Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.Cl.[NH2:17][NH2:18].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[NH:18][N:17]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: O=Cc1ccccc1
Reactant: NN
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Agent: Cl
Solvent: CCO
Product: O=C1CC(c2ccccc2Cl)Cc2[nH]nc(-c3ccccc3)c21
Yield: 4.1 %

Procedure:
A solution of 5-(2-chlorophenyl)-cyclohexane-1,3-dione (1.0 g), hydrazine hydrochloride (0.31 g) in ethanol (10 ml) was refluxed for 3 hours. To the solution was added benzaldehyde (1.5 g), and the mixture was refluxed for 4 days. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give crystals, which were recrystallized from ethyl acetate-hexane to give 6-(2-chlorophenyl)-3-phenyl-4,5,6,7-tetrahydroindazol-4-one (0.06 g) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:18]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CC(NC(=O)OC(C)(C)C)C2)s1
Yield: 59.9 %

Procedure:
A solution of 3-tert-butoxycarbonylaminoazetidine (300 mg, 1.74 mmol), ethyl 2-bromothiazole-5-carboxylate (0.29 mL, 1.92 mmol) and diisopropylethylamine (0.61 mL, 3.48 mmol) in DMF (17 mL) was stirred at 70° C. for 10.5 hours. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 341 mg of the title compound as a pale yellow solid (60%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:42])=[C:4]([C:8]([I:41])=[C:9]([C:12](=[O:40])[NH:13][CH2:14][CH:15]([O:36][C:37](=[O:39])[CH3:38])[CH:16]([O:32][C:33](=[O:35])[CH3:34])[CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:10]=1[I:11])[C:5](O)=[O:6].S(Cl)([Cl:45])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[NH2:1][C:2]1[C:3]([I:42])=[C:4]([C:8]([I:41])=[C:9]([C:12](=[O:40])[NH:13][CH2:14][CH:15]([O:36][C:37](=[O:39])[CH3:38])[CH:16]([O:32][C:33](=[O:35])[CH3:34])[CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:10]=1[I:11])[C:5]([Cl:45])=[O:6]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I)OC(C)=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(CNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I)OC(C)=O
Reaction time: 1.5 h

Procedure:
15.5 g (16.4 mmol) of 3-amino-5-(2,3,4,5,6-pentaacetoxyhexylcarbamoyl)-2,4,6-triiodobenzoic acid [Example 18a)] is suspended in 80 ml of ethyl acetate and refluxed with 1.9 ml (24.6 mmol) of thionyl chloride for 5 hours. The reaction mixture is added to 30 g of sodium bicarbonate in 300 ml of water and stirred vigorously for 1.5 hours. Then, the phases are separated and the organic phase is dried on sodium sulfate, filtered, and the solution is concentrated by evaporation. The oily reaction product is foamed up in a high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[ClH:13].[C:18]1([CH2:17][NH:16][CH2:15][CH2:14][NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: ClCCNCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)Nc1cccc(NCCNCc2ccccc2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Combine N-(3-aminophenyl)acetamide (31 g, 0.206 mol) and N-(2-chloroethyl)benzenemethanamine hydrochloride (17.0 g, 0.083 mol) and heat to 180° C. for 1 h. After this time, allow to cool to approximately 85° C. and add isopropanol (100 mL) to precipitate a solid. Decant the solvent and dissolve the white residue in refluxing methanol (800 mL). Filter hot and allow the solution to cool to room temperature. After 2 h, filter the resulting white solid and wash with methanol (50 mL) to give the title compound.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC.[CH:25]1([N:28]([CH3:47])[C:29]2[C:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[S:42][C:33]=3[N:32]=[C:31]([CH2:43][C:44]([OH:46])=O)[N:30]=2)[CH2:27][CH2:26]1>C1COCC1>[CH:25]1([N:28]([CH3:47])[C:29]2[C:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[S:42][C:33]=3[N:32]=[C:31]([CH2:43][C:44]([N:3]([CH3:4])[CH3:2])=[O:46])[N:30]=2)[CH2:27][CH2:26]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(c1nc(CC(=O)O)nc2sc3c(c12)CCCCC3)C1CC1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
The EDCI (0.477 g, 0.00241 mol), HOBt (0.22 g, 0.00144 mol) and N,N-dimethyl amine in THF (2 M, 1.2 ml, 0.00241 mol) were added to a solution of [4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diazabenz[a]azulen-2-yl]-acetic acid (0.4 g, 0.0012 mol) in 10 ml of THF. The mixture was stirred for 3 h at room temperature then concentrated under vacuum. The crude was purified by chromatography on silica gel using 2% MeOH-DCM to give 2-[4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl]-N,N-dimethyl-acetamide (0.25 g, 58%) as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.98 (s, 2H), 3.06 (s, 3H), 2.92-3.02 (m, 8H), 2.84-2.88 (m, 2H), 2.72-2.83 (m, 1H), 1.82-1.90 (m, 2H), 1.67-1.78 (m, 2H), 1.50-1.60 (m, 2H), 0.62-0.72 (m, 2H), 0.40-0.48 (m, 2H); LC-MS: [M+H]=359.4 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:57]=[CH:56][CH:55]=[C:54]2[C:50]=1[CH2:51][O:52][C:53]2=[O:58]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:49]2[CH:57]=[CH:56][CH:55]=[C:54]3[C:50]=2[CH2:51][O:52][C:53]3=[O:58])=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1OCc2c(O)cccc21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cccc3c2COC3=O)cc1

