Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24](Br)=[CH:23][C:12]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[CH2:1]([O:8][C:9]1[C:24]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[CH:23][C:12]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ccccc2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ccccc2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a solution of 6-benzyloxy-5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide (85 mg) in 1,2-dimethoxyethane (1.6 ml) was added tetrakis(triphenyl-phosphine)palladium(0) (24.5 mg). The mixture was stirred for 10 min. 4-chlorophenyl-boronic acid (37.2 mg) was dissolved in 0.7 ml EtOH and added to the reaction mixture. A solution of Na2CO3 (190 mg) in water (1 ml) was added. The reaction mixture was stirred at 85° C. for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with brine. The org. phase was dried, filtered and concentrated. The product was purified by flash chromatography (SiO2, CH2Cl2=>CH2Cl2MeOH 4:1) to give 6-benzyloxy-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide (50.6 mg) as a white solid. MS (ISP) 437.2 (M+H)+.
Reaction SMILES: C(O)(=O)C[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=O.C1C2C(=CC=CC=2)CCC1.CC([O-])=O.[K+].C(OC1C2C(=CC=CC=2)C=CC=1)(=O)CCCCCCCCCCC([O-])=O>CC([O-])=O.CC([O-])=O.[Pd+2].O.CCCCCCC>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])CCCCCCCCCCC(=O)Oc1cccc2ccccc12
Solvent: O
Solvent: CCCCCCC
Solvent: c1ccc2c(c1)CCCC2
Product: c1ccc2ccccc2c1
Temperature: 178 °C
Reaction time: 3 h

Procedure:
The procedure of Example 1 was repeated using 70 g (304 mmols) of dodecanedioic acid 13.2 g (100 mmols) of tetralin, 0.16 g (0.71 mmols) of Pd(OAc)2, 0.42 g (1.42 mmols) of Sb(OAc)3, 0.07 g (0.71 mmols) of KOAc and 5 ml heptane. Reaction mixture was heated and the temperature of the reaction was maintained at 178±2° C. Oxygen was bubbled continuously at a rate of 200 cc/min. Reaction was carried out for 3 hrs. during which time the water produced was removed azeotropically with heptane. Reaction mixture was analyzed by GLC which showed the formation of 3.65% (by wt.) naphthyl dodecanedioate. Only a trace of naphthalene formed in the reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)c2ccc3oc4c(c3c2)CN(C(=O)OC(C)(C)C)CC4)cc1
Yield: 33 %

Procedure:
The product of Example 29, step B and sodium 4-methylbenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 90:10 to 50:50 hexane/ethyl acetate) provided tert-butyl 8-(4-methylphenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (65 mg, 33%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.07 (br s, 1H), 7.86-7.78 (m, 3H), 7.49 (d, J=8.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 4.57 (br s, 2H), 3.88-3.78 (m, 2H), 2.90-2.82 (m, 2H), 2.38 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[CH2:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:1]([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1Cc2ccccc2C1
Yield: 69.1 %

Procedure:
Dissolve 2-(carboethoxy)indane (6.49 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 2-indancarboxylic acid as a tan solid (3.82 g, 69%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=5)=[CH:27][C:26]=4[N+:41]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].C(O)C.O1CCCC1>O.C(OCC)(=O)C.[Fe]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=5)=[CH:27][C:26]=4[NH2:41])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Cl)cn3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(C(=O)Nc2ccc(Cl)cn2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
The product of Example 52D (371 mg, 0.5954 mmol), ammonium chloride (208.6 mg, 3.900 mmol), and iron powder (204.5 mg, 3.662 mmol) in a mixture of water (6 mL), ethanol (12 mL) and tetrahydrofuran (12 mL) was heated at 90° under a nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (200 mL), and washed with water (2×50 mL) and brine (50 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to give the product as an off-white solid (321 mg, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH3:17].Br[C:34]1[CH:39]=[N:38][C:37]([Br:40])=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>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>[Br:40][C:37]1[N:38]=[CH:39][C:34]([C:21]2[CH:20]=[CH:19][C:18]([N:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=3[CH3:17])[C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[N:35][CH:36]=1
Reactant: Brc1cnc(Br)cn1
Reactant: Cc1ccc(N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c2ccc(C)cc2C)c(C)c1
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: O
Solvent: C1COCCO1
Product: Cc1ccc(N(c2ccc(-c3cnc(Br)cn3)cc2)c2ccc(C)cc2C)c(C)c1
Temperature: 80 °C

