Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([NH:9][C:10](=[O:39])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH2:36]O)[CH2:26][CH3:27])[C:19]3=[O:38])[CH:12]=2)[CH2:8][CH2:7]1.[CH2:40]([N:42](CC)[CH2:43][CH3:44])[CH3:41].O>ClCCl>[CH:6]1([NH:9][C:10](=[O:39])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH2:36][N:42]4[CH2:43][CH2:44][CH2:41][CH2:40]4)[CH2:26][CH3:27])[C:19]3=[O:38])[CH:12]=2)[CH2:8][CH2:7]1
Reactant: CC[C@@H](Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCN1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.21 mL) was added to a stirred solution of N-cyclopropyl-3-[3-[[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (410 mg) and triethylamine (0.5 mL) in dichloromethane (10 mL) at 0° C. The mixture was stirred for 1 h at 0° C. and 1 h at room temperature. Water was added and the organic phase was separated, (Na2SO4), filtered and concentrated in vacuo. The residue was treated with dichloromethane (10 mL) and pyrrolidine (0.73 mL) and the mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacu. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (147 mg).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.42 min; [M+H]+=472.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:5])[CH3:2].[NH2:17][NH2:18]>C(O)CCC>[CH2:1]([O:3][C:4]([NH:6][CH:7]([CH3:16])[C:8](=[N:17][NH2:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)NC(C)C(=O)c1ccccc1
Solvent: CCCCO
Product: CCOC(=O)NC(C)C(=NN)c1ccccc1
Yield: 84.6 %

Procedure:
A mixture of 2-ethoxycarbonylaminopropiophenone (5 g) and hydrazine (3.5 g) in n-butanol (;b 40 ml) was refluxed for 4 hours. The reaction mixture was evaporated, and the residue was chromatographed on silica gel (400 g) using a mixture of chloroform and methanol (100:1) as an eluent. The first fraction was evaporated to give 2-ethoxycarbonylaminopropiophenone hydrazone (4.5 g).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13](OCC)=[O:14])=[CH:4]2.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CO.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.O>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH2:13][OH:14])=[CH:4]2
Reactant: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: OCC1=Cc2cnc3cccc(n23)S1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 10.757 g (43.676 mM) of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate in 200 ml of dichloromethane was added a 20 ml (approx.) portion of 87.4 ml (131 mM) of 1.5M diisobutylaluminum hydride-toluene at −78° C. and the temperature was increased to about 0° C. After this mixture was cooled to −78° C. again, about 30 ml of 1.5M diisobutylaluminum hydride-toluene was added and the temperature was increased to about 0° C. This reaction mixture was further cooled to −78° C. and the remainder of 1.5M diisobutylaluminum hydride-toluene was added. The mixture was stirred at the prevailing temperature for 0.5 hour. To this reaction mixture was added methanol at −78° C. to decompose the excess diisobutylaluminum hydride. Then, water was added with caution under ice-cooling until a precipitate had formed. The precipitate was filtered off with the aid of celite and washed with aqueous dimethyl sulfoxide. From the pooled filtrate, the solvent was distilled off under reduced pressure and the solid residue was rinsed with diethyl ether to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O:14][C:15]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:17]/[C:15]([O:14][CH3:13])=[O:16])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(Cl)cc1[N+](=O)[O-]
Yield: 98.3 %

