Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[C:4]([CH3:18])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C1CCN2C(=NCCC2)CC1>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:12])=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(I)ccc1Nc1cnccc1C(=O)NS(C)(=O)=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
3-[(4-Iodo-2-methylphenyl)amino]isonicotinic acid (example 3) (50 mg, 0.141 mmol) was dissolved in 4 ml dry THF followed by the addition of 1,1′-carbonyldiimidazole (CDI) (0.311 mmol, 50 mg), methanesulfonamide (0.169 mmol, 16.1 mg) and DBU (0.169 mmol, 26 mg). The mixture was stirred for 16 h at 40° C. and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 20.3 mg (47 μmol; 33% yield) of pure desired product. LC-MS (method III): rt=2.74 min; m/z [M+H]+ 432.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][O-:16].[Na+].[C]=O.[BH4-].[Na+]>CN(C=O)C>[CH:4]1[C:5]2[CH:6]([CH2:15][OH:16])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc2c(c1)Cc1ccccc1C2
Reactant: C[O-]
Agent: [BH4-]
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC1c2ccccc2Cc2ccccc21
Yield: 83 %

Procedure:
According to the procedure described in Example 3, a mixture of 9.0 grams of 9,10-dihydroanthracene, 3.5 grams of sodium methoxide and 25 cc of DMF was treated with carbon monoxide under an initial pressure of 800 psig. At the end, residual CO (400 psig) was released, and a sodium borohydride solution (1 gram in 10 cc of water) was added to the mixture. Excess hydride was destroyed by adding a hydrochloric acid solution. The mixture was then extracted with ether. An 83% yield of 9,10-dihydro-9-anthracenemethanol was realized. The separation was carried out by evaporating off the solvent, then extracting the desired product from the residue with methanol. Recrystallization from benzene-pentane gave 6.0 grams of white powder, mp=105° C. which was identified as 9,10-dihydro-9-anthracenemethanol. Five grams of this product was mixed with 1.0 grams of silica-alumina (Davison SMR5-1020, 87% SiO2 -13% Al2O3, BET surface area 350 m2 /gr) and heated under a nitrogen flow to 250° C. After cooling, the solid was dissolved in benzene, and methanol was added to recrystallize 4.5 grams of white plates which was identified to be pure 5H-dibenzo(a,d)cycloheptene, i.e. a compound having the structure of compound I.
Reaction SMILES: [F:1][S:2]([F:19])([F:18])([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14]O)=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:22]>C1(C)C=CC=CC=1>[Cl:22][CH2:14][C:13]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2]([F:19])([F:18])([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[N:10]=[N:11][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nnnn1-c1ccc(S(F)(F)(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FS(F)(F)(F)(F)c1ccc(-n2nnnc2CCl)cc1
Reaction time: 4 h

