methoxy-N-methylaniline (44 g) and diethyl ethoxymethylenemalonate (69 ml) was heated on a steam bath for 2 hours, the ethanol formed being removed by distillation. The residue was cooled to ambient temperature to give the novel compound diethyl (3-methoxy-N-methylanilino)methylenemalonate as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[CH2:11][C:12]([OH:14])=[O:13].Cl>[OH-].[Na+]>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([OH:14])=[O:13])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1cccc(OCC(=O)O)c1

Procedure:
A solution of 3-hydroxybenzaldehyde and 0.3 mol of chloroacetic acid in 300 ml of 2N sodium hydroxide was refluxed for 6 hours. After cooling, the solution was acidified with hydrochloric acid and the precipitate was filtered off and crystallized from ethyl acetate/petroleum ether 60-80.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].Cl>>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH:38][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:31]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(C)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 543.3 [(M+H)+]; mp 233° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10]([CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:12])[CH3:19]
Reactant: CCO
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1Cc2ccccc2C1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of indan-2-carboxylic acid (2.50 g) in ethanol (77 mL) at 25° C. was added concentrated H2SO4 (9 mL). The colorless solution was stirred at 75° C. over a period of 48 h. Solvent was removed under reduced pressure and the residue was diluted with dichloromethane (10 mL) and water (10 mL). The pH of the solution was brought from 1 to 14. Two layers were separated and the aqueous phase was extracted with ethyl acetate (30 mL). Organic layers were combined, dried over magnesium sulfate, filtered and concentrated under high vacuum. The solid obtained was purified on a Biotage™ 40M column (silica, hexanes/ethyl acetate 1:0 to 97:3) to give indan-2-carboxylic acid ethyl ester. Off-white oil; 1H NMR (400 MHz, CDCl3): δ 7.22-7.14 (m, 4H), 4.19 (q, J=7.04 Hz, 4H), 3.36-3.10 (m, 5H), 1.29 (t, J=7.04 Hz, 3H); LRMS (ESI): m/z 190 (MH+); HPLC: 4.3 min.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:21][NH2:22]>CCO>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:21][NH2:22])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(F)cc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(F)cc2)CC1
Yield: 90.9 %

Procedure:
Synthesized according to General Procedure C: 51f (3.0 g, 10.7 mmol, 1.0 equiv.), anhydrous hydrazine (1.4 mL, 42.8 mmol, 4.0 equiv.), EtOH (20 mL, 0.5 M). 46f (2.59 g, 91.1%) was obtained as a white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.15 (br s, 1H), 7.22-7.19 (m, 2H), 6.95-6.91 (m, 2H), 3.84 (br s, 2H), 3.40 (s, 2H), 3.01 (s, 2H), 2.47 (br s, 4H), 2.39 (br s, 4H). 13C-NMR (125 MHz, CDCl3) δ 170.5, 162.0 (d, JC-F=243.6 Hz), 133.7 (d, JC-F=2.8 Hz), 130.6 (d, JC-F=8.3 Hz), 115.1 (d, JC-F=21.1 Hz), 62.0, 60.6, 53.7, 53.0. 19F-NMR (470 MHz, CDCl3) δ −118.9. HRMS (ESI): 267.1630 (M+1); calcd. for C13H20FN4O: 267.1621.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH3:23])=[O:10])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(Oc2ccccc2C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Oc1ccc(C)cc1

Procedure:
A solution of 37.70 g of 2-(4-methylphenoxy)-benzoic acid was 12.0 mL of concentrated sulfuric acid in 500 mL of methanol was refluxed for 14 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was added to a mixture of methylene chloride and water. The organic phase was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was kugelrohr distilled (120°-135°/0.025 torr) to furnish 35.08 g of methyl 2-(4-methylphenoxyl)benzoate, m.p. 31°-34°. NMR (200 MHz, CDCl3) δ7.87 (d, of d, 1H); 7.39 (t of d, 1H); 7.11 (m, 3H); 6.88 (m, 3H); 3.81 (s, 3H); 2.30 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.[C:11]([C:13]1[C:18]2[N:19]=[C:20]([C:22](OCC)=[O:23])[O:21][C:17]=2[C:16]([F:27])=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]=1[CH3:34])#[N:12].Cl>ClCCl>[F:27][C:16]1[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:14]([CH3:34])[C:13]([C:11]#[N:12])=[C:18]2[C:17]=1[O:21][C:20]([C:22]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:23])=[N:19]2
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: C1COCCN1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N3CCOCC3)nc2c1C#N
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
Morpholine (269 μl, 3.08 mmol) was dissolved in dichloromethane (3 ml), and under nitrogen atmosphere at room temperature, trimethylaluminium (1.03 M hexane solution, 2.99 ml, 3.08 mmol) was added. After stirring at the same temperature for 15 minutes, a solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (500 mg, 1.54 mmol) dissolved in dichloromethane (7 ml) was added at the same temperature. After stirring at the same temperature for 30 hours, an aqueous 1 M hydrochloric acid solution was gradually added at 0° C. The solution was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=3:2) to obtain the entitled compound (460 mg, 82%) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH3:16])[CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:30]1[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:1]([CH:3]([CH2:15][CH3:16])[CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:31][CH2:32][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:34][CH2:35]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCC(CC)CNCc1ccc(B(O)O)s1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Temperature: 150 °C
Reaction time: 0.13 h

