Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@@H:11]([C:12]2[O:23][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]=2)[C@@H:24]([OH:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 25.6 %

Procedure:
The crude material from the reaction above N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 1b) (20.46 g, 52.89 mmol) was added to THF (800 mL) stirred at room temperature. Polystyrene fixed (2-tert-butylamino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazophosphorine) PS-BEMP (72.12 g, 158.67 mmol base, 2.2 mmol loading per gram base, Aldrich Chemical Company) was added to the solution followed by slow addition of para-toluenesulfonyl chloride (p-TSCl) (12.10 g, 63.47 mmol). The reaction mixture was stirred for 3 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed on silica gel with hexanes:EtOAc (6:4) to get the product (5.0 g). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.94 (d, J=9 Hz, 2H), 7.54 (m, 1H), 7.48 (m, 2H), 7.42 (d, J=9 Hz, 1H), 6.67 (d, J=9 Hz, 1H), 5.26 (d, J=9 Hz, 1H), 4.74 (d, J=9 Hz, 1H), 4.64 (m, 1H), 3.16 (d, J=5 Hz, 1H), 2.35 (s, 3H), 1.43 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C([O-])(=O)/C=C/C([O-])=O>>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([O:16][S:18]([CH3:17])(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN1CCN(c2cccc(O)c2)CC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CCCN1CCN(c2cccc(OS(C)(=O)=O)c2)CC1

Procedure:
Beginning with 3-(4-propyl-piperazin-1-yl)-phenol and methanesulfonyl chloride: m.p 143-144° C. (fumarate); MS m/z (rel. intensity, 70 eV) 298 (M+, 35), 269 (95), 121 (25), 84 (30), 70 (bp);
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[N:18]=[CH:17][C:16]=1Cl.OS([O-])(=O)=O.[Na+]>O1CCOCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1ccc2ncc(Cl)c(Br)c2c1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccnc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 113.3 %

Procedure:
To a suspension of NaH (60% in oil dispersion, 2.2 g, 54 mmol) in 1,4-dioxane (26 mL) was added diethyl malonate (9 mL, 59 mmol). The reaction mixture was stirred at rt for 5 min and heated at 80° C. for 1 h. After cooling to rt, CuBr (1.0 g) and 4-bromo-3-chloro-6-fluoro-quinoline (5 g, 19.4 mmol) in dioxane (8 mL) were successively added. The mixture was stirred at 100° C. overnight. After cooling, 10% aq. NaHSO4 (100 mL) was added. The mixture was stirred 30 min. The two layers were decanted and the aq. layer was extracted three times with EA (3×150 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated in DCM to yield the title compound as a yellow solid (6.71 g, 100% yield).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:15]([NH2:17])=[O:16])[C:8]([NH2:14])=[N:9]3)=[CH:4][C:3]=2[O:2]1.C[O-].[Na+].[C:21](OCC)(=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]4[C:15](=[O:16])[NH:17][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:14][C:8]4=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: NC(=O)c1cc2cc3c(cc2nc1N)OCO3
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1nc2nc3cc4c(cc3cc2c(=O)[nH]1)OCO4
Temperature: 150 °C

Procedure:
A mixture of 6,7-methylenedioxy-2-aminoquinoline-3-carboxamide (1.50 g., 6.5 millimoles), sodium methoxide (0.05 g., 1.25 millimoles) and diethyl oxalate (150 ml.) is heated to 150° C. for 3.5 hours. The mixture is then cooled to room temperature to precipitate the product which is recovered by filtration (1.0 g.). It is purified by chromatography on silica gel using chloroform:methanol (99:1) as eluant. The product is recovered by evaporation of the eluate and recrystallization of the residue from ethanol. Yield = 0.414 g. (20.4%) of the cyclized product. M.P. 267° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=O)=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][NH2:19])[CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccccc1
Solvent: CCO
Product: NN=C(c1ccc(Cl)cc1)C(O)c1ccccc1
Yield: 62.8 %