Procedure:
Analogously to Method G, 0210 g of tert-butyl 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.094 g of 4-hydroxy-3H-isobenzofuran-1-one are reacted. The title compound is obtained as a white solid. Rf=0.32 (1:1 EtOAc-heptane); Rt=5.84.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=3)[C:34](Cl)=[C:33](Br)[C:32]=2[O:49][CH2:50][CH2:51][CH2:52]Cl)[O:11][C@@H:10]1[CH2:54][O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[NH4+].[Cl-:69]>C1COCC1>[Cl:69][C:34]1[C:35]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:36][C:31]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:10]([CH2:54][O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[O:11]2)=[C:32]2[C:33]=1[CH2:52][CH2:51][CH2:50][O:49]2
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCCl)c(Br)c2Cl)cc1
Reactant: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCCO3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
To a solution of chloride 29-1 (1.03 g, 1.09 mmol) in THF (30 mL) was added n-BuLi (2.5M in hexane, 0.87 mL, 2.18 mmol) at −78° C. The mixture was allowed to slowly warm to r.t. and stirred at r.t. for 12 hours. To the mixtures was added aqueous saturated NH4Cl solution (50 mL). The mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the title product 30 (255 mg, 28%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:17]=[C:14]([CH:15]=[O:16])[C:13]([OH:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:18][C:13]1[CH:12]=[CH:11][C:10]([Br:9])=[CH:17][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A mixture of benzyl bromide (2.04 g, 11.926 mmol), 5-bromosalicylaldehyde (1.844 g, 9.174 mmol), potassium carbonate (5.07 g, 36.696 mmol) and dimethylformamide (15 ml) was stirred at 50° C. for 2 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with methanol to give the title compound (1.2 g, 44.9%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:6]3=[C:5]([CH3:17])[C:4]=2[CH:3]=1.[Cl:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[ClH:18].[CH2:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][C:6]2[C:7](=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[C:5]=2[CH3:17])[CH2:12][CH2:13]1)=[O:20])[CH3:23]
Reactant: Cc1c2c(nc3ccc(Br)cc13)CCNCC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3ccc(Br)cc3c(C)c2CC1
Product: Cl
Yield: 62 %