Procedure:
4-Chloro-2-nitrobenzaldehyde (5 g, 0.027M) was dissolved in toluene (150 ml) with methyl (triphenylphosphoranylidene) acetate (9.91 g, 1.1 molar equivalents) and heated under reflux for 1h. The reaction mixture was concentrated under vacuum and the residue was purified by chromatography on silica gel using dichloromethane as eluent to give the required compound (6.4 g, 98%) as a solid. δ(360MHz, CDCl3) 3.83 (3H, s, CH3), 6.36 (1H, d, J=15.9Hz, CHA =CHB), 7.58 (1H, d, J=8.4Hz, 6H), 7.63 (1H, dd, J=8.4 and 2.0Hz, 5-H), 8.04 (1H, d, J=2.0Hz, 3-H), 8.05 (1H, d, J=8.4Hz, CHA =CHB); MS (EI) m/e 241 [M+ ].
Reaction SMILES: C([Li])CCC.[CH2:6]([O:14][CH:15]1[NH:19][C:18](=[O:20])[CH2:17][CH2:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCCCCC.O1CCCC1>[C:21]([N:19]1[CH:15]([O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17][C:18]1=[O:20])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCCCCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
16.5 cm3 of a 15% solution of butyllithium in hexane is added at -60° C. to 5.3 g of 5-n-octyloxy pyrrolidin-2-one in solution in 200 cm3 of tetrahydrofuran. After agitation for 20 minutes at -60° C., then, while maintaining these conditions, a solution of 3.5 g of benzoyl chloride in 50 cm3 of tetrahydrofuran is added. Agitation is continued while allowing to return to ambient temperature. After concentration and chromatography on silica (eluent: toluene-ethyl acetate 8-2), 4.2 g of the product sought is obtained.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Br:1][C:2]1[N:10]([CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[Br:14])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: BrCc1ccccc1Br
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1Br

Procedure:
8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and 2-bromobenzyl bromide were reacted and purified as described in the General procedure G, step A, to afford 80A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([CH:29]=O)=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)=[CH:21][CH:22]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccc(-c2ccccc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccc(-c2ccccc2CN2CCN(c3ccccc3OC)CC2)cc1

Procedure:
149 mg of the target compound (0.38 mmol, 81.6%) was obtained using 1-(2-methoxyphenyl)piperazine (181 mg, 0.94 mmol), 4′-methoxybiphenyl-2-carbaldehyde (100 mg, 0.47 mmol) and NaBH(OAc)3 (303 mg, 1.41 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH:1]1[C:17]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18]C(C)([O-])C.[K+].COS(OC)(=O)=O.[OH-].[Na+]>C(Cl)Cl.C1COCC1>[CH3:18][N:9]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:17]=3[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: c1ccc2c(c1)ccc1[nH]c3ccccc3c12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Product: Cn1c2ccccc2c2c3ccccc3ccc21
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser and N2 inlet line with bubbler was added 7H-benzo[c]carbazole (H. G. Pars Pharmaceutical Laboratories, Inc., 6.6 g, 30.4 mmol) and dry THF (250 mL). To the flask was added in one portion potassium t-butoxide (Aldrich, 4.2 g, 37.4 mmol). Dimethylsulfate (Aldrich, 7.56 g, 60.0 mmol, 5.9 mL) was added dropwise to the solution and the mixture stirred for 15 min. TLC (SiO2 /PhCH3) showed the reaction to be complete. The reaction mixture was then poured into a 1N NaOH solution (2 L) and stirred. The white solid which formed was collected by filtration, washed with H2O (3×500 mL), sucked semidry, dissolved in PhCH3 (300 mL) and eluted through a plug of SiO2 (5×5 cm) using PhCH3 as the eluting solvent. Appropriate fractions were combined and the solvent removed to give a crude white product. This material was dissolved in CH2Cl2 (400 mL), filtered and diluted to 1 L with hexane. The mixture was concentrated to 500 mL by rotary evaporation. A white solid formed which was filtered, washed with pentane and dried in a vacuum to give 5.0 g of 7-methyl-7H-benzo[c]carbazole, mp 116°-118°, (C, H, N). A further 1.06 g of product was obtained on standing and further concentration of the filtrate to give a combined yield of 87.3%.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][NH:20][C:21](=O)[O:22]C1C=CC([N+]([O-])=O)=CC=1>N1C=CC=CC=1>[CH3:18][O:19][NH:20][C:21]([NH:17][C:14]1[CH:15]=[CH:16][C:10]2[C:11]([N:13]=1)=[N:12][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:8][N:9]=2)=[O:22]
Reactant: CONC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2ncc(-c3ccccc3)nc2n1
Solvent: c1ccncc1
Product: CONC(=O)Nc1ccc2ncc(-c3ccccc3)nc2n1