Procedure:
A mixture of N-(2,4-dimethylphenyl)-2,4-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)aniline (Compound 17) (6.0 g, 14 mmol), 2,5-dibromopyrazine (7.74 g, 30 mmol), Pd(PPh3)4 (0.5 g, 0.43 mmol), K2CO3 (4.14 g, 30 mmol) in dioxane/water (80 mL/17 mL) was degassed and heated at about 80° C. overnight. The resulting mixture was poured into ethyl acetate (200 mL), washed with brine, dried over Na2SO4, then loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1 to 6:1 to 7:3. The desired yellow fraction was collected, and a yellow solid (Compound 18) was obtained after removal of solvents (3.83 g, 60% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:17]([CH2:18][CH2:19][CH:20]=C)=[C:16]2[C:11]([CH2:12][CH2:13][C@@H:14]([C:22](C)(C)[O:23][SiH2]C(C)(C)C)[O:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:17](=[C:16]3[C:11](=[CH:10][CH:9]=2)[CH2:12][CH2:13][C@@H:14]([CH2:22][OH:23])[O:15]3)[CH2:18][CH2:19][CH:20]1[OH:33])=[O:31])([CH3:3])([CH3:4])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1c2ccc3c(c2CCC1O)O[C@H](CO)CC3
Reaction time: 48 h
Yield: 76.6 %

Procedure:
To a solution of (2S)-[8-but-3-enyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-chroman-7-yl]-carbamic acid tert-butyl ester (0.33 g, 0.74 mmole) in anhydrous tetrahydrofuran (15 mL) and water (3 mL) at 0° C. was added osmium tetroxide (0.1 mL, 5% in water), followed by sodium periodate (0.47 g, 2.2 mmole). The mixture was stirred for 48 hours. The solution was diluted with ethyl acetate and the organic layer was washed with water, dried over Na2SO4, filtered, and the solvent evaporated in vacuum. Column chromatography on silica gel (80% ethyl acetate/hexane) afforded 0.19 g (76%) of the title compound as an oil, the t-butyldimethylsilyl protecting group having been cleaved in the course of the reaction. [α]25D=+40.66° (c=7.7, DMSO)
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:21]1([CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH2:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[C:30]1([CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][NH:29][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCC(c2ccccc2)c2ccccc2)nc1
Yield: 67.6 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 536 mg, 2.00 mmol), 2,2-diphenylethylamine (473 mg, 2.40 mmol), Ti(iPrO)4 (1.14 g, 4.00 mmol), TiCl4 (1.0 M/DCM, 4.00 ml, 4.00 mmol), and NaBH3CN (251 mg, 4.00 mmol) gives the title compound (608 mg) as a white solid. Mass spectrum (ion spray): m/z=450 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.14 (d, 1H), 7.33-7.18 (m, 11H), 6.98-6.90 (m, 3H), 5.85 (br. s, 2H), 4.33-4.23 (m, 2H), 3.41-3.31 (m, 2H), 2.95 (m, 1H), 2.81 (m, 1H), 2.46 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1cncc2cccc([N+](=O)[O-])c12
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To 45 ml of concentrated sulfuric acid was added 12.75 g of 4-methylisoquinoline (produced according to Tetrahedron, 1982, 38, 3347) under ice-cooling, and a solution of 9.02 g of potassium nitrate in 34 ml of concentrated sulfuric acid was added dropwise at a temperature not exceeding 0° C. After 30 minutes of stirring, the reaction mixture was poured in iced water containing aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to provide 12.0 g of light-yellow crystals.
Reaction SMILES: [ClH:1].C([O:4][C:5](=[O:24])[C@@H:6]([NH:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[NH:16])[NH2:15])=[CH:10][CH:9]=1)C>Cl>[ClH:1].[CH2:21]([O:20][C:18]([NH:17][C@@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[NH:15])[NH2:16])=[CH:10][CH:9]=1)[C:5]([OH:24])=[O:4])=[O:19])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)OCC
Agent: Cl
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)O

Procedure:
17 g (0.048 mol) of (S)-2-allyloxycarbonylamino-3-(4-carbamimidoylphenyl)propionic acid ethyl ester hydrochloride were treated with 400 ml of half-concentrated hydrochloric acid for 3 h at RT. The solvent was evaporated (<30° C.) and the residue was stirred with ether. Yield=15 g (95%). MS=292.2 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[SH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)([OH:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Reactant: Clc1cccc(I)c1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2Sc2cccc(Cl)c2)CC1