Procedure:
Thionyl chloride (1.72 g, 14.4 mmol) was added to a stirred solution of {1-[4-(pentafluoro-λ6-sulfanyl)phenyl]-1H-tetrazol-5-yl}methanol (Intermediate 44, 3.50 g, 11.6 mmol) in toluene (40 mL), SOCl2 at room temperature. The reaction mixture was stirred for 4 hr at reflux. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM and washed with ice-water, saturated aq NaHCO3 and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluted with 20%-30% EtOAc/pet-ether to give the title compound as a brown gum (3.50 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:14]=1
Reactant: COC(=O)CCNCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCNCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Methyl 3-[(4-benzyloxyphenyl)methylamino]-propionate (27.3 g, 91.1 mmol) was dissolved in ethanol (300 mL), and the resulting solution was cooled with ice and 10% palladium-carbon (3.0 g) was added. The resulting solution was stirred for 4.5 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite to remove insoluble matter, and the filtrate was concentrated under reduced pressure to thereby yield 19.1 g of the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:17][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][CH:14]=[CH:13]3)=[C:8]2[CH2:7][CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.CN(C)[CH:28]=[O:29]>>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:17][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][CH:14]=[C:13]3[CH:28]=[O:29])=[C:8]2[CH2:7][CH2:6]1)[CH2:19][CH3:20]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)C1CCc2c(ccc3cc[nH]c23)C1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1CCc2c(ccc3c(C=O)c[nH]c23)C1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A solution of di-n-propyl-(6,7,8,9-tetrahydro-1H-benzo[g]indol-7yl)amine, (3a, Chart 1)(0.90 g, 3.33 mmol) in dimethyl formamide (10 mL) was added dropwise to an ice-cooled solution of phosphorous oxychloride (1.2 ml, 0.73 g, 4.8 mmol) under an inert atmosphere. The solution was stirred for 10 minutes and was then heated to 50° C. After stirring for 3 hours, the solution was allowed to reach ambient temperature, stirred overnight and was then poured on ice. After basification, the mixture was heated to 80° C. for 10 minutes and then cooled. Extraction three times (dichloromethane), followed by drying (magnesium sulfate), filtering and evaporation several times with 99% ethanol, yielded 0.82 g (82%) of the material. This material was further purified on a silica column (dichloromethane/methanol, 3:1) to yield 0.53 g (53%) of the pure material as an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:21](=O)[CH:20]2[CH:16]([CH2:17][NH:18][CH2:19]2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:15][C@@H:16]2[C@@H:20]([CH2:19][NH:18][CH2:17]2)[CH2:21]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C2CNCC2C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2C[C@H]3CNC[C@H]3C2)cc1
Temperature: 70 °C
Yield: 80 %

Procedure:
Lithium aluminium hydride (1M in THF, 85 ml, 85 mmol) was added slowly to a stirred solution of 2-benzyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione (6.4 g, 27.8 mmol) in dry tetrahydrofuran (60 ml) at room temperature under nitrogen. Upon complete addition, the mixture was stirred and heated at 70° C. for 16 h. The mixture was then cooled to 0° C. and carefully quenched with water (3.2 ml), followed by 4N sodium hydroxide (3.2 ml) and water (4.5 ml). The mixture was filtered, washing with ethyl acetate. The filtrate was evaporated and the residue was purified by chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (40:8:1→30:8:1) to give the title amine (4.5 g, 80%) as a clear oil. 1H NMR δ (360 MHz, CDCl3) 2.24-2.28 (2H, m), 2.42 (1H, s), 2.56-2.64 (4H, m), 2.68 (1H, dd, J=11.5. 2.4 Hz), 2.77-2.83 (2H, m), 3.44 (2H, s, CH2Ph), 7.13-7.30 (5H, m, Ar--H). 13C NMR δ (90.5 MHz, CDCl3) 43.6 (CH), 54.4 (CH2), 59.9 (CH2), 60.8 (CH2), 126.8 (CH), 128.2 (CH), 128.8 (CH), 139.3 (C).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH3:5])[CH2:2]1.COC1C=CC(O)=CC=1.[OH-].[K+].[C:17]([OH:22])(=[O:21])[C:18]([CH3:20])=[CH2:19]>[OH-].[Na+]>[C:17]([O:22][CH2:2][CH:3]([OH:1])[CH2:4][CH3:5])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: CCC1CO1
Reactant: C=C(C)C(=O)O
Agent: COc1ccc(O)cc1
Agent: [K+]
Agent: [Na+]
Product: C=C(C)C(=O)OCC(O)CC
Temperature: 88 °C
Reaction time: 8 h