Procedure:
To a solution of 3.5 g 4-chlorobenzil in 15 ml ethanol is added 0.45 g anhydrous hydrazine. The solution is refluxed for 1 hour, filtered and water added to the cloud point, and allowed to crystallize yielding 2.3 g of 4-chlorobenzoin hydrazone.
Reaction SMILES: C[C@@H]1CC2C(=CC=C([C@@H:12]3[CH2:17][N:16]4[CH2:18][CH2:19][NH:20][CH2:21][C@H:15]4[CH2:14][N:13]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])C=2)C(=O)O1.Br[C:31]1[CH:32]=[CH:33][C:34]([F:39])=[C:35]([CH:38]=1)[C:36]#[N:37]>>[C:36]([C:35]1[CH:38]=[C:31]([C@@H:12]2[CH2:17][N:16]3[CH2:18][CH2:19][NH:20][CH2:21][C@H:15]3[CH2:14][N:13]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:32]=[CH:33][C:34]=1[F:39])#[N:37]
Reactant: C[C@@H]1Cc2cc([C@@H]3CN4CCNC[C@H]4CN3C(=O)OC(C)(C)C)ccc2C(=O)O1
Reactant: N#Cc1cc(Br)ccc1F
Product: CC(C)(C)OC(=O)N1C[C@@H]2CNCCN2C[C@H]1c1ccc(F)c(C#N)c1

Procedure:
(3R,9aS)-tert-butyl 3-(3-cyano-4-fluorophenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate was synthesized following the procedure of (3R,9aS)-tert-butyl 3-((R)-3-methyl-1-oxoisochroman-6-yl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate starting from 5-bromo-2-fluorobenzonitrile: LC/MS: (M+1)+: 361.17.
Reaction SMILES: [Si]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[N:20]([CH2:21][CH3:22])[C:19]2[C:18](OC3C=CC=CC=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1)(C(C)(C)C)(C)C.[CH3:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=1)[NH2:34].Cl.N1C=CC=CC=1.C1(O)C=CC=CC=1>ClCCl>[CH2:21]([N:20]1[C:19]2[C:18]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([O:38][C:39]4[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=4)=[C:31]([CH3:30])[CH:32]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=[C:12]1/[CH:11]=[CH:10]/[CH2:9][OH:8])[CH3:22]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CCn1c(/C=C/CO[Si](C)(C)C(C)(C)C)cc2ncnc(Oc3ccccc3)c21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Oc1ccccc1
Product: CCn1c(/C=C/CO)cc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 120 °C
Yield: 40.4 %

