Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C@@H:15]([CH3:20])[CH2:14][C@H:13]2[NH:21][C:22](=[O:24])[CH3:23].N1C=CC=CC=1>ClCCl>[CH:5]([O:4][C:2]([N:16]1[C:17]2[C:12](=[N:11][C:10]([O:9][CH3:8])=[CH:19][CH:18]=2)[C@H:13]([NH:21][C:22](=[O:24])[CH3:23])[CH2:14][C@@H:15]1[CH3:20])=[O:3])([CH3:7])[CH3:6]
Reactant: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.7 %

Procedure:
Add isopropyl chloroformate (8.50 mL, 8.50 mmol) to a solution of (+/−)-cis-N-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide (0.404 g, 1.702 mmol), pyridine (1.370 mL, 17.02 mmol) in dichloromethane (10 mL) at 0° C. and slowly warm to room temperature. After 12 h, remove the solvent under reduced pressure. Purify the crude material using silica gel chromatography, eluting with ethyl acetate (neat), to afford the title compound (0.496 g, 91%). MS (ES+): 322 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.C([Li])CCC.[O:20]=[C:21]1[CH2:27][CH:26]2[CH2:28][CH:22]1[CH2:23][N:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25]2>C(OCC)C.C1COCC1>[OH:20][C:21]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=2)[CH2:27][CH:26]2[CH2:28][CH:22]1[CH2:23][N:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25]2
Reactant: Brc1cncc(Oc2ccccc2)c1
Reactant: CCOC(=O)N1CC2CC(=O)C(C2)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CC2CC(C1)C(O)(c1cncc(Oc3ccccc3)c1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of 3-bromo-5-phenoxypyridine (0.51 g, 2.0 mmol) in dry diethyl ether (15 mL) at −78° C. was added 2.5 M n-butyllithium (0.80 mL, 2.0 mmol). The reaction was stirred for 30 min under nitrogen at −78° C. and then slowly transferred by cannula into a solution of ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.20 g, 1.0 mmol) in THF (15 mL) at −78° C. The reaction was stirred 4 h at −78° C. and then warmed to ambient temperature overnight, at which time it was quenched with saturated aqueous ammonium chloride (20 mL). The mixture was then extracted with chloroform (2×10 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Excess pyridine was removed by repeated azeotropic rotary evaporation with toluene, and the residue was chromatographed on a silica gel column (with 5% methanol in chloroform) to yield the desired product (0.31 g, 84%).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[F:31][C:32]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CN(C=O)C>[F:31][C:32]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:33]=1[C:34]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:35]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(F)cc1F

Procedure:
1-(2,4-Difluorobenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 2,4-difluorobenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-])=O>O1CCCC1.[Pd]>[NH:15]1[C:6]2[C:5](=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]=2)[CH:4]=[CH:3]1
Reactant: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc[nH]c2c1
Yield: 85 %

Procedure:
A solution of methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (5.58 g) in tetrahydrofuran (100 ml) was hydrogenated at 3.45 bar in the presence of 10% (w/w) palladium on carbon (1.1 g) for 35 min. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the solution obtained was washed successively with 10% (v/v) hydrochloric acid, water, and brine; then dried (MgSO4) and evaporated to give methyl indole-6-carboxylate (3.32 g, 85%) as a white solid; NMR (80 MHz, CDCl3): 3.92(s, 3H, OCH3), 6.57(m, 1H, H3 -indole), 7.32(t, 1H, H2 -indole), 7.10(d, 1H, H4 -indole), 7.87(dd, 1H, H5 -indole), 8.16(broad s, 1H, H7 -indole).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH2:26][OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH2:26][O:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.16 ml of methanesulphonyl chloride followed by 3.86 ml of triethylamine are added to a solution of 5 g of (R)-3-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester in 80 ml of DCM cooled to 0° C. The medium is stirred at 0° C. for 1 h 30 min and 0.7 ml of triethylamine and 0.54 ml of methanesulphonyl chloride are again added. After 30 min at 0° C., the medium is hydrolysed, and the organic phase is washed twice in water and then with a saturated NaCl solution, and then dried over MgSO4. The medium is evaporated, to give 6.8 g of a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[N:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:9]1[C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=4[O:13][CH3:14])[N:4]=3)[CH2:21][CH2:20]1)=[N:4]2
Reactant: C1CNCCNC1
Reactant: COc1cc2nc(CCl)ccc2c(OC)c1OC
Product: COc1cc2nc(CN3CCCN(Cc4ccc5c(OC)c(OC)c(OC)cc5n4)CC3)ccc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxyquinoline (400 mg) and homopiperazine (765 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]1[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[N:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 6-fluoropyridin-3-ylboronic acid (0.284 g, 2.016 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 47 h to give 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=309.0 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]([CH2:24][CH2:25][CH3:26])=[C:22]([C:27]([OH:29])=O)[N:21]=[N:20]3)=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:34]1([NH:36][C:27]([C:22]2[N:21]=[N:20][N:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:12])=[CH:18][CH:17]=3)[C:23]=2[CH2:24][CH2:25][CH3:26])=[O:29])[CH2:35][CH2:33]1
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 182 %

