Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.CO.C(OC([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:22]([CH2:23][CH2:24][O:25][CH2:26][CH3:27])[C:21]3[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)=O)C.O.NN.[OH-].[K+]>C(O)CO.O>[CH2:26]([O:25][CH2:24][CH2:23][N:22]1[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[N:19]=[C:18]1[N:14]1[CH2:15][CH2:16][CH2:17][NH:11][CH2:12][CH2:13]1)[CH3:27]
Reactant: CCOCCn1c(N2CCCN(C(=O)OCC)CC2)nc2ccccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Solvent: CO
Product: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reaction time: 5 h

Procedure:
Combine 1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.79 g, 5.9 mmol) and ethyl chloroformate (0.75 mL, 7.8 mmol) in toluene (20 mL). Heat to 80° C. After 2 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.87 (silica gel, dichloromethane/methanol, 90/10). Combine 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (17.2 g, 47.6 mmol), hydrazine hydrate (40 mL), and potassium hydroxide (40.7 g, 725 mmol) in ethylene glycol (150 mL). Heat to reflux. After 5 hours, cool the reaction mixture and dilute with water (500 mL). Extract three times with dichloromethane. Combine the dichloromethane layers and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf =0.25 (silica gel, dichloromethane/methanol, 90/10).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:18])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][N:13]=[C:12]([Cl:17])[CH:11]=2)(=O)=O.[F:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:23]=1[NH2:24].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>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>[Cl:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([C:26]3[C:27]([CH3:29])=[CH:28][C:22]([F:21])=[C:23]([CH:25]=3)[NH2:24])[C:8]([CH3:18])=[N:9]2)=[CH:14][N:13]=1
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc2cc(Cl)ncc2cc1OS(=O)(=O)C(F)(F)F
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
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(N)cc1-c1cc2cnc(Cl)cc2nc1C
Temperature: 60 °C
Yield: 61.4 %

Procedure:
Sparge a mixture of 7-chloro-2-methyl-1,6-naphthyridin-3-yl trifluoromethanesulfonate (2.250 g, 6.89 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.729 g, 6.89 mmol) in dioxane (32 mL) with argon, add a solution of K2CO3 (2.86 g, 20.66 mmol) in H2O (16 mL) followed by Pd(PPh3)4 (252 mg, 0.689 mmol) and heat at 60° C. for 1 h. Cool to RT, add EtOAc, wash successively with H2O, satd. NaHCO3, then brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (1.277 g, 61%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (d, J=0.8 Hz, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.00 (d, J=12.4 Hz, 1H), 6.59 (d, J=9.3 Hz, 1H), 5.08 (s, 2H), 2.42 (s, 3H), 1.85 (s, 3H); MS (ESI) m/z: 302.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:19][N:20]([CH3:36])[C:21]([CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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.[Pd].[Pd].C1(C)C=CC=CC=1>[C:13]([O:12][C:11]([NH:10][C:4]1[C:3]([Cl:18])=[C:2]([N:27]2[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH:23]([C:21](=[O:22])[N:20]([CH3:36])[CH3:19])[CH2:28]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C)C(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C1CN(c2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)CCN1C(=O)OC(C)(C)C
Temperature: 105 °C
Yield: 35.2 %

Procedure:
Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (834 mg, 2.52 mmol), tert-butyl 2-(dimethylcarbamoyl)piperazine-1-carboxylate (647 mg, 2.52 mmol), Pd2(dba)3 (230 mg, 0.252 mmol), BINAP (157 mg, 0.252 mmol), Cs2CO3 (1229 mg, 3.77 mmol), and toluene (20 mL) were combined in a 250 ml flask. The flask was evacuated and backfilled with N2 3×, and the reaction was heated at 105° C. for 12 h. LCMS indicated SM was still present, so an additional 0.1 eq. each of catalyst and ligand were added, and the reaction was again purged with N2 and heated at 105° C. for 13 h. An additional 0.1 eq. each of catalyst and ligand were added, and the reaction was again purged with N2 and heated at 105° C. for 2 h. The reaction was cooled to room temperature and diluted with EtOAc. The solution was filtered through celite and the filtrate concentrated in vacuo. The crude material was purified by flash column chromatography (0-50% EtOAc/Hex; 120 g column). Tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate (450 mg) was obtained as an orange glass.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]([C:27]([Cl:29])=[O:28])[CH2:19]1>C(N(CC)CC)C>[ClH:29].[ClH:1].[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:27]([CH:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18](=[O:17])[CH2:19]2)=[O:28])[CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1
Reactant: O=C1CC(C(=O)Cl)c2ccccc21
Reactant: CN1CCNC(CN2CCCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CC(=O)c3ccccc32)C(CN2CCCC2)C1
Yield: 31.9 %