Procedure:
A mixture of 6-((1E)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propenyl)-5-ethyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (78 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (61.2 mg), pyridine hydrochloride (26 mg) and phenol (122 mg) was stirred with heating at 120° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with dichloromethane (30 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→80:20) to give the title compound (32 mg) as a powder.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[CH3:9][C:10]1[C:11]([NH:13][C:14](=[O:17])[C:15]=1[CH3:16])=[O:12].C(N(CC)CC)C.CO>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:13]1[C:14](=[O:17])[C:15]([CH3:16])=[C:10]([CH3:9])[C:11]1=[O:12])=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: CC1=C(C)C(=O)NC1=O
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: CC1=C(C)C(=O)N(C(=O)OCC(C)C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
iso-Butyl chloroformate (0.13 ml, 1 mmol) was added dropwise to a stirred solution of 2,3-dimethylmaleimide (0.1 g, 0.8 mmol) and triethylamine (0.13 ml, 0.92 mmol) in dimethylformamide (1.5 ml) at 0-5° C. The reaction mixture was allowed to warm to room temperature and stand for 4 h. Methyl alcohol (0.5 ml) was added, diluted with chloroform (5 ml) and washed with water (3×3 ml). The chloroform solution was dried (Na2SO4) and concentrated in vacuum to give N-iso-butoxycarbonyl-2,3-dimethylmaleimide (yield 83%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH2:15][OH:16])[O:12][C:11](=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:20]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH:15]([OH:20])[OH:16])[O:12][C:11](=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CO)C1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C(O)O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A mixture of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)-tetrahydropyran-2-one (150 mg, 0.58 mmol) and Dess-Martin periodinane (380 mg, 0.86 mmol) in CH2Cl2 (15 mL) is stirred at ambient temperature for 3 hours. The mixture is diluted with tBuMeO (20 mL), washed with saturated Na2S2O3 solution, saturated NaHCO3 solution, dried (MgSO4) and concentrated to give 139 mg (87%) of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dihydroxy methyl)tetrahydro-2H-pyran-2-one as white powder which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([CH3:20])[CH2:15][CH2:14][O:13][C:12]2=[O:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C1OCCC1S(=O)(=O)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(S(=O)(=O)c2ccc(Cl)cc2)CCOC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-(4-chlorobenzenesulfonyl)-dihydro-furan-2-one (0.599 g; 2.29 mmol) in DMF (5 mL) at 0-5° C. was added portionwise NaH (0.23 g of a 60% dispersion in mineral oil; 5.74 mmol). The mixture stirred 30 minutes and iodomethane (0.43 mL; 6.89 mmol) was added. The reaction warmed to room temperature while stiffing overnight and was quenched with water. The solid was filtered and dried in vacuo to provide the desired product. Wt 0.488 g. 1H NMR (CDCl3) δ 7.82 (d, 2H), 7.56 (d, 2H), 4.56 (m, 1H), 4.39 (m, 1H), 3.32 (m, 1H), 2.42 (m, 1H), 1.51 (s, 3H).
Reaction SMILES: C[CH:2]([CH2:11][CH2:12][CH:13]=[C:14](C)C)[CH2:3][CH2:4][CH2:5][C:6](=O)[C:7]([O-:9])=O.C[CH:18]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]CCCCCCC)[C:19](=[O:33])[C:20]([O:22]CCC(C)CCC=C(C)C)=O.CC(CC)C(=O)C(OCCC(C)CCC=C(C)C)=O.CC(CCC=C(C)C)CCC(C)C(=O)C([O-])=O.O=C(C1C=CC=CC=1)C(OCCC(C)CCC=C(C)C)=O.C1(C(=O)C(OC/C=C(\C)/CCC=C(C)C)=O)CCCCC1>>[CH:18]1([C:19](=[O:33])[C:20]([O:9][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:11][CH2:12][CH2:13][CH3:14])=[O:22])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Reactant: CCCCCCCCCCCCC(C)C(=O)C(=O)OCCC(C)CCC=C(C)C
Agent: CC(C)=CCC/C(C)=C/COC(=O)C(=O)C1CCCCC1
Agent: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCOC(=O)C(=O)c1ccccc1
Product: CCCCCCCCCCOC(=O)C(=O)C1CCCCC1

Procedure:
MS (EI): 296 (M+, 2); 185 (1); 158 (1); 156 (1); 112 (7); 111 (88); 110 (3); 85 (2); 84 (7); 83 (100); 81 (1); 79 (1); 71 82); 70 (1); 69 (2); 68 (1); 67 (3); 57 (5); 56 (3); 55 (23); 54 (1); 53 (1); 43 (7); 42 (2); 41 (10); 39 (2); 29 (2); 27 (1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:22][C:23]([C@H:25]([C@@:43]([OH:55])([CH2:51][C:52]([O-:54])=[O:53])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:24])[C:14]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:56]([O:59][CH2:60][CH2:61]Br)(=[O:58])[CH3:57].C(N(CC)C(C)C)(C)C.[I-].[Na+].[Cl-].[NH4+]>ClCCl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:22][C:23]([C@H:25]([C@@:43]([OH:55])([CH2:51][C:52]([O:54][CH:60]([O:59][C:56](=[O:58])[CH3:57])[CH3:61])=[O:53])[C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:24])[C:14]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC(=O)OCCBr
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)[O-])C(=O)OC(C)(C)C)C(=O)OCC(=O)OC)cc1
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)OC(C)OC(C)=O)C(=O)OC(C)(C)C)C(=O)OCC(=O)OC)cc1
Temperature: 40 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
1-tert-Butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonylmethoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate (18 mg, 0.0233 mmol) was dissolved in dichloromethane (1.8 mL), and bromoethyl acetate (8.2 μL, 0.0700 mmol), N,N-diisopropylethylamine (12.2 μL, 0.0700 mmol), and sodium iodide (10.5 mg, 0.0700 mol) were added. The mixture was stirred at 40° C. for 19 hours and cooled to room temperature, and a saturated aqueous solution of ammonium chloride (15 mL) was then added. After ethyl acetate extraction, the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off to obtain 19 mg of crude 1-tert-butyl 4-(1-acetoxy-ethyl) (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonylmethoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate. The obtained crude product was used in the next reaction without further purification (ESI (LC/MS positive mode) m/z 858 (M+H); Rt 2.82 min.).
Reaction SMILES: CC(O)C.[CH2:5]([P:9]([CH2:12][CH:13]([CH3:15])[CH3:14])(=[S:11])[SH:10])[CH:6]([CH3:8])[CH3:7].[OH-].[CH2:17]([N+:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].CCCCCC>O>[CH2:5]([P:9]([CH2:12][CH:13]([CH3:15])[CH3:14])(=[S:10])[S-:11])[CH:6]([CH3:8])[CH3:7].[CH2:30]([N+:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)CP(=S)(S)CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC(C)CP(=S)([S-])CC(C)C
Reaction time: 1 h

