Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][CH2:33][OH:34])[N:27]=[CH:26]3)=[O:12])[N:7]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]=[O:42])=[CH:37][CH:36]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][CH2:33][OH:34])[N:27]=[CH:26]3)=[O:12])[N:7]([C:35]2[CH:36]=[CH:37][C:38]([CH2:41][OH:42])=[CH:39][CH:40]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)n(-c2ccc(C=O)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)n(-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.3 %

Procedure:
1-(3-tert-butyl-1-(4-formylphenyl)-1H-pyrazol-5-yl)-3-((5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)phenyl)methyl)urea was treated with NaBH4 in MeOH and stirred at ambient temperature for 2 hours. The reaction was quenched with 2 N HCl, then neutralized with Na2CO3 and extracted into DCM. The organic layer was dried and concentrated, and the residue purified on a pyridine column eluting with 20% ethanol in hexanes to provide 1.3 mg (6.3%) of the desired material. MS M+1 (573).
Reaction SMILES: [I-].[CH2:2]([N+:9]1[CH:10]([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:12][C:13]=1SC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:2]([N:9]1[C:13](=[CH:23][N+:20]([O-:22])=[O:21])[CH2:12][CH2:11][CH:10]1[C:16]([O:18][CH3:19])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C1CCC(SC)=[N+]1Cc1ccccc1
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCC(=C[N+](=O)[O-])N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Benzyl-2-(methoxycarbonyl)-5-(methylthio)-3,4-dihydro-2H-pyrrolium iodide (25.68 g, 65.6 mmol) in dry N,N-dimethylformamide (80 mL) was treated with nitromethane (17.8 mL, 328 mmol) and diisopropylethyl amine (12.6 mL, 72.2 mmol) and stirred overnight at room temperature. The mixture was heated at 60° C. for 5 hours, allowed to cool to room temperature, and concentrated under reduce pressure. The residue was purified by chromatography on silica gel (3:2 hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 277 (M+H)+; 1H NMR (CDCl3) δ 2.22 (m, 1H), 2.34 (m, 1H), 3.39 (5, 1H), 3.69 & 3.75 (dd & dd, 1H), 3.72 (s, 3H), 4.24 (dd, 1H), 4.30 (d, 1H), 4.51 (d, 1H), 6.87 (s, 1H), 7.16 (dd, 2H), 7.35 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[O:30][N:29]=1.CC#N>CCOC(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[N:4]([CH2:27][C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=3)[O:30][N:29]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1C(F)(F)F
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(cc(C(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 75 °C
Reaction time: 18 h
Yield: 61.7 %

Procedure:
A mixture of 2,4-bis(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.18 mmol), Cs2CO3 (0.064 g, 0.20 mmol.), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.052 g, 0.20 mmol.) and CH3CN (4 mL) was stirred at 75° C. for 18 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.056 g, 62%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J=8.8 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H) 8.23 (s, 1H), 8.09-8.06 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.48 (s, 1H), 6.03 (s, 2H); MS m/z 527 (M+Na).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:22][C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24]>C(Cl)(Cl)Cl>[C:19]([C:16]1[S:15][C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([N:1]3[CH2:6][CH2:5][N:4]([CH2:22][C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH2:3][CH2:2]3)[CH:8]=2)=[N:18][CH:17]=1)#[N:20]
Reactant: O=C(CBr)NC1CC1
Reactant: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1
Solvent: ClC(Cl)Cl
Product: N#Cc1cnc(Nc2cc(N3CCN(CC(=O)NC4CC4)CC3)ncn2)s1
Temperature: 100 °C

