Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].C(N(C(C)C)CC)(C)C.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH2:40][NH2:41])[CH:37]=[CH:38][CH:39]=1>ClCCl>[O:1]=[C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([NH:41][CH2:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:42])[F:43])[CH:35]=1)=[O:21]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.051 g, 0.173 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.072 g, 0.190 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.045 mL, 0.259 mmol) followed by (3-(trifluoromethyl)phenyl)methanamine (0.030 mL, 0.207 mmol). After stirring overnight, the reaction was loaded onto a silica gel column (SF15-12, Analogix®, Burlington, Wis.), and the title compound was eluted with a gradient of 0.4% to 4.5% methanol/dichloromethane over 20 minutes with a flow rate of 30 mL/minute. 1H NMR (300 MHz, CDCl3) δ ppm 7.50-7.55 (m, 1H), 7.37-7.44 (m, 2H), 7.17-7.34 (m, 11H), 6.30 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 4.07 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H); MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=3[N:6]=[C:5]2[C:15]2[CH:16]=[C:17]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[N:19][CH:20]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:28]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=3[N:6]=[C:5]2[C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]([O:24][CH3:28])([CH3:22])[CH3:23])[CH:16]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)c1cncc(-c2nc3cc(F)c(F)cc3n2C2CC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(C)(C)c1cncc(-c2nc3cc(F)c(F)cc3n2C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 2-[5-(1-Cyclopropyl-5,6-difluoro-1H-benzimidazol-2-yl)pyridin-3-yl]propan-2-ol (from Example 38 Step E) (0.086 g, 0.26 mmol) in tetrahydrofuran (1.3 mL) was added sodium hydride (60% dispersion in mineral oil, 0.026 g, 0.65 mmol). After 1 hour, iodomethane (0.024 mL, 0.389 mmol) was added. The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 344.03 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (d, J=1.9 H, 1 H), 8.79 (d, J=2.0 Hz, 1 H), 8.29 (t, J=2.0, 2.0 Hz, 1 H), 7.58 (dd, J=10.3, 7.3 Hz, 1 H), 7.40 (dd, J=9.7, 7.1 Hz, 1 H), 3.59-3.57 (m, 1 H), 3.16 (s, 3 H), 1.63 (s, 3 H), 1.60 (s, 3 H), 1.20-1.17 (m, 2 H), 0.79-0.76 (m, 2 H).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:25](C)[C:26](=O)OC(C)(C)C)[S:14]2)[C@@H:10]1[F:34])C1C=CC=CC=1.[Si](C(F)(F)F)(C)(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[F:34][C@H:10]1[C@H:11]2[N:12]=[C:13]([NH:25][CH3:26])[S:14][C@H:15]2[O:16][C@H:17]([C@@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[C@H:9]1[OH:8]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](OCc3ccccc3)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1
Agent: C[Si](C)(C)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC1=N[C@@H]2[C@H](F)[C@H](O)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (minor isomer from the TMSCF3 addition step) (0.136 g, 0.277 mmol) and PMB (0.10 g, 0.68 mmol) in dry DCM (5 mL) at −78° C. under N2, was added BCl3 (1.0 M in DCM, 2.0 mL, 2.0 mmol). The mixture was stirred for ˜4 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:13), affording (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.081 g, 92%). 1H NMR (600 MHz, CD3OD) δ 6.34 (d, J=6.7 Hz, 1H), 4.84 (ddd, J=3.5, 5.0, 46.3 Hz, 1H), 4.63-4.60 (m, 1H), 4.36-4.33 (m, 1H), 3.75 (d, J=6.9 Hz), 2.88 (s, 3H), 1.35 (s, 3H); 13C NMR (150.9 MHz, CD3OD) δ 165.25, 127.26 (q, J=287.0 Hz), 90.46 (d, J=9.1 Hz), 89.55 (d, J=186.4 Hz), 79.12 (d, J=4.0 Hz), 75.77 (q, J=27.3 Hz), 73.26 (d, J=16.6 Hz), 67.35 (d, J=16.9 Hz), 30.96, 18.72; MS, (ES, m/z) [M+H]+ 319.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:4]([CH2:3][NH:2][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[Cl:13])#[N:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N#CCN
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CCNC(=O)c1ccccc1Cl

Procedure:
To a stirred mixture of 9.3 g (0.1 mole) aminoacetonitrile hydrochloride and 20.2 g (0.2 moles) triethylamine in 200 ml chloroform, 17.5 g (0.1 mole) o-chlorobenzoyl chloride in 25 ml methylene chloride were dropped in over 30 minutes in a moderately exothermic addition. The reaction mixture was washed twice with 75 ml water. On the second washing, solids separated which were filtered and washed well with water. Beige solids were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH2:33][CH:32]([CH2:34][OH:35])[O:31][N:30]=2)=[N:27][CH:28]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:23]1[CH:28]=[N:27][C:26]([C:29]2[CH2:33][CH:32]([CH2:34][OH:35])[O:31][N:30]=2)=[CH:25][CH:24]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)nc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)nc2)c(F)c1
Temperature: 90 °C
Yield: 44.1 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (342 mg, 0.88 mM), {3-[5-(trimethylstannyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl}methanol (300 mg, 0.88 mM), tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct (91 mg, 0.088 mM, 0.1 equiv.) and tri-2-furylphosphine (41 mg, 0.176 mM, 0.2 equiv) were placed in a flask. The contents of the flask were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the mixture was heated at 90° C. for 5 hours and then cooled to room temperature. Solvent was evaporated under reduced pressure and the residue was purified by chromatography (silica gel; elution with 5% methanol in dichloromethane) to give the title compound (170 mg).