Procedure:
Prepared from 4-hydroxy-4-(2-mercapto-5-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester and 1-chloro-3-iodo-benzene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16]Br.C([O-])([O-])=O.[Cs+].[Cs+].[I-].[Cs+]>CN(C=O)C>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(O)ccc21
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(COc1ccc2c(c1)CCNC2=O)OC

Procedure:
6-Hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline is treated with bromacetaldehyde dimethyl acetal, in the presence of Cs2CO3 and CsI in DMF to yield 6-(2,2-dimethoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline. Treatment with 2-chloromethylpyridine hydrochloride in the presence of sodium hydride in DMF yields 6-(2,2-dimethoxyethoxy)2-(2-pyridylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline. Hydrolysis with 20% aqueous sulfuric acid in THF yields α-[2-(2-pyridylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-acetaldehyde which is then converted to 2-(2-pyridylmethyl)-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]4([CH2:25][CH2:26][C:5]=3[C:4]=2[CH:3]=1)[CH2:17][CH2:16][N:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][CH2:13]4.[CH3:27][N:28]=[C:29]=[O:30]>ClCCl.[Cu]Cl>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([O:1][C:29]([NH:28][CH3:27])=[O:30])=[CH:3][C:4]=2[C:5]2[CH2:26][CH2:25][C:12]3([CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)[C:6]1=2
Reactant: Cn1c2c(c3cc(O)ccc31)CCC21CCN(Cc2ccccc2)CC1
Reactant: CN=C=O
Agent: Cl[Cu]
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C2(CC1)CCN(Cc1ccccc1)CC2
Yield: 70.7 %

Procedure:
To a solution of 1,4-dihydro-7-hydroxy4-methyl-1′-phenylmethylspiro[cyclopent[b]indole-3(2H), 4′-piperidine] (0.25 g) and copper (I) chloride (0.01 g) in dichloromethane (10 ml) was added methyl isocyanate (0.04 g), under nitrogen, with stirring. The reaction mixture was stirred for 24 hrs. The mixture was flash chromatographed (neutral alumina) and eluted with 25% ethyl acetate/dichloromethane. The appropriate fractions were collected and concentrated to give 0.2 g (69%) of product, mp 189-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH:9]=O)=[CH:4][CH:3]=1.[C:30]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[CH:30])=[CH:4][CH:3]=1
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indol-4-yl)carbamate (412 mg, 1 mmol), as described in Example 21 Step B, and K2CO3 (276 mg, 2 mmol) in methanol (10 mL) was added dimethyl 1-diazo-2-oxopropylphosphonate (230 mg, 1.2 mmol) at room temperature. The mixture was stirred for 2 h and the solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with PE/EA (20/1 to 10/1, v/v) to give the title compound as colorless amorphous solid. LC/MS m/z=352.9[M-tBu+H]+.
Reaction SMILES: [ClH:1].[C:2]([O:5][C:6]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][C:11]2([CH2:22][NH:23][C:24](=[O:40])[C@H:25]([CH3:39])[NH:26][C:27](=[O:38])[C@H:28]([CH3:37])[NH:29]C(OC(C)(C)C)=O)C=O)(=[O:4])[CH3:3].Cl>C(OCC)C>[ClH:1].[C:2]([O:5][C:6]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH:9]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:10]=[C:11]2[CH2:22][NH:23][C:24](=[O:40])[C@H:25]([CH3:39])[NH:26][C:27](=[O:38])[C@H:28]([CH3:37])[NH2:29])(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1ccc2c(c1OC(C)=O)CC(c1ccccc1)CC2(C=O)CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CC(=O)Oc1ccc2c(c1OC(C)=O)CC(c1ccccc1)C=C2CNC(=O)[C@H](C)NC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
5,6-Bis(acetoxy)-1-(N-t-butoxycarbonyl-alanyl-alanyl)aminomethyl-3-phenyl-3,4-dihydronaphthal hydrochloride (2.00 g, 3.36 mmol) from Step 1 was dissolved in 25 mL of diethyl ether. The resultant solution was cooled and saturated with hydrogen chloride. The solution was stirred at ambient temperature for 3 h. The precipitate was filtered and washed thoroughly with dry diethyl ether. The solid was dried overnight at 60° C. in vacuo to give 1.69 g (95% yield) of the title compound as an off-white solid, m.p. 145°-161° C. (dec); 1H NMR (CDCl3) δ: 1.35 (dd, 3H), 1.41 (m, 3H), 2.23 (s, 3H), 2.26 (s, 3H), 2.70 (dt, 1H), 2.95 (dd, 1H), 3.69 (br s, 1H), 3.89 (dq, 1H), 4.17-4.45 (m, 3H), 6.11 (d, 1H), 7.0 (d, 1H), 7.25 (m, 6H), 8.27 (m, 1H). Analysis calculated for C27H33N3O6 +1.3HCl: C, 59.73; H, 6.37; N, 7.74. Found: C, 59.94; H, 6.08; N, 7.64.
Reaction SMILES: CN1CCN(C2C=CC=CC=2CN)CC1.[CH:16]1([C:22]2([CH2:49][CH:50]([CH3:52])[CH3:51])[C:26]3[CH2:27][N:28]([C:31]([NH:33][CH2:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]4[N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)=[O:32])[CH2:29][CH2:30][C:25]=3[C:24](=[O:48])[O:23]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[CH2:49]([C:22]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:26]2[CH2:27][N:28]([C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N:41]3[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]3)=[O:32])[CH2:29][CH2:30][C:25]=2[C:24](=[O:48])[O:23]1)[CH:50]([CH3:52])[CH3:51]
Reactant: CC(C)CC1(C2CCCCC2)OC(=O)C2=C1CN(C(=O)NCC1CCCCC1N1CCN(C)CC1)CC2
Agent: CN1CCN(c2ccccc2CN)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1N1CCN(C)CC1)CC2