Procedure:
12-3 (0.2 g, 0.39 mmol) and 2-bromo-N-cyclopropylacetamide 38-1 (0.069 g, 0.39 mmol) were suspended in chloroform/2M Na2CO3 in a sealed tube and heated in a Smith Personal Chemistry microwave reactor at 100° C. for 20 minutes. The solid was then filtered off and purified on a silica column to afford 38-2. Hi-Res MS: calc: 385.1554 found: 385.1548. 1H-NMR (CD3OD): 8.39(s, 1H); 7.99(s, 1H); 6.14(s, 1H); 3.68(m, 4H); 3.05(s, 2H); 2.70(m, 1H); 2.58(m, 4H); 0.75(m, 2H); 0.55(m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=N)[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.C(=O)(O)[O-:23]>Cl>[CH3:1][C:2]1([CH3:21])[C:6](=[O:23])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=N
Reactant: O=C([O-])O
Agent: Cl
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Yield: 95 %

Procedure:
A suspension of the compound 10a in 6N HCl (25 mL) was refluxed for 35 min. The cooled solution was poured in a 10% bicarbonate solution, extracted using ethyl acetate (3×25 mL). The organic layer was washed with brine, and finally dried over magnesium sulphate to give of desired compound 11a (950 mg, 95%) which was used as such in the next step. 1H NMR (300 MHz, Acetone-d6) δ: 1.54 (s, 6H), 7.81 (broad s, 1H), 8.17 (m, 2H), 8.26 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:3]=1.CC1(C)C(C)(C)OB([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+].[Cl-]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cc(Cl)cc(-c2cccc(Cl)c2)n1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Temperature: 25 °C

Procedure:
A 20-mL sealed tube, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyridine (0.263 g, 0.90 mol), methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.261 g, 0.90 mmol), Pd(dppf)Cl2 (0.073 g, 0.09 mmol), and powdered Na2CO3 (0.286 g, 2.70 mmol). Dioxane (8 mL) and water (4 mL) were added. The resulting mixture was stirred under Ar at 90° C. for 27 h. until the starting chloride was consumed. After cooling to room temperature, the reaction mixture was absorbed onto silica and purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford methyl 2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetate
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:29].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:29]
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Temperature: 80 °C

Procedure:
To a solution of 11 mg of 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone in 2.5 mL of CCl4 was added 12 mg of N-bromosuccinimide and 6 mg of 2,2′azobis(2-methylpropionitrile). The mixture was heated to 80° C. for 1.5 h, then concentrated and purified by preparative thin-layer chromatography, eluting with 1:1 hexanes-EtOAc, to yield 1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-7-methoxy-2(1H)-quinolinone. Mass spectrum (ESI) 432.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.56 (m, 3H); 7.44 (m, 1H); 7.37 (m, 1H); 7.02 (m, 2H); 6.76 (s, 1H); 6.58 (d, J=10 Hz, 1H); 6.01 (s, 1H); 3.73 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:36]([O:35][C:33](=[O:34])[C:32]1[CH:38]=[CH:39][C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:30][CH:31]=1)[CH3:37]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
To the solution of 0.3 g (0.77 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 3 mL tetrahydrofuran, 0.13 g (0.84 mmol) ethyl 4-hydroxybenzoate and 0.22 g (084 mmol) triphenylphosphine were added. The solution was cooled to 0° C., 0.15 g (0.84 mmol) diethyl azodicarboxylate dissolved in 2 mL tetrahydrofuran were added dropwise and the reaction stirred at room temperature for 18 h. The reaction was adsorbed on silica gel and purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 100:40 v/v) to yield the title compound as a white foam (55%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: OCCC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCC(CCO)CC2)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To an ice-cold solution of 3,4-dimethoxyphenylacetic acid (7.60 g, 38.7 mmol), N,N-dimethylaminopyridine (DMAP; 11.4 g, 93 mmol), and 4-piperidin-ethanol (5 g, 39 mmol) in dry dichloromethane (DCM; 80 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC.HCl; 9.65 g, 50.3 mmol) in one portion. The cooling bath was removed and the reaction was allowed to warm to room temperature. After five hours, HPLC analysis revealed the 3,4-dimethoxyphenylacetic acid was consumed. The reaction mixture was washed once with 1 N HCl(aq) (90 mL) and concentrated in vacuo. The residue was chromatographed to yield the title compound (A; 10.67 g, 90% yield) as viscous oil.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3](O)[OH:4].S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].Cl.NO>O>[CH3:2][C:3]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([Cl:15])[CH:17]=1)=[O:4]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Agent: NO
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(=O)Nc1cccc(Cl)c1