Procedure:
100 mg of 3-phenylpyrido[2,3-b]pyrazin-6-ylamine (0.45 mmol) were dissolved in pyridine and admixed with 191 mg of p-nitrophenyl N-methoxycarbamate (0.90 mmol). The mixture was heated under reflux for 4 h. For workup, the pyridine was removed under reduced pressure, and the residue was partitioned in ethyl acetate and distilled water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol eluent). A light beige solid was isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=3)[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Reactant: Cc1cccc(CBr)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
To a solution of Intermediate 2 (460 mg, 1.68 mmol) in N,N-dimethylformamide (2 mL) was added 2-(bromomethyl)-6-methylpyridine (312 mg, 1.68 mmol), potassium carbonate (350 mg, 2.53 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for one hour. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white semi-solid (100 mg, 16% yield). MS (M+H): 380
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([C@H:37](O)[CH2:38][CH2:39][CH3:40])=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)=[O:7])=[CH:25][CH:26]=2)[CH2:38][CH2:39][CH3:40])=[CH:35][CH:36]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CCC[C@@H](O)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)c2ccccn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)OCC)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 49 %

Procedure:
To a mixture of ethyl 4-[1-(4-hydroxybenzoyl)indolizin- 3-yl]butyrate (392 mg), (R)-1-(4-isobutylphenyl)butan-1-ol (230 mg) and triphenylphosphine (292 mg) in tetrahydrofuran (3 ml) and toluene (15 ml) was added diethyl azodicarboxylate (0.178 ml) at -20° C. under nitrogen atmosphere. After the mixture was stirred at -20° C. under nitrogen for 2.5 hours, acetic acid (0.05 ml) was added and the mixture was warmed up to room temperature. The solvent was evaporated under reduced pressure and the residue was poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 4-[1-[4-[(S)-1-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyrate (295 mg) as an oil.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1.[CH3:15]O>>[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1
Reactant: CO
Reactant: N[C@H]1CCC[C@H](C(=O)O)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCC[C@H](N)C1
Temperature: 65 °C
Yield: 90.9 %

Procedure:
Thionyl chloride (0.6 ml) was added to a solution of trans-3-amino-cyclohexane carboxylic acid (0.5 g, 2.8 mmol) in MeOH (20 ml) at 0° C. The reaction mixture was heated to 65° C. and concentrated in vacuum. The resulting residue was partitioned between saturated sodium bicarbonate (10 ml) and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 400 mg (90.9%) of trans-methyl 3-aminocyclohexanecarboxylate as colorless liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 52.7 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-4-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (52 mg, 53% over 2 steps) as a red solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.37 (s, 1H), 8.21 (m, 3H), 8.02 (d, J=8.8 Hz, 1H), 7.72 (dd, J=9.3, 2.9 Hz, 1H), 7.36 (s, 2H), 7.18 (d, J=9.2 Hz, 1H), 4.52 (d, J=13.2 Hz, 2H), 3.44 (m, 1H), 3.14 (t, J=11.8 Hz, 2H), 2.83 (m, 1H), 2.15 (d, J=11.5 Hz, 2H), 1.69 (dd, J=24.5, 7.9 Hz, 2H), 1.21 (m, 4H); ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC 99.0% (AUC), tR=10.73 min.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH:36]=O)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](C=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
A solution, cooled to -20° C., of 331.6 g of tetrabromomethane in 1 l of dry methylene chloride was treated dropwise under nitrogen gasification within 30 minutes with a solution of 524.6 g of triphenylphosphine in 1 l of methylene chloride. The mixture was subsequently stirred at -5° C. for a further 30 minutes, then treated dropwise at this temperature within 30 minutes with a solution of 91.2 g of trans-4-pentylcyclohexanecarboxaldehyde in 500 ml of methylene chloride and stirred at -5° C. for a further 2 hours. The mixture was poured into 6 l of hexane, the mixture was stirred at -20° C. for 1 hour and then the precipitate was filtered off under suction and washed well with about 1 l of cold (-20° C.) hexane. The filtrate was concentrated to a volume of about 1 l on a rotary evaporator, dilued with 2 l of hexane, again concentrated to a volume of about 1 l and stirred at -20° C. for a further 1 hour. The precipitate was filtered off under suction and rinsed well with about 500 ml of cold (-20° C.) hexane. The filtrate was freed from solvent on a rotary evaporator and the yellow oil obtained was filtered chromatographically on silica gel with about 3 l of hexane. The eluate was evaporated up to constant weight on a rotary evaporator, there being obtained 122.8 g (72.6%) of trans-1-(2,2-dibromovinyl)-4-pentylcyclohexane as a colourless oil; Rf-value (hexane) 0.55.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[C:15](/[CH3:22])=[CH:16]\[C:17](OCC)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>CCOCC.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([CH3:22])[CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C(/C)c1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC(CCO)c1cccc(OCc2ccccc2)c1