Procedure:
The procedure described in Example 24 was repeated, but using 3.21 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 6.9 ml of triethylamine and 4.5 g of 3-oxoindan-1-carbonyl chloride, to afford 1.45 g of the title compound, melting at 252°-255° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(F)c(CO)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-fluoro-5-nitro-benzaldehyde (1000 mg, 5.91 mmoles) in MeOH (10 mL) was added NaBH4 (182 mg, 4.82 mmoles). The reaction mixture was stirred for 3 h at 0° C. The reaction mixture was acidified with HCl 1M until pH4, concentrated. 50 mL of water was added and the compound was extracted with Et2O. The organic layer was dried over MgSO4, filtered, evaporated. Expected compound was obtained as a pale yellow solid (1007 mg, 99% yield). mp=62-64° C. 1H NMR (300 MHz, CDCl3) δ8.43; (dd, 6-CH, J=6.2 Hz and 2.9 Hz, 1H), 8.19; (ddd, J=9 Hz, 4.5 Hz and 2.9 Hz, 1H), 7.20; (dd, J=9.0 Hz and 9.0 Hz, 1H), 4.85; (d, J=3.6 Hz, 2H), 2.12; (s large, 1H). 13C NMR (75 MHz, CDCl3) δ125.0; (CH, d, J=10.0 Hz), 124.7; (CH, d, J=6.9 Hz), 116.2; (CH, d, J=23.6 Hz), 58.2; (CH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[C:15]([Si:19]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(O)ccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-fluoro-3-methylphenol (15 g, 0.12 mol) and imidazole (18 g, 0.26 mol) in N,N-dimethylformamide (100 mL) was added tert-butyl(chloro)dimethylsilane (20 g, 0.13 mol) at 0° C. The reaction mixture was stirred at room temperature for 20 h, and quenched by the addition of water. The aqueous layer was extracted with diethyl ether (400 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, and evaporated to afford 30 g (quant.) of the title compound as a yellow oil:
Reaction SMILES: O.[O:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][C:4]1=2>[Pd].COCCOCCOC.ClCCl>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:13][OH:14]
Reactant: O=C1CCCc2c1ccn2CCO
Agent: [Pd]
Solvent: COCCOCCOC
Solvent: O
Solvent: ClCCl
Product: OCCn1ccc2c(O)cccc21
Temperature: 162 °C
Yield: 44.5 %

Procedure:
15 g of palladium on carbon at 5% by weight and containing 50% of water were added to a solution of 25 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(β-hydroxyethyl)indole, obtained in the preceding stage, in 300 cm3 of diglyme. The temperature of the mixture was raised and maintained at 162° C. for 10 hours. The mixture was then allowed to return to a temperature of 40° C. and then the catalyst was filtered off. The solvents were then removed under vacuum until 21.4 g of crude product were obtained which were taken up in a mixture of 30 cm3 of dichloromethane and 200 cm3 of petroleum ether. The crystals obtained were drained, washed with petroleum ether and then dried under vacuum over phosphorus pentoxide. 11 g of 4-hydroxy-1-N-(β-hydroxyethyl)indole were obtained whose elemental analysis, calculated for C10H11NO2, was:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=1)[CH3:2].[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][NH:30][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=1)[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CCOc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: CCOc1cc(CNCCc2ccccc2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 99 %

Procedure:
The compound of example 224 step 1 was reductively aminated with phenethylamine using procedures similarly to those previously described to afford the title compound in 99% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1.F[C:16]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:17]=1[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:16]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:17]=2[CH:18]=[O:19])[CH:6]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)Cc1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 65 °C
Yield: 23.5 %