Procedure:
To a stirred solution of 113.23 g (0.686 mol) of chloral hydrate in 2 liters of water was added 419 g (2.95 mol) of sodium sulfate, followed by a solution prepared from 89.25 g (0.70 mol) of 3-chloroaniline, 62 ml of concentrated hydrochloric acid and 500 ml of water. A thick precipitate formed. To the reaction mixture was then added, with stirring, a solution of 155 g (2.23 mol) of hydroxylamine in 500 ml of water. Stirring was continued and the reaction mixture was warmed slowly and it was maintained between 60° and 75° C. for approximately 6 hours, during which time an additional 1 liter of water had been added to facilitate stirring. The reaction mixture was then cooled and the precipitate was recovered by filtration. The wet solid was dried to give 136.1 g of isonitroso-3-chloroacetanilide.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)=[C:8]([S:20][CH2:21][CH3:22])[CH:7]=[C:6]([CH3:23])[N:5]=1)[CH3:2].C(N(CC)CC)C.[CH2:31]([NH:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][OH:49])[CH2:43][CH2:42]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1.O>[CH2:1]([S:3][C:4]1[C:9]([NH:10][C:11](=[O:19])[N:38]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][OH:49])[CH2:43][CH2:42]2)=[C:8]([S:20][CH2:21][CH3:22])[CH:7]=[C:6]([CH3:23])[N:5]=1)[CH3:2]
Reactant: CCCCCCCNCCN1CCN(CCO)CC1
Reactant: CCSc1cc(C)nc(SCC)c1NC(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCN(CCN1CCN(CCO)CC1)C(=O)Nc1c(SCC)cc(C)nc1SCC
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of this phenyl carbamate (1.46 g, 4.19 mmol) in toluene (20 ml) were added triethylamine (509 mg, 5.03 mmol) and 2-[4-(2-heptylaminoethyl)piperazin-1-yl]ethanol (1.14 g, 4.20 mmol) obtained in Example 16 and the mixture was stirred at 80° C. for 2 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 100 g, developing solvent; chloroform:methanol=40:1 20:1) to provide 1.95 g (yield 88%) of N′-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]-N-heptyl-N-[2-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl]urea as pale yellow oil.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@@:10]3([O:23][CH3:24])[C@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4.C(=O)(O)[O-].[Na+].[CH2:30](Br)[CH:31]1[O:35][CH2:34][CH2:33][CH2:32]1.Cl>CN(C)C=O>[ClH:1].[CH2:30]([N:20]1[CH2:19][CH2:18][C@@:15]23[C:16]4[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=4[CH2:8][C@@H:9]1[C@:10]2([O:23][CH3:24])[C@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]3)[CH:31]1[O:35][CH2:34][CH2:33][CH2:32]1
Reactant: BrCC1CCCO1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CCCO4)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Temperature: 110 °C