Procedure:
A blend of 72 grams 1,2-epoxybutane (Aldrich), 0.85 g 4-methoxyphenol (Aldrich), and 6.5 g potassium hydroxide was stirred in a 500 ml round bottomed flask equipped with an addition funnel and thermocouple thermometer. 172 g methacrylic acid was added via the addition funnel, and the blend was slowly to 75° C., and stirred overnight under an air, then increased to 88° C. for 4 hours. The mixture was cooled, and 700 ml of 2.0 N NaOH was added to the mixture in a separatory funnel. The upper layer was washed with borate buffered saline three times. Ethyl ether (200 ml) was added to the combined saline washes to extract any product. The combined organic layers were dried over NaSO4. The NaSO4 was filtered out and the product was distilled (90-98° C./˜4 mm Hg). 17.5 g product was collected, to which was added 4 mg 4-methoxyphenol. 1H NMR: 6.1 ppm (1H, m), 5.5 (1H, m), 4.8 (0.25H m), 4.2 (0.64H, dd, 8.1 and 11.7 Hz), 4.0 (0.64 Hz, dd, 6.9 and 11.4 Hz), 3.6-3.8 1.26H, m), 2.3 (OH, br s), 1.9 (3 H, m), 1.4-1.7 (2 H, m), 0.9 (3H, m); consistent with a blend of 2-hydroxy-1-propylmethacrylate and 1-hydroxy-2-propylmethacrylate.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 82464.7 %

Procedure:
To a solution of 1.018 g (2.95 mM) of 3-hexadecylthio-2-methoxypropylamine IVa2 in 15 ml of dichloromethane and 0.534 ml (3.83 mM) of triethylamine is added 0.563 mg (3.24 mM) of 3-chloropropanesulfonyl chloride with ice-cooling and the mixture is stirred at 0° C. for 3 hours. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (4:1) mixture as an eluent. The product is recrystallized from chloroform-n-hexane to give 1.275 g (2.62 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecylthio-2-methoxypropane IIIa2 as a colorless powder in 89% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: Cc1ccccc1S(=O)(=O)Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[F:13][C:14](F)([F:17])[CH2:15][OH:16].[OH-].[Li+]>>[F:13][CH:14]([F:17])[CH2:15][O:16][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC(F)F)nc1
Temperature: 25 °C
Yield: 79 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 79% yield starting from ethyl 6-chloronicotinate and 2,2,2-trifluoroethanol. The reduction was performed using 3 equiv of lithium hydroxide, the reaction mixture was stirred at ambient temperature over night; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (d, 1 H), 8.20 (dd, 1 H), 7.02 (d, 1 H), 6.21-6.57 (m, 1 H), 4.65 (dt, 2 H); MS (ESI) m/z 202[M−H+].
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:29]([O:33][C:34]([NH:36][C:37]1[S:41][C:40]([C:42]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([O:49][CH3:50])[C:43]=2[F:51])=[N:39][C:38]=1[C:52](O)=[O:53])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:52]([C:38]3[N:39]=[C:40]([C:42]4[C:47]([F:48])=[CH:46][CH:45]=[C:44]([O:49][CH3:50])[C:43]=4[F:51])[S:41][C:37]=3[NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[O:53])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)c(NC(=O)OC(C)(C)C)s2)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.5 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (10.0 mg, 0.0256 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylic acid (9.9 mg, 0.026 mmol) and HATU (24.3 mg, 0.064 mmol) in DMF (0.06 mL) and DIPEA (0.014 mL, 0.077 mmol) was stirred at room temperature for 4 h. The mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (3.2 mg, 16%). LCMS calc. for C36H45F2N6O8S (M+H)+: m/z=759.3. Found: 759.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:31])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:14]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:31])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COCOc1ccc(Cc2c(C)cc(C(=O)OC)cc2C)cc1Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOc1ccc(Cc2c(C)cc(C(=O)O)cc2C)cc1Cc1ccc(F)cc1
Temperature: 50 °C
Yield: 99.7 %

