Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:3][CH2:2]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:11][CH2:10]2)[O:3][CH2:2]1
Reactant: O=C1CCN(CCC2CCOCO2)CC1
Reactant: NCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(CNC2CCN(CCC3CCOCO3)CC2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of 128NLS50 (1.73 g, 8.13 mmol) in methanol (100 mL) was added dropwise 4-fluorobenzylamine (0.93 mL, 8.13 mmol) and acetic acid. Sodium cyanoborohydride (2.15 g, 40 mmol) was added slowly to the mixture at 0° C. and stirring was continued at rt overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and 1M NaOH, the aqueous layer extracted twice with dichloromethane and the combined organic layers dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue by a short silica gel column chromatography eluting with 0–30% methanol in dichloromethane gave the title compound (1.51 g, 58%) as a colourless solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][CH2:28][CH2:29][CH2:30]CS([O-])(=O)=O)=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>>[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]2[C:3]([CH3:15])=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[CH:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccc(SCCCCCS(=O)(=O)[O-])cc1
Reactant: Cc1cc2c(cc1O)C(C)(C)OC(=O)N2
Product: CC(=O)Nc1ccc(SCCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and 4-(4-acetamidophenylmercapto)-butylmesylate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][CH2:20][C:21](O)=[O:22])=[O:18])=[CH:11]2>CCOCC>[N:1]1([C:21](=[O:22])[CH2:20][NH:19][C:17]([C:12]2[NH:13][C:14]3[C:10]([CH:11]=2)=[CH:9][C:8]([Cl:7])=[CH:16][CH:15]=3)=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C(NCC(=O)N1CCOCC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Morpholine (1.0 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (1.0 mmol) were coupled according to Procedure A. The resulting solid was suspended in ether, filtered and dried to give a beige solid: Yield, 264 mg, 71%; HPLC (60/40) 3.28 minutes (100%); TSPMS 322/324 (MH+, 100%);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:4]=1[CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([NH:11][C:12](=[O:13])[C:7]=12)=[O:10].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[Br:22][CH2:21][C:17]1[C:4]([CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[C:8]3[C:9]([NH:11][C:12](=[O:13])[C:7]=23)=[O:10])=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C)c1Cc1cccc2c1C(=O)NC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1cccc(CBr)c1Cc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a solution of (2-methoxy-6-methylbenzyl)phthalimide (0.286 g, 1.02 mmol) in CCl4 (25 mL) was added recrystallized N-bromosuccinimide (0.177 g, 0.99 mmol) followed by benzoyl peroxide (28 mg, 0.11 mmol). The resultant mixture was heated to reflux for 90 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (25 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (3:1 hexanes-EtOAc) provided 0.31 g (86%) of (6-(bromomethyl)-2-methoxybenzyl)phthalimide as a white solid. 1H NMR (CDCl3) δ3.78 (s, 3H), 4.90 (s, 2H), 5.00 (s, 2H), 6.83 (d, 1H, J=8.4 Hz), 6.98 (d, 1H, J=7.2 Hz), 7.25 (dd, 1H, J=7.2, 8.4 Hz), 7.67-7.69 (m, 2H), 7.78-7.81 (m, 2H). ES-MS m/z 382 (M+Na), 384 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:11]([CH3:16])[C:12](Cl)=[N:13][CH:14]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.[N:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([NH:26][CH2:25][CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:13][CH:14]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C(O)c2cccc(F)c2)cnc1Cl
Reactant: NCCCN1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(O)c2cccc(F)c2)cnc1NCCCN1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of (3-fluoro-phenyl)-(2-chloro-3-methyl-3H-imidazol-4-yl)-methanol (1 equivalent) in THF (0.2 M) is added 3-piperidin-1-ylpropylamine (1.5 equivalents) and diisopropylethylamine (1.5 equivalents). The mixture is heated at reflux until HPLC analysis shows consumption of the starting material. The reaction mixture is cooled to rt, quenched with satd. aq. NH4Cl, and extracted with EtOAc (2×). The combined organic extracts are washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material is purified by chromatography or recrystallization to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]N(C)C=O.C(Cl)(=O)C(Cl)=O.CO>ClCCl>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
A slurry of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 mL dichloromethane was cooled in an ice bath. Dimethylformamide (0.40 ml) was added to the reaction mixture followed by dropwise addition of 13.85 g (109 mmol) of oxalyl chloride. The reaction was allowed to warm to room temperature and was stirred for 6 h. Methanol (200 mL) was added dropwise and the reaction was stirred overnight. The solvent was evaporated in vacuo. The residue was triturated with n-hexane. The resulting solid was collected by filtration, washed with hexane and dried in vacuo to give 21.0 g (98%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:17]=[CH:16][C:9]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:8]([O:18][CH3:19])[C:7]=2[CH3:20])[CH2:2]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34](OCC)=[O:35])=[N:31][N:30]=2)=[CH:25][CH:24]=1>>[CH3:19][O:18][C:8]1[C:7]([CH3:20])=[C:6]([CH:17]=[CH:16][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[O:5][CH:3]1[CH2:4][N:1]([C:34]([C:32]2[O:33][C:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[N:30][N:31]=2)=[O:35])[CH2:2]1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Reactant: COc1c(CN2CCCC2)ccc(OC2CNC2)c1C
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCCC5)c(OC)c4C)C3)o2)cc1
Yield: 37.2 %