Reaction SMILES: [Cl-].[NH4+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH3:36])[C:17]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[N:30]=3)=[C:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)[C:12]=2[C:11]1=[O:37])=[O:9])([CH3:6])([CH3:5])[CH3:4].O>O1CCOCC1.[Zn]>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH3:36])[C:17]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[N:30]=3)=[C:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=3)[C:12]=2[C:11]1=[O:37])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: Cn1c2c(c(Cc3cccc([N+](=O)[O-])c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c2c(c(Cc3cccc(N)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Yield: 100 %

Procedure:
Zn (0.041 g, 0.632 mmol) and ammonium chloride (0.034 g, 1.58 mmol) were added to a solution of 2-(2-Amino-pyrimidin-4-yl)-1-methyl-3-(3-nitro-benzyl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.075 g, 0.158 mmol) was dissolved in dioxane (5 ml) and purite water (1.0 ml) and the reaction mixture was stirred at 75° C. for 2 hours. A solution of Na2HPO4 (10 ml) was then added and the water layer was extracted with EtOAc (3×10 ml). The organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure yielding 3-(3-Amino-benzyl)-2-(2-amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo-[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.071 g, 0.158 mmol, 100%).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:31][NH:30][C:29](=[O:32])[C:4]=2[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:4]2[C:29](=[O:32])[NH:30][CH2:31][C:3]=2[C:2]=1[F:1]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1
Yield: 59.8 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (15 mg, 0.034 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (0.5 mL) was stirred at RT for 30 min. The reaction mixture was concentrated and the resulting residue was purified by preparative HPLC to give a TFA salt of the title compound (7 mg, 60.2%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37-2.01 (m, 8H), 3.67 (br s, 1H), 3.89 (s, 3H), 4.32-4.43 (m, 2H), 4.45 (br s, 1H), 6.77 (d, J=6.35 Hz, 1H), 7.93 (br s, 3H), 8.30 (s, 1H), 8.36 (s, 1H), 8.84 (s, 1H). [M+H] calc'd for C17H21FN6O, 345. found, 345.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[OH:25]O.[OH-].[Na+]>CO.ClCCl.O>[O:25]1[C:11]23[C@:16]([CH3:17])([CH2:15][CH2:14][C:13](=[O:23])[CH:12]12)[C@@H:18]1[C@H:8]([C@H:7]2[C@:21]([CH3:22])([CH2:20][CH2:19]1)[C@@H:4]([C@H:3]([CH3:24])[CH2:2][OH:1])[CH2:5][CH2:6]2)[CH2:9][CH2:10]3
Reactant: OO
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one (12.8 mmole) in methanol (55 mL) and dichloromethane (11 mL) was cooled to 12° C. and treated in one portion with 30% aqueous hydrogen peroxide (3.3 mL) followed by dropwise addition of an aqueous sodium hydroxide solution prepared by dissolving sodium hydroxide (0.38 g) in water (2.2 mL). After one hour, the cooling bath was removed and the reaction was stirred for an additional 3 hours. Most of the solvent was then removed in vacuo. The residue was dissolved in dichloromethane and purified by flash chromatography (hexane-20% ethyl acetate and hexane-40% ethyl acetate) to give (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one (73.1%). This material was a mixture of the 4α,5α- and 4β,5β-isomers and it was used as is in further reactions.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C#N)=[C:4]([CH3:10])[CH:3]=1.C([O:15][CH:16]([N:20]([CH3:22])C)N(C)C)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:8][CH:9]=1)[C:16](=[O:15])[NH:20][CH:22]=[CH:10]2
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: O=c1[nH]ccc2cc(Br)ccc12