Procedure:
1-(4-{[(3-Phenylpropyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (505 mg, 1.29 mmol) obtained in Example 60b), HOBt (87.8 mg, 0.643 mmol, 0.5 eq.) and cyclopropylamine (0.120 ml, 1.67 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (302 mg, 1.54 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (505 mg, 1.17 mmol, 90.7%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([SH:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)C(=O)C>[CH2:16]([S:28][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCS
Reactant: N#Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCCCCCCCCCSc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A suspension consisting of 75.66 g (0.55 mol) of 4-chlorobenzonitrile, 106.42 g (0.77 mol) of potassium carbonate and 111.32 g (0.55 mol) of 1-dodecanethiol is heated, with stirring, under an inert gas atmosphere in 280 ml of N,N-dimethylacetamide to 130° C. and is then stirred at this temperature for 24 hours. After cooling the reaction mixture to room temperature, it is poured on a mixture of 700 g of ice and 750 ml of water. The mixture is filtered and the filter cake is washed with water. The product is recrystallised from methanol and dried at 50° C. under vacuum, affording 160.2 g (96% of theory) of 4-(dodecyl-thio)benzonitrile.
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]2[CH2:7][CH:8]([OH:10])[CH2:9][C@H:3]1[CH2:4][CH2:5]2.Cl.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:16]([Cl:18])=[O:17].Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][C:20]1[CH:19]=[C:15]([C:16]([O:10][CH:8]2[CH2:9][C@H:3]3[N:2]([CH3:1])[C@H:6]([CH2:5][CH2:4]3)[CH2:7]2)=[O:17])[CH:14]=[C:13]([CH3:12])[CH:21]=1.[ClH:18]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CN1[C@@H]2CC[C@H]1CC(O)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C)cc(C(=O)OC2C[C@H]3CC[C@@H](C2)N3C)c1
Yield: 58.8 %

Procedure:
A stirred mixture of tropine hydrochloride (5.27 g) and 3,5-dimethylbenzoyl chloride (5 g) is heated at 130°-140° C. for 30 minutes during which time the mixture liquifies, evolves hydrogen chloride gas and resolidifies. A solution of the cooled solid in water is basified with a solution of potassium carbonate and the base extracted with ethyl acetate. The ethyl acetate solution is washed several times with water, dried over mangnesium sulphate, and evaporated to yield the free base which is converted to the hydrochloride by the addition of ethereal hydrogen chloride. Recrystallization of the precipitated solid from ethanol yields tropyl 3,5-dimethylbenzoate hydrochloride (5.4 g) m.p. 260° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[O:23]([C:25]#[N:26])[Na]>C(O)(=O)C.CCOC(C)=O>[CH2:20]1[O:21][C:16]2=[CH:15][C:14]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH2:26])=[O:23])=[CH:3][CH:4]=4)=[N:9][NH:10][C:11](=[O:22])[CH2:12][C:13]=3[CH:18]=[C:17]2[O:19]1
Reactant: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Reactant: N#CO[Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.8 %