Procedure:
9-Bromo-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 9-bromo-1,2,4,5-tetrahydro-11-methyl- 3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: C(O)(=O)C.NC1C=CC=CC=1S.[CH3:13][C:14]1([CH3:36])[S:18]C(C(NC(CC2C=CC=CC=2)=O)C(O)=O)[NH:16][CH:15]1[C:33]([OH:35])=[O:34]>O>[NH2:16][C@@H:15]([C:33]([OH:35])=[O:34])[C:14]([SH:18])([CH3:36])[CH3:13]
Reactant: CC1(C)SC(C(NC(=O)Cc2ccccc2)C(=O)O)NC1C(=O)O
Agent: Nc1ccccc1S
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(S)[C@@H](N)C(=O)O
Reaction time: 2.5 h

Procedure:
To a solution of 2.4 g (0.04 mole) of acetic acid in 20 ml of water, were added 1.38 g (0.011 mole) of o-aminothiophenol and 3.52 g (0.01 mole) of benzylpenicilloic acid. The mixture was heated under reflux, with stirring, for 2.5 hours in a nitrogen atmosphere. The reaction mixture was then treated as described in Example 6 to give D-penicillamine as colorless crystals: yield 1.03 g (69.1%), m.p. 202°-203° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:14](Cl)(=O)[C:15](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C.C1C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([C:15]2[CH:14]=[CH:3][CH:2]=[CH:1][CH:5]=2)=[O:11])=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 4-isobutylbenzoic acid (5.00 g, 28.0 mmol) in CH2Cl2 was cooled in an ice bath and treated with oxalyl chloride (5 mL) and DMF (1 drop). The mixture was warmed to room temp and stirred 1 h. The volatiles were removed in vacuo to give the crude acid chloride which as dissolved in benzene (50 mL). Aluminum chloride (4.49 g, 33.3 mmol) was added and the mixture was heated to reflux for 3.5 h. The mixture was cooled to room temp and then poured onto ice (ca. 100 g). The mixture was extracted with EtOAc (3×100 mL) and the combined organic extracts were washed with ½ satd aqueous NaHCO3 (100 mL), dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by silica gel chromatography (elute with 10:1 hexane/EtOAc) to give 4-isobutylbenzophenone (5.48 g, 81%). 1H NMR (CDCl3) 7.75 (m, 4H), 7.53 (d, 1H), 7.47 (t, 2H), 7.23 (d, 2H), 2.53 (d, 2H), 1.91 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:5][CH:6]=1.[CH3:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1O.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C@@H:16]2[CH2:17][CH2:18][CH2:19][C@@H:15]2[CH3:14])[CH:6]=1
Reactant: CCOC(=O)/C=C/c1cc(Br)c[nH]1
Reactant: C[C@@H]1CCC[C@H]1O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(Br)cn1[C@@H]1CCC[C@@H]1C
Yield: 35 %

Procedure:
A solution of ethyl (2E)-3-(4-bromo-1H-pyrrol-2-yl)acrylate (1.3 g), trans-2-methylcyclopentanol (0.64 g) and 2-(tributylphosphoranylidene)acetonitrile (1.928 g) in toluene (12.6 mL) was stirred with heating under reflux for 22 hr under argon atmosphere. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (608 mg).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[CH3:25]>>[CH2:24]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][N:7]=1)[CH3:25]
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(Oc3ccc(C)cc3)CC2)cn1
Yield: 20 %

