Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:18][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([OH:20])[CH3:21])[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CN(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (1 g, 5 mmol) was dissolved in 15 mL DMF and stirred for 10 min at 0° C. Sodium hydride (600 mg, 15 mmol) was added portionwise at RT and stirred for 10 min. 3-(2-Methyl-oxiranyl)-pyridine (1.01 g, 7.5 mmol) was added dropwise at the same temperature and the mixture stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (4×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated and the residue was crystallized in EtOH and ether to obtain 375 mg of 1-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-3-yl-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.76 (d, 1H), 8.55 (dd, 1H), 7.703 (d, 1H), 7.24 (s, 1H), 7.23 (dd, 1H), 7.15 (d, 1H), 6.95 (d, 1H), 4.13 (d, 1H), 4.08 (d, 1H), 3.38 (dd, 2H), 2.79 (q, 2H), 2.74 (q, 2H), 2.46 (s, 3H), 2.43 (s, 3H), 1.64 (s, 3H). Separation by chiral HPLC provided enantiomers 14a and 14b. Optical rotations: Compound 14a, (+)31.28 (c 0.58, Chloroform, 96.04% HPLC purity); Compound 14b, (−)27.23 (c 0.57, Chloroform, 96.09% HPLC purity).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][Si:10]([CH3:15])([O:13][CH3:14])[O:11][CH3:12].N.[Cl-]>>[C:2]1([NH:1][CH2:9][Si:10]([O:13][CH3:14])([O:11][CH3:12])[CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[Si](C)(CCl)OC
Reactant: Nc1ccccc1
Agent: N
Agent: [Cl-]
Product: CO[Si](C)(CNc1ccccc1)OC
Temperature: 30 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
In a 500 ml four-neck flask with reflux condenser, precision glass stirrer, thermometer and gas inlet tube, 298 g of dry aniline were heated to 130° C. and admixed with 124 g of (chloromethyl)methyl-dimethoxysilane with stirring within 60 min. When the addition had ended, ammonia was passed through the mixture with uniform temperature with stirring until no further reaction was observed (approx. 60 min). Thereafter, excess aniline was removed under reduced pressure, and the suspension was cooled to 30° C. and then admixed with 150 ml of isohexane. Subsequently, the white precipitate formed was filtered through a suction filter and washed with 2×80 ml of isohexane. Filtrate and wash solutions were combined and freed from the solvent under reduced pressure. The subsequent fractional distillation gave 160 g (95% yield) of (N-phenylaminomethyl)dimethoxy(methyl)silane with a chloride content of <20 ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)#[N:2].[OH-:31].[K+]>C(O)CCC>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:31]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccccc4)cc23)CC1
Agent: [K+]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 85 °C
Yield: 59.9 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(7-cyano-5-phenyl-1H-indazol-3-yl)-1-piperidine-carboxylate (Intermediate 4) (1.1 g, 2.7 mmols), and potassium hydroxide (1.53 g, 27.3 mmols) in n-butanol (100 mL) was heated at 85° C. for 2-3 days then at reflux overnight. The solution was cooled and the solvent removed in vacuo. The resulting residue was purified via silica gel chromatography eluting with 50% ethyl acetate/pentane, 100% ethyl acetate, and 30% methanol/ethyl acetate to give 0.68 g of a yellow solid. LC/MS M+H 421
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]=[CH2:5].I[CH3:16]>O1CCCC1.O>[CH2:3]([O:6][N:7]([CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]=[CH2:5]
Reactant: C=CCONC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCON(C)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
Sodium hydride (NaH, 60% dispersion in mineral oil; 390 mg, 9.7 mmol, 1.1 equiv) was added to a stirred solution of tert-butyl 2-propenyloxycarbamate (2.0 g, 8.8 mmol, 1.0 equiv) in tetrahydrofuran (THF; 23 mL) at 0° C. The resulting bubbling white mixture was warmed to 23° C. and stirred for 15 minutes (min) Iodomethane (660 μL, 11 mmol, 1.2 equiv) was added and the resulting colorless solution was stirred at 23° C. for 18 h. The reaction mixture was diluted with H2O (100 mL) and extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford a yellow oil (1.6 g, 99%): 1H NMR (300 MHz, CDCl3) δ 5.98 (m, 1H), 5.37-5.24 (m, 2H), 4.33 (dt, J=6, 1 Hz, 2H), 3.10 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: Br[CH:2]1[C:8](=O)[CH2:7][CH2:6][CH2:5][N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:3]1=[O:19].[O:20]([CH2:27][C:28]([NH2:30])=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:4]2[CH2:5][CH2:6][CH2:7][C:8]3[N:30]=[C:28]([CH2:27][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:29][C:2]=3[C:3]2=[O:19])=[CH:12][CH:13]=1