Procedure:
(3-Hydroxy-4-methoxy-phenyl)-acetic acid methyl ester (1 g, 5.2 mmol), 2-fluoro-5-(trifluoromethyl)benzaldehyde (1 g, 5.2 mmol), and potassium carbonate (1.3 g, 10.4 mmol) were combined in THF (10 mL) and heated to 65° C. for 8 hours. After working-up the mixture with H2O and EtOAc, the crude material was purified by silica gel chromatography to give the desired product as a white solid (0.45 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>CN(C=O)C.O>[CH2:17]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
To a solution of 4-cyanophenol (1.2 g, 10 mmol) in dry DMF (20 mL) was added triethylamine (20 mmol) followed by i-butyl bromide (2.7 g, 20 mmol). The resulting reaction mixture was stirred at 100° C. for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed with 4 M KOH (3×30 mL) and then with water, dried over Na2SO4 and concentrated under vacuum to provide 1.5 g (85%) 4-iso-butoxybenzo-nitrile that was used for the next step without further purification. 1H NMR (DMSO-D6): δ 0.95 (d, 6H, 2CH3), 2.0 (m, 1H, CH(CH3)2), 3.8 (d, 2H, CH2), 7.4 (AA′BB′, Δ=20 Hz, 4H, Ar).
Reaction SMILES: C(O)C.[Na].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](=[NH:15])[NH2:14])[CH:9]=[CH:10][CH:11]=1.[CH2:16]([N:23]1[CH2:29][CH2:28][C:27](=O)[CH:26]([C:31](OCC)=[O:32])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([N:23]1[CH2:24][CH2:25][C:26]2[C:31](=[O:32])[NH:15][C:13]([CH2:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[CH:7]=3)=[N:14][C:27]=2[CH2:28][CH2:29]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N=C(N)Cc1cccc(Cl)c1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CCC1=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1CCN(Cc1ccccc1)CC2
Yield: 33 %

Procedure:
Ethanol (30 ml) was cooled in an ice bath then sodium (160 mg, 6.70 mmol) was added, with vigorous stirring. Once the sodium was dissolved, 2-(3-chlorophenyl)ethanimidamide (474 mg, 2.81 mmol) and ethyl 1-benzyl-5-oxoazepane-4-carboxylate (876 mg, 2.81 mmol) was added. The reaction mixture was refluxed, under nitrogen, for 17 h. Water (2 ml) was added to quench the reaction then the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. Trituration of the residue with diethyl ether afforded the title compound as a solid in 33% yield, 361 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]([CH3:38])[C:21]1=[O:39])=[O:18])[CH3:16]>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[C:26](=[O:27])[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]([CH3:38])[C:21]2=[O:39])=[O:18])[CH3:16])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(C)c2ccccc2N(c2ccccc2)C1=O
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure D above using 3,5-difluoromandelic acid (Fluorochem) and 3-(L-alaninyl)amino-2,4-dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (Example 8-N), the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (30:70).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Sn](CCCC)(CCCC)CCCC)[CH:16]=1>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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[C:15]([CH3:14])[CH:20]=[CH:19][N:18]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Reactant: Cc1c(Cl)nc2cnccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccnc(-c2nc3cnccc3c(Cl)c2C)c1

Procedure:
Prepared according to procedure E using 2,4-dichloro-3-methyl-1,7-naphthyridine (100 mg, 0.469 mmol), 4-methyl-2-(tributylstannyl)pyridine (215 mg, 0.563 mmol) and Pd(PPh3)4 (54.2 mg, 0.047 mmol). After purification 4-chloro-3-methyl-2-(4-methylpyridin-2-yl)-1,7-naphthyridine was obtained as a white solid. Mass Spectrum (ESI) m/e=270.0 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=2)=[O:30])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CN1C(=O)[C@H](NC(=O)Nc2cccc(Cl)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 178°-180° C.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[C@@H:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:20]([O:19][C:17]([C@H:4]1[CH2:3][C:2](=[O:1])[O:6][C@@H:5]1[C:7]([OH:9])=[O:8])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)O
Yield: 95.4 %

Procedure:
6.4 g of 2-benzyl 3-tert-butyl (2S,3S)-5-oxotetrahydrofuran-2,3-dicarboxylate in 80 ml of ethyl acetate was catalytically reduced with 640 mg of a 10% palladium-carbon catalyst at room temperature at atmospheric pressure of hydrogen for 3 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness to give 4.39 g of the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2C(O)=O)[CH:6]=1)([O:3][CH3:4])=[O:2].C(Cl)(=O)C(Cl)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][CH2:14]2)[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=CC2CC[C@H]3[C@@H]4CC[C@H](C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C1=CC2CC[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 1 h