Procedure:
To 40 ml of 2-propanol, 3.63 g diisobutyldithiophosphinic acid and 7.34 g of 55-60% by weight tetrabutylammonium hydroxide in water were added. The mixture was stirred under nitrogen for one hour. The solvent was removed by distillation. To remove residual water, 2-propanol was twice added and subsequently removed by distillation. The liquid was cooled to less than 0 C for 16 hours. To the precipitates that formed, a small amount of hexane was added to give a slurry. The slurry was filtered, washed with hexane, and dried under reduced pressure yielding 6.07 g of a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[CH2:18][C:19](OCC)=[O:20])=[CH:11][CH:10]=1.O.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.C(OCC)(=O)C>[OH:20][CH2:19][CH2:18][CH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[CH:17]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)CC1CCc2ccc(OC)cc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCO)CC2
Yield: 92.5 %

Procedure:
To a suspension of lithium aluminum hydride (1.06 g, 27.9 mmol) in THF (150 ml) was added dropwise, under ice-cooling, a solution of ethyl (6-methoxyindan-1-yl)acetate (6.53 g, 27.9 mmol) in THF (20 ml), and the mixture was stirred for 15 minutes. To the reaction mixture was added water (1 ml), to which were further added ethyl acetate, anhydrous magnesium sulfate and celite. The mixture was subjected to filtration. The filtrate was concentrated under reduced pressure to give 4.96 g (yield 93%) of the above-titled compound as an oily product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Cl)[CH:10]=2)=[CH:5][CH:4]=1.C[O:22][C:23](=[O:36])[CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([SH:35])=[C:31]2[C:27]=1[CH2:28][CH2:29][CH2:30]2>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH2:15][S:35][C:32]2[CH:33]=[CH:34][C:26]([O:25][CH2:24][C:23]([OH:36])=[O:22])=[C:27]3[C:31]=2[CH2:30][CH2:29][CH2:28]3)=[CH:5][CH:4]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: FC(F)(F)c1ccc(COc2cccc(CCl)c2)cc1
Product: O=C(O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 79B and 12C. MS m/z 503 (M+1).
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:11]2)=[CH:6][CH:5]=1)#[N:3].[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][C@H:43]([O:46][C:47]2[CH:52]=[CH:51][C:50]([C:53](=O)[C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:49][CH:48]=2)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C1CCN2C(=NCCC2)CC1.CCCCCC.C(OCC)(=O)C>O1CCCC1.C(O)C>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][C@H:43]([O:46][C:47]2[CH:48]=[CH:49][C:50]([C:53](=[CH:14][C:10]3[CH:9]=[CH:8][C:7]4[C:12](=[CH:13][C:4]([C:2]#[N:3])=[CH:5][CH:6]=4)[CH:11]=3)[C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:51][CH:52]=2)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: N#Cc1ccc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Reactant: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=Cc1ccc2ccc(C#N)cc2c1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Yield: 85.9 %