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2-methylbenzonitrile (26 g) dissolved in 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (47.9 mL) was stirred at 140° C. for 2 h (flask open to evaporate t-butanol). The reaction mixture was cooled to room temperature, diluted with water (600 mL), and extracted with ethyl acetate (500 mL). The aqueous was further extracted with ethyl acetate (250 mL), the combined organics were washed with water (500 mL), brine (150 mL), dried (MgSO4) filtered and evaporated. The residual oil was dissolved in ethanol (250 mL) at 80° C. and treated with 37% hydrochloric acid (250 mL) at such a rate as to maintain a solution. The reaction mixture was stirred at 110° C. for 3 h, cooled to room temperature, diluted with water (600 mL) and the resulting suspension stirred for 2 h and filtered. The filtered solid was slurried in diethyl ether (400 mL) for 2 h, filtered and dried to give the subtitle compound (26.4 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[N:26]3[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.Cl>CN1CCCC1=O.CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[N:26]4[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc([C@@H]2CC[C@@H]3CCCCN32)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: Clc1ccc(Sc2ccc([C@@H]3CC[C@@H]4CCCCN43)cc2)cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
A solution of 4.1 g (0.028 mole) of 4-chlorothiophenol in 40 mL of dry N-methylpyrrolidinone was added to 0.028 mole of sodium hydride (from 1.36 g of 50% sodium hydride washed free of oil with hexane) under an atmosphere of nitrogen. Then a solution of 5.3 (0.019 mole) of trans-3-(4-bromophenyl)octahydroindolizine in 50 mL of dry N-methylpyrrolidinone and 1.35 g of cuprous oxide was added to the mixture and the reaction mixture was refluxed overnight. Then the reaction was cooled to room temperature, MeOH was added, and the mixture was filtered. The solvent was evaporated in vacuo to a brown oil. The oil was flash chromatographed in SiO2 using 98% hexane, 2% acetone as the eluant. The product was collected in fractions 6 and 7, and evaporation of the solvent in vacuo gave an oil. The oil was treated with ethereal HCl to give a solid salt. The solid was recrystallized from acetonitrile to give 77 g (10% yield) of the title compound as a white solid, mp=198°-201° C.
Reaction SMILES: N[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[BrH:12].N([O-])=O.[Na+]>O.[Cu]Br>[Br:12][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1cccc(C)c1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cccc(C)c1Br
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a solution of 1-(2-amino-3-methylphenyl)ethanone (Helv. Chim. Acta; EN; 62, 1979, 271-303,) (850 mg, 5.7 mmol) in hydrobromic acid (9 ml, 5.7 mmol) and water (6 ml), at 0° C., was added aqueous sodium nitrite solution (503 mg, 7.3 mmol) and the mixture was stirred for 15 min. This mixture was added to copper (I) bromide (899 mg, 6.3 mmol) in hydrobromic acid (9 ml, 5.7 mmol) at 60° C. and the reaction mixture was heated at 95° C. for a further 30 min. After cooling, the mixture was poured into an ice/water slurry and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated in vacuo. To the residue was added ethyl acetate:cyclohexane [1:4] and the solution was filtered through silica. The filtrate was concentrated in vacuo to give the title compound (1.06 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCCCCCC1CCCCC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1C#CCCCCCCC1CCCCC1

Procedure:
To an ice cold solution of 1-hexyne (49.6 mmoles) in freshly distilled tetrahydrofuran (50 ml) containing a trace of triphenylmethane was added dropwise n-butyl lithium in hexane (49.5 mmoles). About 10 minutes after the addition was stopped, sieve dried hexamethylphosphoramide (57.5 mmoles) was added and the solution stirred for 10 minutes. A solution of 2-cyclohexylethyl bromide (51.3 mmoles) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred for about 3 hours as the temperature rose to room temperature. The mixture was taken up in ether (100 ml) and washed with water (3×100 ml) and sodium chloride solution (100 ml). The organic phase was dried over magnesium sulfate and evaporated to leave an oil which was purified by