Procedure:
3-Carbomethoxy-3-androstene-17β-carboxylic acid, (360 mg, 0.78 mmol) was suspended in 10 ml of dry toluene and treated with 0.4 ml of oxalyl chloride for 2 hours under argon. The reaction mixture was then evaporated (1 mm Hg) and the residue was dissolved in 10 ml dry THF. A solution of 0.6 ml diisopropylamine in 2 ml dry THF was added and the reaction mixture stirred for 1 hour. The mixture was diluted with ice water and extracted with dichlorome thane. The organic layer was then washed twice with cold 5% hydrochloric acid, sodium hydroxide and brine; dried over sodium sulfate and evaporated. Chromatography on silica gel eluting with 20% ethyl acetate in hexane followed by recrystallization from diethyl ether afforded 3-carbomethoxy-3-androstene 178 N,N -diisopropylcarboxamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](CC(O)=O)=[CH:2]1.SCC1N=CC=C[C:13]=1[C:14]([OH:16])=[O:15]>>[S:1]1[CH:2]=[CH:3][CH:4]=[C:5]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)Cc1ccsc1
Reactant: O=C(O)c1cccnc1CS
Product: O=C(O)Cc1cccs1

Procedure:
3-thienylacetic acid; 1- or 2-furylacetic acid; 2-, 3- or 4-pyridylacetic acid; 2-mercaptomethylnicotinic acid;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[N:3]=1.S(=O)(=O)(O)[OH:21]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[N:3]=1
Reactant: COC(=O)c1cccc(C#Cc2cccc(Br)n2)c1
Reactant: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(=O)Cc2cccc(Br)n2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5.2 g of 2-bromo-6-[2-(3-methoxycarbonylphenyl)-ethinyl]-pyridine in 30 ml of 60% sulfuric acid is heated to 140° C. with stirring for 1.5 hours. After cooling to room temperature, the reaction mixture is poured on ice water, the precipitate is suctioned off, and washed neutral with water. After drying at 50° C. in a vacuum, the crude product is dissolved in 35 ml of methanol, mixed with 3 drops of concentrated sulfuric acid and refluxed for 8 hours. Then, the reaction mixture is concentrated by evaporation, distributed between water and ethyl acetate, the organic phase is washed with 10% sodium bicarbonate and water, dried on sodium sulfate and concentrated by evaporation. 3.5 g of 2-bromo-6-[(3-methoxycarbonylbenzoyl)-methyl]-pyridine of melting point 84°-86° C. is obtained.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]12([C:18]([NH:20][NH2:21])=[O:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:21][NH:20][C:18]([C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:19])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: NNC(=O)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)NNC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Valeryl chloride (E) (0.981 mL, 8.1 mmol) was added dropwise to a solution of adamantane-1-carbohydrazide (F) (1.5 g, 7.72 mmol) and triethylamine (1.18 mL, 8.49 mmol) in methylene chloride (30 mL) at room temperature, and the mixture stirred at room temperature for 3.5 h. A solution of 10% NaHCO3 (15 mL) was added and the mixture stirred rapidly for 1.5 h. The mixture was extracted with methylene chloride (3×) and the combined extracts washed with water, dried (MgSO4) and concentrated in vacuo to give N′-pentanoyladamantane-1-carbohydrazide (G). 1H NMR (CDCl3): δ 0.94 (t, 3H); 1.38 (m, 2H); 1.75 (m, 8H); 1.93 (d, 6H); 2.08 (s, 3H); 2.29 (t, 2H); 8.47 (d, 1H); 8.7 (d, 1H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:21])=[O:20])=[C:15]2[S:22]([N:25]1[CH2:30][CH2:29][O:28][C@H:27]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26]1)(=[O:24])=[O:23]>>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:21])=[O:20])=[C:15]2[S:22]([N:25]1[CH2:30][CH2:29][O:28][C@H:27]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26]1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCO[C@H](COc2ccccc2)C1
Reactant: O=Cc1ccccc1
Product: NC(=O)c1[nH]c2c(NCc3ccccc3)cccc2c1S(=O)(=O)N1CCO[C@H](COc2ccccc2)C1

Procedure:
Using the method described in Example 85, replacing 4-formylpyridine with benzaldehyde, 7-Amino-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide was converted to the titled product. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C27H29N4O5S (M+H+): 521.1853. Found 521.1856.