Procedure:
A mixture of 3,14-dimethoxy-8α-methylmorphinan-6-one hydrochloride (26) (0.24 g, 0.68 mmol), sodium bicarbonate (0.6 g, 7.14 mmol), (+) tetrahydrofurfuryl bromide (0.4 g, 2.42 mmol) and dimethylformamide (15 ml) was heated at 110° C. for 16 hours with stirring under a nitrogen atmosphere. The mixture was filtered hot and the residue washed with 10 milliliters of dimethylformamide. Most of the DMF was removed by distillation under high vacuum (bath temperature 35° C.) and the resulting brownish material was treated with CHCl3 (50 ml) and water (25 ml). After separation of the two layers, the aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×25 ml). The organic extracts were combined, dried (MgSO4) and filtered. The filtrate was concentrated to an oily solid which was chromatographed over silica gel to give a mixture of R and S isomers of the product; yield 0.181 g (66.5% theory). A portion of the free base was converted to the HCl salt by treatment with ethereal HCl to form the title compound as a tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([SH:18])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([S:18][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:14][CH2:13]2)=[O:11])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(S)CC1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)CSC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 1-p-nitrobenzyloxycarbonyl-4-mercaptopiperidine (1.19 g), t-butyl bromoacetate (780 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (608 mg) in benzene (10 ml) was stirred for 5 minutes under nitrogen atmosphere. The reaction mixture was washed successively with water, dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to give 1-p-nitrobenzyloxycarbonyl-4-t-butoxycarbonylmethylthiopiperidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:45]>>[ClH:45].[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:23])[C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=4)[C:4]=23)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccc(C(F)(F)F)c4)c23)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccc(C(F)(F)F)c4)c23)C1
Yield: 91 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(3-(trifluoromethyl)benzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.258 mmol) was treated with TFA (1 mL) followed by 1M HCl as described in Example 62, Step C, to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethyl)benzamide hydrochloride (0.130 g, 91% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.24 (s, 1H), 8.12 (s, 1H), 8.05-8.04 (d, 1H), 7.88-7.86 (d, 1H), 7.66-7.62 (m, 1H), 7.42 (s, 1H), 3.63-3.60 (m, 1H), 3.36-3.32 (m, 1H), 3.22-3.17 (m, 2H), 3.13-3.08 (m, 1H), 1.84-1.81 (m, 1H), 1.65-1.61 (m, 1H), 1.45-1.42 (m, 1H), 1.34-1.31 (m, 1H); LCMS (APCI+) m/z 482, 484 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([N:11]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[N:13][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:10]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(-c2n[nH]c(-c3ccccc3C)n2)c1
Product: COc1cccc(-c2nc(-c3ccccc3C)n(C(C)=O)n2)c1
Reaction time: 8 h

Procedure:
A solution of 0.8 g (0.003 mole) of 3-(3-methoxyphenyl)-5-(2-methylphenyl)-1H-1,2,4-triazole and 3 ml (0.00317 mole) of acetic anhydride was heated for two hours on a hot water bath. After evaporating the excess of anhydride by distillation under vacuum, the obtained residue was taken up with a mixture of diisopropyl ether and light petroleum. After standing overnight, a precipitate formed which was recovered by filtration. Yield: 0.72 g (78%) of the title compound M.p. 107°-110° C. Δδ=-0.26.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[C:20](=[O:21])[C@H:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[NH:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:45])[N:35]([CH2:36][C:37](Cl)=[O:38])[C:34](=[O:40])[C:33]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:32]12.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:20](=[O:21])[C@H:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[N:17]([C:37](=[O:38])[CH2:36][N:35]3[C:34](=[O:40])[C:33]4=[CH:41][CH:42]=[CH:43][CH:44]=[C:32]4[C:31]3=[O:45])[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)=[CH:29][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccc(OCc3ccccc3)cc2)C(=O)[C@H]2CCC[C@H]21
Yield: 41.6 %

Procedure:
To a solution of (3aR*,10aS*)-9-(4-benzyloxybenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b ]cyclopenta[e][1,4]diazepin-10(1H)-one (3.1 g, 7.8 mmol) in 1,2-dichloroethane was added phthalimidoacetyl chloride (1.9 g, 8.5 mmol). The mixture was refluxed for 17 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was parified by silica-gel column chromatography (hexane-ethyl acetate 1:3), which was crystallized from diethyl ether to give the desired product (1.9 g, 42%), m.p.179°-181° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:8]3[C:7]([OH:22])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)=[CH:20][CH:19]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(Cl)cc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccc(Cl)cc3)sc2c1O
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (58 mg, 0.17 mmol) and glycine (259 mg, 3.45 mmol) in 0.5 M sodium methoxide/methanol (6.6 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. Water (20 mL) was added and the mixture was extracted with dichloromethane. The remaining aqueous layer was acidified to pH=2 with 1N HCl. The suspension was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (11 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.44 (br s, 1H), 8.90 (s, 1H), 8.16 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.6 Hz, 2H), 4.02 (d, 2H); MS: (+) m/z 364.0 (M+1)