Reactant: NC(=S)COc1ccccc1
Reactant: COc1ccc(CN2CCCC(=O)C(Br)C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CCCc3nc(COc4ccccc4)sc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
A mixture of 3-bromodihydro-1-[(4-methoxyphenyl)methyl]-1H-azepine-2,4(3H,5H)-dione (0.78 g, 2.38 mmol) and 2-phenoxythioacetamide (0.36 g, 2.14 mmol) in DMF (12.5 mL) was stirred at room temperature for 15 minutes. Then NaHCO3 (0.32 g, 3.81 mmol) was added and the reaction was stirred at 100° C. for 30 minutes. The reaction was diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 5,6,7,8-tetrahydro-5-[(4-methoxyphenyl)methyl]-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.58 g, 62% yield) as an orange oil. C22H22N2O3S LCMS: Rt 3.01, m/z 395 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[CH3:20][C:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:24]([C:21]3([CH3:20])[CH2:23][CH2:22]3)=[O:25])=[CH:9][C:8]=2[C:14]([F:15])([F:16])[F:17])=[CH:18][CH:19]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(C(F)(F)F)c1
Reactant: CC1(C(=O)Cl)CC1
Solvent: C1CCOC1
Product: CC1(C(=O)Nc2ccc(Oc3ccc(Cl)cc3)c(C(F)(F)F)c2)CC1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a stirred solution of 5.75 g (0.02 mole) of the amine prepared under (b) above in 40 ml of tetrahydrofuran was added dropwise 2.4 g (0.02 mole) of 1-methylcyclopropylcarboxylic chloride. The mixture was stirred and heated at 60° C. for 0.5 hour, poured into ice water and filtered. The filter cake was recrystallized from ether-hexane (1:3) to give 6.5 g (88%) of product, m.p. 115°-117° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:31])=[CH:22][C:23]=2C2C=CC=CC=2Cl)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[C:39]([CH3:46])[CH:38]=1>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:32])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:31])=[CH:22][C:23]=2[C:40]2[CH:41]=[CH:42][C:37]([F:36])=[CH:38][C:39]=2[CH3:46])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:34])([F:35])[F:1])[CH:8]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Product: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared according to the procedures described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide (Example 24) using (4-fluoro-2-methylphenyl)boronic acid instead of 2-chlorophenylboronic acid in step c).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13]CC)=O)=[C:9]([NH2:16])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1)=[O:5])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31](Cl)[C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:11](=[O:13])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][CH:28]=3)[C:31]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[N:16][C:9]=2[N:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(N)c1C(=O)OCC
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1nn(-c2ccccc2)c2nc(-c3ccc(-c4ccccc4)cc3)n(-c3ccc(Cl)cc3)c(=O)c12

Procedure:
6-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid ethyl ester is prepared from 5-amino-1-phenyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester and N-(4-chloro-phenyl)-biphenyl-4-carboximidoyl chloride by following a similar procedure as described in example 2 and purified by preparative LC/MS. 1H NMR (CDCfe) δ(ppm) 8.14(d, 2H), 7.36˜7.57(m, 12H), 7.33(d, 2H), 7.14(d, 2H), 4.53(q, 2H), 1.46(t, 3H); HPLC-MS calculated for C32H23ClN4O3 (M+H+): 547.2. Found: 547.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:12][C:11]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:10]2)=[N:6][CH:7]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:29]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3B(O)O)=[N:32][N:31]=[N:30]2)C=CC=CC=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH2:18]([C:11]1[N:12]=[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])[N:9]([CH2:8][C:5]2[N:6]=[CH:7][C:2]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:3][CH:4]=2)[N:10]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1nc(CCCC)n(Cc2ccc(Br)cn2)n1
Reactant: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cn2)n1
Yield: 29.4 %

Procedure:
Under nitrogen, 2.04 g (5.8 mmol) of 5-bromo-2-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine from step 4 and 2.83 g (6.6 mmol) of 2-(N-triphenylmethyltetrazol-5-yl)phenylboronic acid from step 5 were treated with 1.0 g (0.86 mmol) of tetrakis(triphenylphosphine)palladium zero, 18 mL of toluene, 14 mL of ethanol, and 7.5 mL of 2M aqueous sodium carbonate. The reaction mixture was heated to reflux and vigorously stirred overnight. The product was purified by reverse phase chromatography (Waters Deltaprep-3000) using acetonitrile/water (20-40:80-60) (0.05% TFA). The pure fractions (by analytical HPLC) were combined, the acetonitrile removed in vacuo, the pH adjusted to four with dilute sodium hydroxide, and the resulting suspension extracted 4 times with ether. The extracts were combined, dried (MgSO4), and concentrated in vacuo to give 710 mg (30%) of 5-[2-[6-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-3 -pyridinyl]phenyl]-1H-tetrazole as a colorless solid: mp 136°-138° C.; NMR (CD3OD) δ0.88-0.98 (m, 6H), 1.27-1.45 (m, 4H), 1.60-1.75 (m, 4H), 2.66 (t, J=7 Hz, 2H), 2.84 (t, J=7 Hz, 2H), 5.45 (s, 2H), 7.21 (d, J=8 Hz, 1H), 7.56-7.68 (m, 3H), 7.70-7.78 (m, 2H), 8.29 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 417 (100), 389 (10), 374 (10), 360 (10), 208 (35), 182 (25); HRMS. Calc'd for M+H: 417.2515. Found: 417.2486.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=1)[CH3:3].[NH2:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[C:25]([Cl:30])[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:30][C:25]1[CH:26]=[C:27]([O:21][CH:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]2[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)[C:17]([F:18])([F:20])[F:19])[N:28]=[C:23]([NH2:22])[N:24]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN(C)Cc1ccc(-c2ccccc2C(O)C(F)(F)F)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)Cc1ccc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)o1
Temperature: 110 °C
Yield: 38.5 %

Procedure:
The mixture of 1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]-2,2,2-trifluoro-ethanol (225 mg, 0.75 mmol), 2-amino-4,6-dichloro-pyrimidine (111 mg, 0.67 mmol), cesium carbonate (978 mg, 3.01 mmol) and 1,4-dioxane (3 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 110 mg of 4-chloro-6-{1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]2,2,2-trifluoro-ethoxy}-pyrimidin-2-ylamine, yield 87%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[C:7](=[O:23])[N:8](CC2C=CC(OC)=CC=2OC)[CH2:9][CH2:10][CH:11]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[C:7](=[O:23])[NH:8][CH2:9][CH2:10][CH:11]=1
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC1=CCCNC1=O
Temperature: 80 °C
Yield: 74 %

Procedure:
310 mg of 3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid methyl ester (d) (0.93 mM) was dissolved in 3 ml of trifluoroacetic acid solution. Then 0.222 ml of triethyl silane (1.395 mmol) was added thereto and the mixture was heated for 20 min at 80° C. The solvent was removed in vacuo and the remaining residue was diluted in 20 ml of chloroform. The organic layer was washed with 5 ml of sat. NaHCO3 solution and 5 ml of sat. NaCl solution. Then the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with EtOAc solvent as an eluant to give 126 mg of the title compound (f) (yield: 55%).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]=4[C@@:7]2([C:22]([O:24][CH3:25])=[O:23])[CH2:6][C@@H:5]([CH2:10]3)[CH:4]=1.[CH3:26][CH2:27][C:28]12[C@@H:46]([O:47][C:48]([CH3:50])=[O:49])[C@:45]([OH:55])([C:51]([O:53][CH3:54])=[O:52])[C@H:44]3[C@@:34]4([C:37]5[CH:38]=[CH:39][C:40]([O:57][CH3:58])=[CH:41][C:42]=5[N:43]3[CH3:56])[CH2:35][CH2:36][N:32]([C@@H:33]14)[CH2:31][CH:30]=[CH:29]2>>[CH3:1][CH2:2][C:3]1[CH2:8][N:9]2[CH2:10][C@@H:5]([CH2:6][C@:7]([C:22]([O:24][CH3:25])=[O:23])([C:39]3[CH:38]=[C:37]4[C@@:34]56[C@@H:44]([N:43]([CH3:56])[C:42]4=[CH:41][C:40]=3[O:57][CH3:58])[C@@:45]([OH:55])([C:51]([O:53][CH3:54])=[O:52])[C@H:46]([O:47][C:48]([CH3:50])=[O:49])[C@:28]3([CH2:27][CH3:26])[CH:29]=[CH:30][CH2:31][N:32]([C@H:33]53)[CH2:36][CH2:35]6)[C:14]3[NH:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]=3[CH2:12][CH2:11]2)[CH:4]=1
Reactant: CCC1=C[C@@H]2CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(C2)[C@@H]13
Reactant: CCC12C=CCN3CC[C@@]4(c5ccc(OC)cc5N(C)[C@H]4[C@@](O)(C(=O)OC)[C@@H]1OC(C)=O)[C@@H]32
Product: CCC1=C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1

Procedure:
In J. Am. Chem. Soc./98:22/Oct. 27, 1976, Langlois et al describe a process in which the monomers catharanthine and vindoline are coupled to form AVLB. The coupling is performed using a peracid to generate first the N-oxide of catharanthine, followed by Polonovski-type fragmentation of the N-oxide initiated with addition of trifluoroacetic anhydride to form a dimer. A reducing agent such as sodium borohydride is then added to generate AVLB which can be isolated e.g. chromatographically.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14](=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:7]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[N:13]=1