Procedure:
To a solution of 1-(4-aminophenyl)-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (119 mg, 0.403 mmol) in acetic acid (2 mL) was added NaOCN (38 mg, 0.58 mmol) at room temperature. The mixture was stirred at room temperature for 4 h, diluted with EtOAc (80 mL), washed with 2 N NaOH, water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography to afford the title compound as a yellow solid (40 mg, 0.12 mmol, 30%), mp: 238°-241° C. 1H NMR (DMSO-d6) 10.79 (s, 1H), 8.77 (s, 1H), 7.47 (d, J=8.7, 2H), 7.40 (d, J=8.7, 2H), 7.07 (s, 1H), 6.61 (s, 1H), 6.10 (s, 2H), 5.95 (s, 2H), 3.33 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)CCC>>[C:35]1([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:20]2[CH:21]=[C:17]([C:2]3[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=3)[N:18]=[CH:19]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: COC(=O)c1ccnc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1

Procedure:
The title compound was prepared from methyl 2-chloropyridine-4-carboxylate and 4-(tributylstannyl)-1-tritylimidazole according to the procedure for Example 1. 1H NMR (400 MHz, DMSO-d6): δ 3.92 (3H, s), 7.16 (5H, m), 7.38-7.46 (11H, m), 7.60 (1H, d, J=1.3 Hz), 7.64 (1H, dd, J=1.6 Hz and 5.0 Hz), 8.32 (1H, s), 8.64 (1H, d, 5.0 Hz).
Reaction SMILES: [OH:1]O.[OH:3][CH:4]([CH2:14][Cl:15])[CH2:5][S:6][C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[Na+].[Cl-]>O.CO>[OH:3][CH:4]([CH2:14][Cl:15])[CH2:5][S:6]([C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:1]
Reactant: OC(CCl)CSc1ncc(Cl)cn1
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(CC(O)CCl)c1ncc(Cl)cn1
Yield: 59 %