Procedure:
A solution of ethyl 3-(3-benzyloxyphenyl)crotonate (17.7 g., 60 mM) in ether (250 ml.) is added to a mixture of lithium aluminum hydride (3.42 g., 90 mM) and ether (250 ml.). Aluminum chloride (0.18 g., 1.35 mM) is added and the mixture refluxed for 12 hours and then cooled. Water (3.4 ml.), sodium hydroxide (3.4 ml. of 6 N) and water (10 ml.) are then added successively to the reaction mixture. The inorganic salts which precipitate are filtered off and the filtrate is then concentrated in vacuo to give the desired alcohol as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[CH:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c([N+](=O)[O-])cn1)c1ccc(F)cc1
Temperature: 180 °C
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyridin-4-amine (Method 90, 0.15 g, 0.54 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.093 g, 0.67 mmol), and DIEA (0.12 ml, 0.67 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 180° C. for 32 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.168 g, 82%). 1H NMR (400 MHz) 12.37 (s, 1H), 9.59 (b, 1H), 8.83 (s, 1H), 8.20 (b, 1H), 7.37 (m, 2H), 7.13 (m, 2H), 6.69 (b, 1H), 5.88 (b, 1H), 5.29 (m, 1H), 1.91 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 0.97 (m, 2H), 0.71 (m 2H). MS: Calcd.: 382; Found: [M+H]+ 383.
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[Mg].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.Cl>O1CCCC1.[Li+].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Cu+2].C(OCC)(=O)C>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: BrCCCCCCCCCCBr
Reactant: CC(C)CBr
Agent: [Cu+2]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCCCCCCCCCCBr
Reaction time: 1 h
Yield: 33.1 %

Procedure:
Isobutyl bromide (27.4 g) was added to magnesium (5.0 g) in tetrahydrofuran (100 ml). The mixture was stirred for 1 hour under nitrogen atmosphere. The mixture was added to a solution of 1,10-dibromodecane (50.0 g) and dilithium tetrachlorocuprate (1 m mole) in tetrahydrofuran (100 ml) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 1 hour and poured into a mixture of 7% hydrochloric acid (200 ml) and ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was distilled under reduced pressure to give a mixture of the product and 1,10-dibromodecane as a colorless oil (27.23 g) (bp.115-120° C./0.5 Torr). The mixture was chromatographed on a silica gel column eluting with n-hexane to give 1-bromo-12-methyltridecane as an oil (15.3 g).
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:3].[CH2:20]([OH:23])[CH2:21][OH:22]>C(Cl)Cl>[O:13]=[C:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:4]([C:2]([O:22][CH2:21][CH2:20][OH:23])=[O:3])=[CH:5][C:6]1=2
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: OCCO
Solvent: ClCCl
Product: O=C(OCCO)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1.0 gm of 2-chlorocarbonyl-6,11-dihydro-11-oxo-dibenz[b,e]oxepin in 50 cc of methylene chloride, add 3 gm of ethylene glycol and stir the mixture for 18 hours at room temperature. Distill off the solvent and excess ethylene glycol under high vacuum (0.1 mm). Chromatograph the residue on a silica gel column (100 gm), eluting with 10% ethyl acetate in benzene to obtain the title product.