Procedure:
8.40 g of (7-cyano-2-naphthyl)methyltriphenylphosphonium bromide and 5.0 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-2-oxoacetate were suspended in a mixture of 100 ml of tetrahydrofuran and 100 ml of ethanol. With stirring, to the resulting suspension was added 2.51 g of 1,8-diazabicyclo[5.4.0]-7-undecene, followed by stirring for 3 hours at room temperature. After distilling off, the solvent, the residue thus obtained was subjected to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent, thereby obtaining 6.06 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(7-cyano-2-naphthyl)acrylate as a mixture of E and Z forms. A portion of the thus obtained compound was separated into E and Z forms.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(F)(F)F.[CH3:18][CH2:19][O:20]CC>C(OC(=O)C)(=O)C>[C:19]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)(=[O:20])[CH3:18]
Reactant: CCOCC
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: FB(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1c2ccccc2c2ccccc21
Temperature: 0 °C

Procedure:
Carbazole (100.24 g) was suspended in acetic anhydride (300 mL) with catalytic boron trifluoride etherate (0.65 mL) and the solution refluxed for 25 min. then cooled to 0° C. and the solid was then collected and recrystallized from hexane to give 82.65 g 9-acetyl-carbazole.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([O:7][CH3:8])=[O:6].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C>ClCCl.CCOCC>[CH3:8][O:7][C:5]([C@@H:2]1[CH2:3][CH2:4][N:1]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:6]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H]1CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
(2S)-Methyl azetidine-2-carboxylate (2.83 g, 18.7 mmol, 1.0 eq) was dissolved in dry dichloromethane (100 mL) and cooled to about 0° C. under an argon atmosphere. After the addition of benzyl chloroformate (3.00 mL, 20.0 mmol, 1.1 eq), diisopropyl ethylamine (8.00 mL, 45.9 mmol, 2.5 eq) was added to the mixture dropwise. The reaction mixture was stirred at about 0° C. for about 30 minutes and then at about room temperature overnight. The solvent was evaporated and then the residue was dissolved in ether, washed with 1N HCl, water and brine, dried over magnesium sulfate and concentrated. Flash chromatography (in ether) gave 3.75 g (80% yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 2.19-2.32 (m, 1H); 2.52-2.66 (m, 1H); 3.74 (s, 3H); 3.94-4.03 (m, 1H); 4.08-4.18 (m, 1H); 4.72 (dd, 1H, J=9.4, 6.9); 5.12 (q, 2H, J=12.9); 7.29-7.42 (m, 5H).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[C:18]([Cl:25])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.BrC1C(Cl)=C([Li])C(OC)=NC=1.[CH3:37][O:38][C:39]1[C:46]([O:47][CH3:48])=[C:45]([O:49][CH3:50])[CH:44]=[C:43]([CH3:51])[C:40]=1[CH:41]=[O:42].[Cl-].[NH4+]>O1CCCC1.O>[CH3:37][O:38][C:39]1[C:46]([O:47][CH3:48])=[C:45]([O:49][CH3:50])[CH:44]=[C:43]([CH3:51])[C:40]=1[CH:41]([C:19]1[C:20]([O:23][CH3:24])=[N:21][CH:22]=[C:17]([Br:16])[C:18]=1[Cl:25])[OH:42]
Reactant: COc1cc(Cl)c(Br)cn1
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(C(O)c2c(OC)ncc(Br)c2Cl)c(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
18.3 ml of n-butyllithium (1.57 mol/l hexane solution, 27 mmol) was dropwise added at 0° C. to a solution having 3.84 g (27 mmol) of 2,2,6,6-tetramethylpiperidine dissolved in 36 ml of tetrahydrofuran under an argon stream, followed by stirring at 0° C. for 30 minutes. The obtained solution was cooled to −78° C., and a solution having 6.10 g (27 mmol) of 5-bromo-4-chloro-2-methoxypyridine dissolved in 24 ml of tetrahydrofuran was added, followed by stirring at the same temperature for 2 hours to prepare 5-bromo-4-chloro-2-methoxy-3-pyridyllithium. Then, a solution having 5.50 g (26 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 24 ml of tetrahydrofuran was added, followed by stirring at the same temperature for 1 hour. To the reaction mixture, 37 ml of a saturated ammonium chloride aqueous solution and then 150 ml of water were added, and the temperature was increased to room temperature, followed by extraction with ethyl acetate (150 ml each) three times. The organic layer was washed with a saturated sodium chloride solution (100 ml), dried over magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 6.53 g (yield: 56%) of (2,3,4-trimethoxy-6-methylphenyl)(5-bromo-4-chloro-2-methoxy-3-pyridyl)methanol.