Procedure:
To a CEM microwave tube containing the crude (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)boronic acid (48 mg, 0.199 mmol) was added a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol) in dioxane (1.75 mL), a solution of K2CO3 (130 mg, 0.942 mmol) in H2O (0.25 mL), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with MeOH (3 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 50° C., and the crude product was taken up in dimethyl sulfoxide (1.1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×100 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50° C. to give impure title compound. The impure title compound was repurified on an Agilent MDAP and free based with the ammonium hydroxide column as shown above to give 8.5 mg of the title compound (10%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Br:16][C:17]1[CH:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(N(CC)CC)C>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Br)ncc2[N+](=O)[O-])CC1
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A solution of 4-(aminomethyl)-1-boc-piperidine (370 mg, 1.73 mmol) in acetonitrile (1 mL) was added over 1 minute to a solution of 2-bromo-4-chloro-5-nitropyridine (373 mg, 1.57 mmol) and triethylamine (0.24 mL, 1.73 mmol) in acetonitrile (5 mL). The solution was stirred for 30 minutes then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (×3) and the combined organic phases were dried (Na2SO4) and concentrated to give tert-butyl 4-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate as a light brown foam (640 mg, 98%) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=3[O:20][CH3:21])[N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH:41][C:2]3[N:22]=[C:5]4[CH:6]=[CH:7][CH:8]=[C:9]([C:10]5[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=5[O:20][CH3:21])[N:4]4[N:3]=3)=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc(C(F)(F)F)ccc1-c1cccc2nc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nn12

Procedure:
2-Chloro-5-(2-methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 2.15 m mol) and 2-methoxy-4-trifluoromethylbenzeneboronic acid (0.71 g, 3.23 mmol), in a manner analogous to Example 2c. Product was isolated as a foam (0.5 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.73 (m, 1H), 7.67 (d, J=7.3 Hz, 1H), 7.61 (d, J=8.1 HZ, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.303 (s, 1H), 7.10 (d, J=7.3 Hz, 1H), 3.87 (s, 3H). MS=328 (MH)+. 236b) 7-[5-(2-Methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-5-(2-Methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 1.5 mmol), and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.6 g, 2.0 mmol). Product was isolated as a foam (0.27 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.69 (d, J=7.99 Hz, 1H), 7.56-7.51 (m, 2H), 7.41 (d, J=7.99 Hz, 1H), 7.32-7.28 (m, 2H), 7.06-7.02 (m, 1H), 6.97-6.93 (m, 1H), 6.75 (brs, 1H), 3.86 (s, 3H), 3.62-3.48 (m, 4H), 2.91-2.77 (m, 4H) 1.52 (s, 9H). MS=554 (MH)+. 236c) [5-(2-Methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepin-7-yl)-amine was prepared from 7-[5-(2-methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-bezazepine-3-carboxylic acid tert-butyl ester (0.27 g, 0.490 mol) in a manner analogous to Example 234c. Product was isolated as a foam (0.20 g, 90%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.70 (d, J=7.9 Hz, 1H), 7.56-7.50 (m, 2H), 7.40 (d, J=7.9 Hz, 1H), 7.32-7.23 (m, 2H), 7.03 (d, J=7.9 Hz 1H), 6.96-6.92 (m, 2H), 6.80 (brs, 1H), 3.86 (s, 3H), 3.03-2.92 (m, 4H), 2.91-2.84 (m, 4H). MS=454 (MH)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([NH:10][S:11](Cl)(=[O:13])=[O:12])[CH3:9].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([O:7][S:11](=[O:13])(=[O:12])[NH:10][CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCNS(=O)(=O)Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCNS(=O)(=O)Oc1ccccc1
Yield: 70.8 %