Procedure:
By reaction and treatment in the same manner as in Example 40 and using (6-bromopyridin-3-yl)(4-p-tolyloxypiperidin-1-yl)methanone (1.2 g) described in Preparation Example 28 and (R)-4-ethyloxazolidin-2-one (525 mg) described in Preparation Example 26, the title compound (262 mg) was obtained.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C(=O)(O)[O-:28].[Na+].I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[Si:1]([O:8][CH:9]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Reactant: O=C([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)[Si](C)(C)OC(CCCCC=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of alkene 182 (1.05 g, 3.23 mmol) in t-butyl alcohol (50 mL) were successively added water (10 mL), solid sodium bicarbonate (2.71 g, 32.3 mmol), sodium periodate (4.15 g, 19.38 mmol), and osmium tetroxide (8 mg, 0.032 mmol). The mixture turned light brown and a precipitate formed in large amount, making magnetic stirring impossible so the mixture was shaken by hand every 10 minutes for 3.5 hours and the brownish color almost disappeared. The reaction was quenched with a 10% aqueous solution of sodium thiosulfate. After 30 minutes, the white precipitate was filtered off and rinsed with diethyl ether. The filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether and water. The aqueous layer was extracted (2×50 mL) with diethyl ether. The combined organic layers were washed successively with a 10% aqueous solution of sodium thiosulfate, water and brine, dried (MgSO4), and concentrated in vacuo, yielding the title compound 183 as a crude oil in 91% yield (1.05 g). 1H NMR: (300 MHz, CDCl3) δ: 9.73 (t, J=1.9 Hz, 1H), 7.83-7.78 (m, 3H), 7.69 (s, 1H), 7.49-7.43 (m, 3H), 4.80 (t, J=6.9 Hz, 1H), 2.39 (td, J=7.1, 1.6 Hz, 2H), 1.81-1.55 (m, 4H), 1.43-1.25 (m, 2H) 0.90 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H). MS (ESI) 225 (M+1-TBSO).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH2:8][CH2:7]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2cccc(O)c2N1
Reactant: BrCCCCSc1ccccc1
Product: O=C1CCc2cccc(OCCCCSc3ccccc3)c2N1