Procedure:
Using a similar protocol as described in Example 16 employing 52B (0.25 g, 0.90 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.34 g, 1.36 mmol) as starting materials afforded 160 mg (37%) of 52 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.77 (s, 4H), 2.19 (s, 3H), 2.52 (s, 4H), 3.60 (s, 2H), 3.76 (s, 3H), 3.89 (s, 3H), 4.35 (dd, 1H), 4.66 (dd, 1H), 4.75 (dd, 1H), 5.07 (m, 1H), 5.13 (dd, 1H), 6.29 (d, 1H), 7.02 (d, 2H), 7.17 (d, 1H), 8.10 (d, 2H), MS (APCI+) m/z 479 [M+H]+, LC purity: 95%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:23])[NH:15][CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19]=4[N:20]=3)[C:6]=2[CH:24]=1.C(=[NH:38])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:38][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:23])[NH:15][CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19]=4[N:20]=3)[C:6]=2[CH:24]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC1(C)CNC(=O)c2sc(N3CCOc4ccc(Br)cc43)nc2C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: CC1(C)CNC(=O)c2sc(N3CCOc4ccc(N)cc43)nc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of Example 67 (0.48 g, 0.98 mmol), benzophenone imine (0.356 g, 1.96 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (40 mg, 0.06 mmol), sodium tert-butoxide (0.192 g, 2.0 mmol) and tris(dibenzylidineacetone)dipalladium(0) (29 mg, catalytic) in THF (10 mL) was heated to 120° C. for 2 h. The reaction mixture was cooled to r.t., concentrated in vacuo, and the residue dissolved in methanol (2 mL). 2N Hydrochloric acid (10 mL) was added and the mixture stirred overnight. It was basified with aqueous sodium carbonate and extracted with DCM (3×25 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was triturated with Et2O to give the title compound (0.30 g, 89%) as a beige solid. δH (CDCl3) 1.11 (6H, s), 2.85 (2H, s), 3.12 (2H, d, J 5.3 Hz), 3.52 (2H, br.s), 4.07-4.13 (2H, m), 4.19-4.26 (2H, m), 5.93 (1H, br.s), 6.40 (1H, dd, J 8.5, 2.6 Hz), 6.75 (1H, d, J 8.7 Hz), 7.29 (1H, d, J 2.6 Hz). LCMS (ES+) 345 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:14]2[O:15]C(C)(C)[O:17][C@@:13]32[C@@H:8]([C@H:9]([C:21]([CH3:25])=[C:22]([Cl:24])[Cl:23])[CH2:10][CH2:11][C@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:26])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CO.CO>[C:1]([O:4][CH:5]1[C:6]([CH3:26])=[CH:7][CH:8]2[C:13]([OH:17])([CH:12]([CH3:20])[CH2:11][CH2:10][CH:9]2[C:21]([CH3:25])=[C:22]([Cl:24])[Cl:23])[CH:14]1[OH:15])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)=C(Cl)Cl)CC[C@@H](C)[C@@]23OC(C)(C)O[C@@H]13
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: CO
Product: CC(=O)OC1C(C)=CC2C(C(C)=C(Cl)Cl)CCC(C)C2(O)C1O
Temperature: 75 °C