Procedure:
A solution of 18.8 g (0.2 mole) of phenol and 38.4 g (0.27 mole) of ethylaminosulfonyl chloride (prepared using procedure of Example 2, pt. a) in 150 ml of toluene was stirred and heated at reflux for 16 hr. The solution was cooled and then treated with 250 ml of a 20% sodium bicarbonate solution. The layers were separated and the organic layer was washed successively with 250 ml of a 20% sodium bicarbonate solution, two 300-ml portions of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the oily residue was purified by chromatography (4.5×105 cm glass column; 550 g of silica gel; ethyl acetate-hexanes, 1:16). Fractions containing the product were combined and the solvents evaporated under reduced pressure to give 28.5 g (71%) of the title compound as a colorless liquid. Elemental analysis suggested that the product contained water.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[N:17]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][C:39](=O)[CH3:40].C([BH3-])#N.[Na+]>CO>[C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:33][CH2:34][N:35]([CH:39]([CH3:40])[CH3:38])[CH2:36][CH2:37]4)=[CH:30][CH:31]=3)[N:17]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(N2CCNCC2)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CCN(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)c5ccccc5)C4)ccc3C(N)=O)cc2)CC1
Yield: 55.4 %

Procedure:
To a mixture of (R)-6-(3-benzamidopiperidin-1-yl)-2-(4-(piperazin-1-yl)phenylamino)nicotinamide (50 mg, 0.100 mmol) and propan-2-one (58.1 mg, 1.001 mmol) in MeOH (1 mL) was added sodium cyanoborohydride (12.58 mg, 0.200 mmol). The reaction mixture was quenched with satd. NaHCO3, extracted twice with CH2Cl2, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, extracted with CH2Cl2, and concentrated to give 30 mg of (R)-6-(3-benzamidopiperidin-1-yl)-2-(4-(4-isopropylpiperazin-1-yl)phenylamino)nicotinamide as yellow solid. LCMS: (M+H)+=542.21. 1H NMR (500 MHz, CDCl3-MIX) δ ppm 7.57 (2H, d, J=7.15 Hz), 7.53 (1 H, d, J=8.80 Hz), 7.35-7.43 (3H, m), 7.31 (2H, t, J=7.70 Hz), 6.77 (2H, d, J=9.35 Hz), 6.01 (1H, d, J=8.80 Hz), 4.07-4.13 (1H, m), 3.75-3.81 (1H, m), 3.66-3.73 (1H, m), 3.58-3.66 (1H, m), 3.49-3.56 (1H, m), 2.98-3.03 (4H, m), 2.60-2.66 (1H, m), 2.56-2.60 (4H, m), 1.82-1.95 (2H, m), 1.66-1.76 (1H, m), 1.60 (1H, td, J=6.74, 3.57 Hz), 1.03 (6H, d, J=6.05 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:4])O.[H-].[Na+].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21]Br)=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]=2[CH:29]=1>CN(C)C=O>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21][N:2]([CH3:4])[CH3:1])=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]=2[CH:29]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CBr)n1-2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 16, a solution of N,N-dimethylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-fluoro-1-(bromomethyl)-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine to give 8-fluoro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][N:13](C)C(=O)C>O>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]

Procedure:
Heat a solution of 2,5-dibromo-3-nitropyridine (1.77 g, 6.3 mmol; Malinowski (1988) Bull. Soc. Chim. Belg. 97:51; see also U.S. Pat. No. 5,801,183) and cuprous cyanide (0.60 g, 6.69 mmol) in N,N-dimethylacetamide (25 mL) at 100° C. for 72 hours. After cooling, dilute the mixture with water (25 mL) and extract twice with EtOAc (25 mL each), then wash twice with water (25 mL each). The combined EtOAc extracts are dried (Na2SO4), evaporated, and purified by flash chromatography (50% EtOAc-hexane) to obtain 5-bromo-3-nitropyridine-2-carbonitrile as a pale solid.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][CH2:29][C:30](=[O:32])[NH2:31])[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO.C(OCC)(=O)C>[C:30]([CH2:29][S:28][CH2:27][C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])(=[O:32])[NH2:31]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)CSC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(carbamoylmethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.10 g) in methanol (40 ml) was added conc. hydrochloric acid (0.72 ml) at ambient temperature. After stirring at the same temperature for 1 hour, this reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (60 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a residue. The residue was washed with a mixture of ethyl acetate (30 ml) and diisopropyl ether (15 ml). The resulting precipitates were collected by filtration and air-dried to give (2S,4R)-2-(carbamoylmethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.08 g).