Procedure:
An analogous procedure to that described for R06039-275 was used to convert [2-(4-methylpiperazin-1-yl)phenyl]methanamine to 3-cyclohexyl-3-isobutyl-N-((2-(4-methylpiperazin-1-yl)cyclohexyl)methyl)-1-oxo-3,4,6,7-tetrahydrofuro[3,4-c]pyridine-5(1H)-carboxamide using triphosgene and triethylamine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.82-0.90 (m, 3H), 0.90-1.00 (m, 3H), 1.58-1.73 (m, 1H), 1.74-1.88 (m, 1H), 2.25-2.46 (m, 3H), 2.34 (s, 3H), 2.49-2.67 (m, 4H), 2.98 (t, J=4.90 Hz, 4H), 3.23-3.38 (m, 1H), 3.55 (dt, J=13.56, 5.09 Hz, 1H), 3.93 (dt, J=19.21, 2.64 Hz, 1H), 4.43-4.59 (m, 3H), 6.05 (t, J=5.27 Hz, 1H), 7.02-7.19 (m, 2H), 7.22-7.43 (m, 7H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]1[CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Brc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1c(Br)ccc2[nH]c3ccccc3c12
Yield: 61.9 %

Procedure:
Prepared from 3-bromo-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.083 g, 0.26 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.10 g, 0.48 mmol) according to the procedure used for Example 2 without heating to give 0.085 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][N:12]=1.[N:22]([Sn](CCCC)(CCCC)CCCC)=[N+:23]=[N-:24]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH:18]=2)[NH:13][N:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2[nH]nc(-c3ccc4ccccc4c3)c2c1
Solvent: Cc1ccccc1
Product: c1ccc2cc(-c3n[nH]c4ccc(-c5nnn[nH]5)cc34)ccc2c1
Reaction time: 4 h
Yield: 64.4 %

Procedure:
A mixture of 3-(2-naphthyl)-1H-indazole-5-carbonitrile (105 mg, 0.390 mmol), azidotributyltin (Bu3SnN3, 710 mg, 2.14 mmol, 5.49 equiv.), and 4.1 mL toluene was refluxed for 49.5 h and concentrated to an oil. The oil was stirred in 31 mL dioxane and 31 mL 6.0 N aq HCl at room temperature for 4 h. The mixture was partitioned between 6.0 N aq. NaOH and hexanes, and the layers separated. The aqueous layer was extracted with hexanes, and 2×EtOAc, and then filtered. The aqueous layer was acidified to pH ca. 4.0 with 6.0 N aq. HCl. The resulting precipitate was either collected by filtration and dried in a vacuum oven, or extracted with EtOAc, dried (Na2SO4), filtered and concentrated to afford the title compound (78.4 mg, 64.3% yield): 1H NMR (DMSO-d6) δ 13.70 (s, 1H), 8.92 (s, 1H), 8.60 (s, 1H), 8.17 (d, 1H), 8.15–8.00 (m, 3H), 7.94 (d, 1H), 7.85 (d, 1H), 7.63–7.58 (m, 2H); ES-MS (m/z) 313 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[C:29]([NH:33][CH3:34])[CH:30]=[CH:31][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[C:29]([N:33]([CH3:34])[C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=3)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:30]=[CH:31][CH:32]=1
Reactant: CNc1cccc(F)c1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cccc(F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (3-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 L, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (3-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 521.9.