Procedure:
To a stirred solution of (3aS,4R,6aR,7R,10R,10aR)-7-(2,2-dichloro-1-methylethenyl)-2,2,5,10-tetramethyl-4,6a,7,8, 9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 170, 0.95 g) in ethylene glycol (40 ml) and methanol (10 ml) was added para-toluenesulphonic acid (95 mg). The reaction mixture was heated to 75° C., after 1.5 h the reaction mixture was concentrated in vacuo to remove the methanol. The resultant solution was diluted with diethyl ether (30 ml) and water (30 ml) and the organic layer separated and washed with sodium hydrogen carbonate (3×30 ml). The aqueous layers were back extracted with diethyl ether (2×20 ml) and the combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=C)[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I([O-])(=O)(=O)=[O:24].[Na+]>O.CC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:24])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc(C2(C)CCN(CCCCCC)CC2C)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCN1CCC(C)(c2cccc(C=O)c2)C(C)C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
1-Hexyl-3,4-dimethyl-4-(3-vinylphenyl)piperidine (Example 26, 200 mg, 0.67 mmol) was dissolved in a mixture of water (2 μL) and acetone (18 mL). Osmium tetroxide (200 μL, 2.5% w/w in tert-butanol) was added, followed by sodium periodate (572 mg, 2.68 mmol) which was added portionwise. The reaction mixture was stirred at room temperature for 26 hours, then it was filtered to remove precipitate and the solvent was removed by evaporation in vacuo. The residue was partitioned between dichloromethane (25 mL) and saturated sodium chloride solution (25 mL). The organic phase was separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (50 g) eluted with ethyl acetate:hexane:0.880 ammonia (74:25:1). The title compound was obtained as an oil (80 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.Cl.Cl.[NH2:30][CH:31]1[CH2:34][NH:33][CH2:32]1.CN1CCCC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH:31]([NH2:30])[CH2:32]2)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To 550 mg of pyridine were added 185 mg of 5-amino-1-(6-amino-3 , 5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 110 mg of 3-aminoazetidine dihydrochloride, and 200 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 30 minutes, and concentrated under reduced pressure. After adding 2 ml of ethanol, the mixture was stirred, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 48 mg of the title compound as a yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:13]2[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 275.3 %

Procedure:
To a solution (100 ml) of ethyl 4-benzyloxy-1H-indole-2-carboxylate (12.0 g) in DMF was added sodium hydride (1.6 g) and the mixture was stirred at room temperature for 10 min. To this reaction mixture was added methyl iodide (2.2 g) and the mixture was stirred for one more hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (13.2 g) as a brown oil.
Reaction SMILES: C(N(CC)CC)C.[Br-].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[CH:16]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:15][C:14]2=[O:41].[N:42]1[CH:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=1>C(Cl)Cl>[CH3:21][O:20][C:19]1[CH:18]=[C:17]2[C:13](=[CH:12][C:11]=1[O:10][CH3:9])[C:14](=[O:41])[O:15][C:16]2=[CH:48][C:45]1[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=1
Reactant: COc1cc2c(cc1OC)C([P+](c1ccccc1)(c1ccccc1)c1ccccc1)OC2=O
Reactant: O=Cc1ccncc1
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(=Cc1ccncc1)OC2=O
Yield: 60.9 %

Procedure:
Triethylamine (20 ml, 145 mmoles) was added dropwise to a suspension of (5,6-dimethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenylphosphonium bromide (78 g, 145 mmoles), obtained as described in example 12, and 4-pyridincarboxaldehyde (13.0 ml, 145 mmoles) in methylene chloride (1 l), at room temperature, under stirring. After 1.5 hours the mixture was filtered and evaporated and the residue was treated with boiling ethanol, cooled and filtered. The mother liquors were chromatographed (eluent: methylene chloride then with 1% methanol) and the residue was brought to dryness and joined to the above filtrate to give 25 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.CCN(C(C)C)C(C)C>CCO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2ccncc2[N+](=O)[O-])C1
Yield: 95 %