Procedure:
A solution of 35% H2O2 (1.7 mmol) and SeO2 (1.7 mmol) in water (2.5 ml) was added to a solution of 2-(2-hydroxy-3-chloropropyl)thio-5-chloropyrimidine (1.7 mmol) in methanol (10 ml). The mixture was stirred at room temperature for 18 h before saturated NaCl aq. (40 ml) was added and the mixture extracted with chloroform (3×20 ml). The dried (MgSO4) chloroform solution was evaporated and the residue crystallized from ethyl acetate; yield 59%; m.p. 170° C. 1H NMR (DMSO-d6): δ3.0-4.4 (6H, m), 9.10 (H-4, H-6). IR (KBr): 3400 (OH), 1060-1070 cm-1 (SO).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
tert-Butyl 3-(4-nitrophenoxy)pyrrolidine-1-carboxylate (9.73 mmol, 3 g) was dissolved in dichloromethane (2.5 mL). Trifluoroacetic acid (1 mL) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction was purified by SCX chromatography to give the title compound (2.11 g). MS (ESI) m/z 209.0 [M+H]+
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:30][C:31]1[N:32]=[CH:33][O:34][C:35]=1[C:36](Cl)=[O:37]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36]([C:35]3[O:34][CH:33]=[N:32][C:31]=3[CH3:30])=[O:37])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cc1ncoc1C(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ncoc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.90 g, 5.9 mmol) in CH3CN (25 ml), were added triethyl amine (2.05 mL, 14.7 mmol) and 4-methyl-oxazole-5-carbonyl-chloride (0.85 g, 5.9 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL) to afford 4-methyl-oxazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (1.82 g, 78%): mp, 308-310° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.49 (98%); 1H NMR (DMSO-d6): δ 2.06-2.10 (m, 1H), 2.38 (s, 3H), 2.59-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.88 (d, J=5.9 Hz, 2H), 5.17 (dd, J=6, 12 Hz, 1H), 7.70-8.47 (m, 4H), 9.05 (t, J=5.9 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 12.52, 21.96, 30.92, 37.57, 48.86, 121.91, 127.09, 131.51, 133.01, 134.81, 138.86, 138.89, 140.67, 151.42, 157.96, 166.94, 167.51, 169.82, 172.74. Anal Calcd for C19H16N4O6: C, 57.58; H, 4.07; N, 14.14. Found: C, 57.48; H, 4.04; N, 14.33.
Reaction SMILES: I[C:2]1[CH2:7][NH:6][C:5]2[CH2:8][C@@:9]3([CH2:27][C:4]=2[CH:3]=1)[C:17]1[C:12](=[N:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]3=[O:26].Br[C:29]([F:36])([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CS(C)=O.[Cu]>[F:35][C:29]([F:36])([C:2]1[CH:3]=[C:4]2[CH2:27][C@@:9]3([C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[C:10]3=[O:26])[CH2:8][C:5]2=[N:6][CH:7]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(CC3=C(C2)NCC(I)=C3)c2cccnc21
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Copper bronze (0.522 g, 8.22 mmol) was added to a solution of (S)-3-iodo-1′-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1H)-one (described in Intermediate 7) (0.811 g, 1.644 mmol) and ethyl bromodifluoroacetate (1.056 mL, 8.22 mmol) in DMSO (10 mL) at ambient temperature. The resulting mixture was heated to 100° C. and stirred for 4 h. The reaction was cooled, partitioned between water (40 mL) and EtOAc (200 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (30 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—85:15 to 0:100, to give the title compound. MS: m/z=489.1 (M+1).
Reaction SMILES: Br.[CH2:2]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]=1N(C)C)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:24][C:25]1[CH:33]=[C:29]([C:30]([OH:32])=[O:31])[C:28]([OH:34])=[CH:27][CH:26]=1>C(O)(=O)C>[C:30]([C:29]1[CH:33]=[C:25]([N:24]2[C:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]=3[CH:2]=[C:3]2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:26]=[CH:27][C:28]=1[OH:34])([OH:32])=[O:31]
Reactant: CN(C)C1=C(CC(=O)c2ccccc2)c2ccccc2CC1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Temperature: 75 °C
Reaction time: 4.5 h

Procedure:
A mixture of 10.0 g of 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide and 4.1 g of 5-aminosalicylic acid in 50 ml of acetic acid is vigorously stirred at 75° C for 4.5 hours. The reaction mixture is then cooled to 20° C, filtered and the precipitate collected, washed successively with one 20 ml portion of acetic acid and five 20 ml portions of hexane and then dried for 20 hours under vacuum to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1)#[N:20].COCCOC>O>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@@:8]2([C:17]3[C:5](=[CH:4][CH:3]=[C:2]([C:23]4[CH:24]=[N:25][CH:26]=[C:21]([CH:22]=4)[C:19]#[N:20])[CH:18]=3)[CH2:6][CH2:7]2)[N:9]=1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Reactant: N#Cc1cncc(B(O)O)c1
Solvent: COCCOC
Solvent: O
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CC3)N=C(N)OCC2(F)F)c1

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with 5-cyanopyridin-3-ylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1.[OH:22]CC12CCN(CC1)CC2=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:15][CH2:16][N:17]([CH2:20][CH2:21]2)[CH2:18][C:19]3=[O:22])=[O:11])=[CH:2]1
Reactant: O=C1CN2CCC1(CO)CC2
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: O=C(OCC12CCN(CC1)CC2=O)c1c[nH]c2ccccc12

Procedure:
(3-oxoquinuclidin-4-yl)methyl 1H-indole-3-carboxylate was prepared in a similar manner to (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate, substituting 4-(Hydroxymethyl)quinuclidin-3-one as the nucleophile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:28])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4]([Cl:28])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)Cl)c(Cl)cc2F)c1=O
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To a stirred solution of 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid (4 g) in chloroform (100 ml) were added oxalyl chloride (1.8 g) and a few drops of N,N-dimethylformamide (DMF) at ambient temperature. The resulting mixture was stirred for three hours at same temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure to give the titled compound (4.3 g) as a brown solid.