Procedure:
To a stirring solution of afford methyl 3,5-dimethyl-4-[3′-(4-fluorobenzyl)-4′-methoxymethoxybenzyl]benzoate (compound 78, step f, 2.8 g, 6.63 mmol) in MeOH (80 mL) at 0° C. was added NaOH (27 mL, 1 N). After heating at 50° C. for 16 h, the solvent was removed under reduced pressure and the residue was acidified with 1 N HCl to pH=1, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3,5-dimethyl-4-[3′-(4-fluorobenzyl)-4′-methoxymethoxybenzyl]benzoic acid as white solid (2.7 g, 100%): 1H NMR (300 MHz, DMSO-d6): 12.71 (s, 1H), 7.64 (s, 2H), 7.01-7.22 (m, 4H), 6.95 (d, J=8.4 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.73 (dd, J=2.1, 8.4 Hz, 1H), 5.15 (s, 2H), 3.98 (s, 2H), 3.86 (s, 2H), 3.27 (s, 3H), 2.25 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:19]=2[N:20]=[CH:21][N:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:15])[C:17]2[C:18]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CN[C@@H]1CCCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)[C@@H]4CCCN(Cc5ccccc5)C4)ncnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of (R)-1-benzyl-N-methylpiperidin-3-amine (800 mg, 3.9 mmol) and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 3.9 mmol) in DMF (10 mL), DIEA (2.02 mL, 15.6 mmol) was added and the reaction mixture was stirred at 60° C. overnight. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (100 mL) and was washed with water (3×40 mL). The EtOAc layer was then dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (750 mg, 40%). 1H-NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.38 (d, 0.1=4.0 Hz, 1H), 7.28 (m, 7H), 6.53 (d, J=3.6 Hz, 1H), 3.59 (d, J=13.2 Hz, 1H), 3.46 (d, J=13.2 Hz, 1H), 3.13 (s, 3H), 2.89 (m, 2H), 2.37 (s, 3H), 2.09 (t, J=10.8 Hz, 1H), 1.96 (dt, J=1.2, 10.8 Hz, 1H), 1.83 (m, 2H), 1.65 (m, 3H). LC-MS: m/z [M+1]=476.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li:10]CCCC.ClB(Cl)C1CCCC1.O>CCOCC>[S:1]1[C:5]([Li:10])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: [Li]CCCC
Agent: ClB(Cl)C1CCCC1
Solvent: CCOCC
Solvent: O
Product: [Li]c1cc2ccccc2s1
Temperature: -90 °C

Procedure:
A dry 100 mL round-bottomed flask equipped with a mechanical stirrer, a reflux condenser, a low temperature thermometer and a silicone rubber septum was flushed with argon. 2-benzo[B]thienyllithium was prepared in situ from 1.1 g of benzo[B]thiophene (8.21 mmol) and 3.3 mL of 2.5 m solution of n-BuLi (in hexanes) in 20 mL of ether. The mixture was cooled to -90° C. and the solution of dichlorocyclopentylborane obtained in step 1 was added over 10 min while stirring was maintained. The mixture was brought to 20° C. and stirred for 2 h at this temperature. Distilled water (20 mL) was added with vigorous stirring. The top layer formed was separated and discarded. The aqueous layer was poured into 30 mL of saturated solution of NME4CL and shaken. The precipitate formed was filtered, washed with 60 ml of distilled water, and recrystallized from acetone/methanol=3/2 yielding 1.2 g (79%) of white crystalline solid. m.p. 234-236° C. 1H NMR (D6 -DMSO, 200 MHz) δ 7.69 (d, J=7.6 Hz, 3H), 7.57 (d, J=7.6 Hz, 3H), 7.14 (t, J=7.4 Hz, 3H), 7.07 (s, 3H), 7.04 (t, J=7.4 Hz, 3H), 3.04 (s, 12H), 1.85 (m, 2H), 1.65 (m, 1H), 1.37 (br s, 6H). 13C NMR (D6 -DMSO, 50 MHz) δ 141.9, 124.1, 122.5, 121.4, 120.9, 54.51 (t, J=4 HZ), 31.38, 27.34. 11B NMR (DMSO, 128 MHz) δ -30.36. Anal. Calcd. for C33H36BNS3 : C, 71.59; H, 6.55; N, 2.53; S, 17.37. Found: C, 71.50; H, 6.63; N, 2.53; S, 17.30.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[H][H]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[C:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:8]1)#[N:2]
Reactant: [H][H]
Reactant: CCCCCc1ccc(-c2ccc(C=C[C@H]3CC[C@H](C#N)CC3)cc2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C#N)CC3)cc2)cc1
Yield: 90.1 %