Procedure:
Prepared analogous to Example 4 from 8-hydroxy-3,4-dihydro-carbostyril (see J. D. Loudon et al., J. Chem. Soc. 1955, 743-744) and 4-phenylmercapto-butyl bromide (bp. 96°-103° C. at 0.02 mm Hg).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].C(N(C)CCO)C.[O:16]=[C:17]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]([CH3:37])[C:29](OCCN(C)C)=[O:30])=[CH:27][C:22]=2[CH:21]=[CH:20][C:19]2[CH:38]=[CH:39][CH:40]=[CH:41][C:18]1=2>>[CH2:1]([N:3]([CH2:4][CH2:5][O:6][C:29](=[O:30])[CH:28]([C:26]1[CH:25]=[CH:24][C:23]2[C:17](=[O:16])[C:18]3[CH:41]=[CH:40][CH:39]=[CH:38][C:19]=3[CH:20]=[CH:21][C:22]=2[CH:27]=1)[CH3:37])[CH2:7][CH3:8])[CH3:2]
Reactant: CCN(CC)CCO
Reactant: CC(C(=O)OCCN(C)C)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: CCN(C)CCO
Product: CCN(CC)CCOC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
In similar manner substituting diethylethanolamine and N-ethyl-N-methylethanolamine for the dimethylethanolamine, there is obtained β-N-N-diethylaminoethyl-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate as an oil (hydrochloride salt: m.p. 117°-123° C; see Example XIV) and β-N-ethyl-N-methylaminoethyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propionate [an oil; n.m.r. spectrum in deuterochloroform relative to tetramethylsilane: 0.94 (triplet, CH2CH3); 1.53 (doublet, CHCH3); 2.08 (singlet, N--CH3); 4.17 (triplet, OCH2) and 7.03 ppm (singlet, 10H,11H); mass spectrum: 363 (M+), 305, 233, 205].
Reaction SMILES: [F:1]/[CH:2]=[C:3](/[CH2:13]O)\[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:27].[Li+]>CC(C)=O>[Br:27][CH2:13]/[C:3](=[CH:2]/[F:1])/[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)NC/C(=C\F)CO
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC/C(=C\F)CBr
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a stirring solution of (E)-tert-butyl 3-fluoro-2-(hydroxymethyl)-allylcarbamate (1.20 g, 5.85 mmol) in acetone (20 mL) at 0° C. under N2 was added sequentially triethylamine (1.22 mL, 8.77 mmol) and methanesulfonyl chloride (0.54 mL, 7.02 mmol). The resulting mixture was stirred at this temperature for 30 min. The reaction mixture was filtered to remove the precipitated salts and the filter cake was washed with further acetone (10 mL). The filtrate was charged with lithium bromide (2.54 g, 29.24 mmol) and the resulting suspension was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (25 mL) and ethyl acetate (25 mL) and the aqueous layer was extracted with further ethyl acetate (25 mL). The combined organics were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo to give (E)-tert-butyl 2-(bromomethyl)-3-fluoroallylcarbamate as a pale yellow oil (1.46 g, 93%). 1H-NMR (300 MHz; CDCl3) δ ppm: 1.47 (9H, s), 3.97 (2H, dd, J 3.5, 0.7 Hz), 4.02 (2H, br d, J 6.1 Hz), 4.78 (1H, br s), 6.79 (1H, d, J 81.1 Hz).
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=[CH2:2].N(OC(C)(C)C)=O.[Br:12][C:13]1[C:14]([F:21])=[CH:15][C:16]([CH3:20])=[C:17](N)[CH:18]=1.[ClH:22]>C(#N)C.[Cu](Cl)Cl>[Br:12][C:13]1[CH:18]=[C:17]([CH2:2][C:1]([Cl:22])([Cl:4])[Cl:3])[C:16]([CH3:20])=[CH:15][C:14]=1[F:21]
Reactant: Cc1cc(F)c(Br)cc1N
Reactant: C=C(Cl)Cl
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1cc(F)c(Br)cc1CC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of vinylidene chloride (127 ml), tert-butyl nitrite (19 ml) and copper(II)chloride (18.4 g) in acetonitrile (150 ml) is added a solution of 5-bromo-4-fluoro-2-methyl-phenylamine (Bioorganic & Medicinal Chemistry Letters (2006), 16(2), 457-460) (21.5 g) in acetonitrile (100 ml) dropwise below 20° C. The reaction mixture is stirred at room temperature for 48 hours, poured on diluted HCl and extracted with tert-butyl methyl ether (3×). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (ethyl acetate/cyclohexane 1:4). Yield: 29.20 g of 1-bromo-2-fluoro-4-methyl-5-(2,2,2-trichloro-ethyl)-benzene as an oil.
Reaction SMILES: [CH:1]1([OH:4])CC1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH+]1C=CC=C[CH:21]=1.[OH2:26]>CN(C=O)C>[CH2:16]([C@H:17]1[CH2:21][C@H:18]1[CH2:19][C:1]([OH:4])=[O:26])[CH3:15]
Reactant: c1cc[nH+]cc1
Reactant: O
Reactant: OC1CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Alcohol 14 (2.30 g; 19.8 mmol) was dissolved in dry DMF (96 ml) and pyridinium dichromate (PDC) (3.5 eq., 26 g) was added in one portion. The reaction mixture was stirred overnight at room temperature and then poured into 300 ml of water and extracted with (4×80 ml) of ether. The organic layers were combined, washed with brine and concentrated under reduced pressure. The residue was then dissolved in chloroform (30 ml) and the solution was extracted two times with 25 ml of a 10% aqueous solution of NaOH. Combined aqueous phases were then extracted with chloroform (2×25 ml) and acidified with 10% aqueous HCl followed by an extraction with ether (4×50 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product (+,−)-cis-2-ethylcyclopropylacetic acid (15) as a colorless oil (1.7 g, 66%) Characterization: Nmr (1H, 13C), ir, ms
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH2:8]>>[N:12]1[CH:13]=[CH:14][C:9]([CH2:7][CH2:8][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: C1CNCCN1
Reactant: C=Cc1ccncc1
Product: c1cc(CCN2CCNCC2)ccn1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To a melt of piperazine (15 g, 0.17 mol) heated to 105° C. was added dropwise 4-vinylpyridine (1.25 mL, 0.012 mol). After refluxing the reaction for 5.5 hours, it was cooled to room temperature and chromatographed to provide 0.92 g of the title compound.