flash chromatography to give 1-cyclohexyloct-3-yne. This compound (20.8 mmoles) was treated with potassium hydride (36.8 mmoles) in propylene diamine to obtain the isomeric 8-cyclohexyloct-1-yne as an oil. A mixture of 2-bromobenzaldehyde (12.59 mmoles), 8-cyclohexyloct-1-yne (14.87 mmoles), cuprous iodide (0.17 mmoles) and bis(triphenylphosphine) palladium (II) chloride (0.26 mmoles) in triethylamine (35 ml) was refluxed under argon for 1.5 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The resulting residue was dissolved in ether (100 ml), washed with 3N hydrochloric acid (50 ml) and saturated sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulfate and charcoal. The solution was evaporated to afford an oil which was purified by flash chromatography (2% ether/hexane) to yield 2-(8-cyclohexyl-1-octynyl)benzaldehyde as an oil. This benzaldehyde (10.22 mmoles) was hydrogenated with 10% palladium on charcoal in ethyl acetate to give the desired product as an oil, after chromatography (3% ether/hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-])=O)=[CH:8][C:7]=1[N+:17]([O-])=O>ClCCl.CO.[Pd]>[CH3:1][O:2][C:3]([C:4]1[NH:17][C:7]2[C:6]([CH:5]=1)=[CH:11][C:10]([O:12][CH3:13])=[C:9]([NH2:14])[CH:8]=2)=[O:21]
Reactant: COC(=O)C(=O)Cc1cc(OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc2cc(OC)c(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(5-methoxy-2,4-dinitro-phenyl)-2-oxo-propionic acid methyl ester (about 100.0 g, 0.32 mol) in a mixture of dichloromethane and methanol (about 1.5 L), 10% Pd/C (about 30 g, 50% wet) is added at about 25° C. The reaction mixture is stirred under hydrogen atmosphere at a temperature of about 25° C. over a period of about 4 hours. The resulting reaction mixture is filtered through celite pad and concentrated under reduced pressure to yield the product [6-amino-5-methoxy-1H-indole-2-carboxylic acid methyl ester] as yellow color solid (about 59 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: N#Cc1ccc(CN([C@H]2CCCCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 3 %

Procedure:
The titled compound (6.4 mg) was prepared in 3% yield from cis-2-(4-chlorobenzenesulfonylamino)-cycloheptanecarboxylic acid amide (150 mg, 0.45 mmol) and 4-bromomethyl-benzonitrile according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.84 (m, 3 H), 7.69 (m, 4 H), 7.50 (d, 1 H, J=8.0 Hz), 7.31 (s br, 1 H), 6.65 (s br, 1 H), 4.60 (AB2,2 H,Δv=16,Jab=96 Hz), 3.93 (m, 1 H), 2.79 (m, 1 H), 2.24 (m, 1 H), 1.72 (m, 2 H), 1.31 (m, 7 H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][C:17]2[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S([O-])([O-])(=O)=O.[Mg+2]>>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[NH:15][CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:19][CH:18]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(C)(C)OC(=O)NCc1ccc(CNc2c(N)c(Cl)nc3ccccc23)cc1
Yield: 96.9 %

Procedure:
The method of Part B of Example 1 was used to hydrogenate tert-butyl 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}benzylcarbamate (20 g, 45 mmol) with the modification that magnesium sulfate was added to the mixture before filtration. tert-Butyl 4-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}benzylcarbamate (18 g) was isolated as a thick, orange-red oil.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:21][C:20]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=3)[NH:6][C:5]=2[CH:19]=1
Reactant: COC(=O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 50 °C
Yield: 91.5 %

Procedure:
A mixture of 5,6-dichloro-2-(4-methoxycarbonylphenyl)benzimidazole (2.4 g, 7.47 mmol), prepared as described in Preparation 7, 20% NaOH (7.5 ml, 37.5 mmol) in THF (25 ml) was heated at 50° C. for 1 h. After cooling at room temperature, solvent was removed under reduced pressure and pH was adjusted to 5 with acetic acid. The solid that was precipitated was filtered and dried at 50° C. to give 2.1 g of the title compound (yield 91.8%) as a brown solid, mp>250° C.