Procedure:
The method of Example 1 was followed using 4-chloro-3-nitropyridine (1.0 eq), tert-butyl pyrrolidin-3-ylcarbamate (2.0 eq), and DIEA (2.0 eq) in EtOH yielding tert-butyl 1-(3-nitropyridin-4-yl)pyrrolidin-3-ylcarbamate (95%) LCMS (m/z): 309.1 (MH+); LC Rt=1.922 min.
Reaction SMILES: [CH3:1][CH:2]([C:14](=O)[CH3:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)C>[CH2:6]([NH:5][C:3](=[O:4])[C:2]([CH3:1])=[C:14]([NH2:17])[CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N
Reactant: CC(=O)C(C)C(=O)NCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CC(N)=C(C)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 2-methyl-3-oxo-N-phenethyl-butyramide of Example 1d (1.10 g, 5.00 mmol) in diethyl ether (300 mL) was saturated with gaseous ammonia for 3 h while cooled in an ice bath. Anhydrous aluminum chloride (99.99% purity, 0.667 g, 5.00 mmol) was then added in small portions and the reaction was allowed to stir at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to give 3-amino-2-methyl-but-2-enoic acid phenethyl-amide (0.97 g, 85% conversion by NMR) as a white solid which was used without purification for the next synthetic step.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([OH:41])=O)[CH:34]=1)C1C=CC=CC=1.[CH3:42][N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:45][CH2:44]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([N:53]2[CH2:52][CH2:51][N:50]([CH2:49][CH:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)[CH2:55][CH2:54]2)=[O:41])[CH:34]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid and 1-(N-methylpiperidin-4-yl-methyl)piperazine as described in general procedure D. LCMS: 550 [M+H].
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.CCOCC>C(Cl)Cl>[O:33]1[C@H:9]2[CH2:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][C@H:10]12
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CC[C@@H]2O[C@H]2C1

Procedure:
A solution of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohex-1-ene (Example 192, 146.3 mg, 0.46 mmol) and mCPBA (156.8 mg, 0.92 mmol) in 8.0 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was poured into ether, washed with NaHCO3 (3×), dried over Na2SO4, filtered through a plug of silica gel and concentrated The residue was purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 1.0/8.0 mL/min) to give the separated cis and trans isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=3)[N:9]=2)[N:8]=1
Reactant: COc1ccc(N)nn1
Reactant: Cc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)cn2n1
Yield: 85.2 %

Procedure:
A stirred solution of 6-methoxypyridazin-3-amine (Apollo Scientific, 0.750 g, 5.99 mmol) and 2-bromo-1-(4-methyl-3-nitrophenyl)ethanone (1.54 g, 5.99 mmol) in acetonitrile (20 mL) is heated at 80° C. for 16 hours. The reaction mixture is concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford the title compound (1.45 g, 85%) as a light yellow solid: Rf 0.45 (1:1 EtOAc:hexanes); LCMS (m/z)=285.4 [M+H]+, tR=7.47 min. (10 min run)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:31](I)[CH3:32].CN(C)C=O>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:31][CH3:32])=[O:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
A mixture of 6.4 g of 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid, 3.1 g of sodium hydrogencarbonate, 8.6 g of ethyl iodide and 20 ml of N,N-dimethylformamide is heated at 100° C. with stirring for 3 hours. Further, 2.9 g of ethyl iodide and 1 g of sodium hydrogencarbonate are added to the reaction solution, followed by heating at 100° C. for 2.5 hours. After cooling, 200 ml of water is added to the reaction solution, and the mixture is extracted with 300 ml of ethyl acetate. The extract is washed with water, 0.1 N hydrochloric acid and dilute aqueous sodium hydrogen-carbonate solution successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5 g of ethyl 7-(1-benzyloxycarbonyl-4piperidyl)heptanoate as an oily material.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([OH:39])=[CH:36][CH:37]=2)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:39][C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=1)=[O:29])[CH2:31][CH2:32]2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: Oc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(O)ccc21

Procedure:
0.15 g (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 mg (0.37 mmol) 2,3-dihydro-1H-indol-5-ol, 150 μL (0.87 mmol) DI PEA and 0.13 g (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.