Reactant: COCCCc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COCCCc1ccc(-c2cc3ccccc3c(Cl)n2)cc1

Procedure:
The resulting 3-[4-(3-methoxypropyl)phenyl]isoquinolin-1-one (1.85 g) was reacted with phosphorus oxychloride (20 ml) according to the method of Example 10-2, to give 1-chloro-3-[4-(3-methoxypropyl)phenyl]isoquinoline. The resulting compound was reacted, as it was, with N-ethylpiperazine (6 ml) at 100° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The resulting ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.63 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])=[N:11][C:10]=1[CH3:21])=[O:8].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:15]2=[O:20])=[N:11][C:10]=1[CH3:21])=[O:8]
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1cccc(F)c1
Product: Cc1nc(N2CCCC(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccc(F)c1
Yield: 46 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-(3-fluorobenzyl)-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-fluorobenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 46% yield: mp 173-175° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.15-6.88 (m, 7H), 6.12 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 4.29-4.21 (m, 1H), 3.98-3.86 (m, 1H), 3.40-3.27 (m, 1H), 2.86-2.69 (m, 2H), 2.62 (s, 3H), 2.08-1.95 (m, 1H), 1.93-1.73 (m, 2H), 1.61-1.44 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.9, 162.9, 162.6, 161.6, 156.9, 152.4, 140.6, 134.5, 130.5, 130.2, 123.2, 119.1, 115.3, 114.6, 114.4, 47.9, 44.1, 43.4, 36.6, 24.8, 21.2, 17.3; MS (ES+) m/z 456.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([F:13])[F:12])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:14]([Mg]Br)=[CH2:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([F:12])[F:13])=[C:6]([CH:7]([OH:8])[CH:14]=[CH2:15])[CH:9]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cc(Cl)ccc1OC(F)F
Solvent: C1CCOC1
Product: C=CC(O)c1cc(Cl)ccc1OC(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
5-Chloro-2-(difluoromethoxy)benzaldehyde (0.480 g, 2.324 mmol) was dissolved in dry THF (11.62 mL) and the reaction was cooled to −78° C. under argon. Vinyl magnesium bromide (3.49 mL, 3.49 mmol) was then added dropwise. After the reaction was complete, the ice bath was removed and reaction was allowed to warm to rt and stirred for an additional 2 h. The reaction was cooled to 0° C. and then carefully quenched with saturated ammonium chloride. The mixture was then diluted with water and extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4, filtered and concentrated to yield 1-(5-chloro-2-(difluoromethoxy)phenyl)prop-2-en-1-ol (561 mg, 103%) as a clear oil. MS (ESI) m/z: 236.9 (M+H, Chlorine isotope peak)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>CN(C=O)C>[CH:12]1([CH2:11][N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]2)[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: O=Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cnn(CC2CC2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Add 1H-pyrazole-4-carbaldehyde (0.200 g, 2.08 mmol) to a suspension of sodium hydride (0.092 g, 2.29 mmol) in DMF (3 mL) at 0° C. Stir for 20 min. at 0° C. Add a solution of 1-(bromomethyl)cyclopropane (0.295 g, 2.18 mmol) in DMF (4 mL) dropwise to the reaction mixture. Stir reaction to ambient temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, dry combined organics (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 60:40 ethyl acetate:hexanes) to give the title preparation (175 mg, 56%). GC-MS: m/z=150 [M+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]OCCOC)=[C:7]([O:15][CH3:16])[N:6]=[C:5]([C:17]([F:20])([F:19])[F:18])[C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[ClH:26]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:26][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([C:17]([F:20])([F:19])[F:18])=[N:6][C:7]=1[O:15][CH3:16]
Reactant: Cl
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(OC)c(COCCOC)c1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)nc(OC)c(CCl)c1OC
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a solution of 15.5 g (0.0289 mol) of product of Example 26 in 30 ml of CH2Cl2 cooled in a ice water bath was added 12.0 g of titanium tetrachloride. The reaction mixture turned brown with formation of a white precipitate. After stirring at 10°-15° C. for 20 minutes, then at 20° C. for 20 minutes, the reaction mixture was poured into 70 ml of 6N HCl. The CH2Cl2 layer was separated, dried (MgSO4) and concentrated. The residue was kugelrohr distilled at 2 torr (pot temperature 140° C.) to give 9.1 g (97%) of product as a colorless liquid: nD25 1.4738.