Procedure:
3.4 g of 4-[2-(trans-4-cyanocyclohexyl)ethenyl]-4'-pentylbiphenyl were dissolved in 150 ml of toluene/ethanol (volume ratio 4:1), treated with 300 ml of 10% palladium/carbon and hydrogenated at normal pressure and room temperature until the hydrogen uptake came to a standstill. Filtration of the mixture and low-pressure chromatography (0.5 bar) of the concentrated filtrate on silica gel with 5% ethyl acetate/petroleum ether as the eluant gave 3.08 g of 4-[2-(trans-4-cyanocyclohexyl)-ethyl]-4'-pentylbiphenyl as colourless crystals (purity 99.2%; yield 86% based on trans-4-cyanocyclohexanecarboxaldehyde). By additional recrystallization of a sample from ethanol there was obtained pure product of melting point (C-S) 59.7° C., t.p. (S-S) 68.1° C., t.p. (S-N) 89.0° C. and cl.p. (N-I) 134.5° C.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:46][O:47]C2CCC=C2)[C:9]([NH:11][C@@H:12]2[C:44](=[O:45])[N:14]3[C:15]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:29])=[C:16]([CH2:19][N+:20]4[N:21]([CH3:27])[CH:22]=[C:23]([CH2:25][OH:26])[CH:24]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:46][OH:47])[C:9]([NH:11][C@@H:12]2[C:44](=[O:45])[N:14]3[C:15]([C:28]([O-:30])=[O:29])=[C:16]([CH2:19][N+:20]4[N:21]([CH3:27])[CH:22]=[C:23]([CH2:25][OH:26])[CH:24]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1
Reactant: Cn1cc(CO)c[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cn1cc(CO)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Yield: 26 %

Procedure:
To a solution of benzhydryl 7β-[2-(2-aminothiazol-4-yl)-2-(2-cyclopenten-1-yloxyimino)acetamido]-3-(4-hydroxymethyl-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate chloride (syn isomer, 1.9 g), anisole (2 ml) and methylene chloride (6 ml) was added trifluoroacetic acid (4 ml) under ice-cooling with stirring. After stirring at the same temperature for 1 hour, the mixture was dissolved in water and the solution was adjusted to pH 4 with 5% aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" and eluted with 3% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected, combined, concentrated, and finally lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(4-hydroxymethyl-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer, 0.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[N:16]=[C:15](O)[CH:14]=[C:13]([CH3:18])[N:12]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11](/[CH:10]=[CH:9]/[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2ccc(Cl)cc2Cl)n1
Product: Cc1cc(Cl)nc(/C=C/c2ccc(Cl)cc2Cl)n1
Yield: 92.1 %

Procedure:
In analogy to example 12c), by heating (E)-2-[2-(2,4-dichloro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (0.5 g, 1.78 mmol) in POCl3 (3.26 ml, 35.6 mmol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(2,4-dichloro-phenyl)-vinyl]-6-methyl-pyrimidine (0.491 g, 92%) as a pink solid. EI mass spectrum, m/e: 298 (M calculated for C13H9Cl3N2: 298).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[CH:15]=[CH:14][C:13]3[C:17]4[C:22]([CH:23]=[CH:24][C:12]=3[C:11]=2[NH:10][C:9]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=[CH:19][CH:18]=4>C(Cl)Cl.CCCCCC>[CH3:5][N:10]1[C:11]2[C:12]3[CH:24]=[CH:23][C:22]4[C:17]([C:13]=3[CH:14]=[CH:15][C:16]=2[CH:8]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:19]=[CH:20][CH:21]=4
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2[nH]1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2n1C
Yield: 74.5 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 3H-naphth[1,2-g]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 74.5% yield of ethyl 3-methyl-3H-naphth[1,2-g]indol-2-carboxylate, mp 136°-138°, (CH2Cl2 /hexane), (C,H,N).