Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.O.[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:11][C:10]=2[CH:28]=1>C(O)(=O)C.C(O)C>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([S:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[O:1])=[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:11][C:10]=2[CH:28]=1
Reactant: CCOC(=O)c1sc2cc(CO)ccc2c1Sc1cccc(OC)c1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1sc2cc(CO)ccc2c1S(=O)c1cccc(OC)c1
Temperature: 100 °C

Procedure:
Hydrogen peroxide in water (0.52 ml of 30% w/v, 4.6 mmol) was added to a solution of ethyl 6-(hydroxymethyl)-3-[(3-methoxyphenyl)sulfanyl]benzo[b]thiophene-2-carboxylate (Preparation 16, 1.73 g, 4.6 mmol) in a mixture of acetic acid (20 ml) and ethanol (10 ml). The mixture was heated to 100° C. for 60 minutes. The solvents were removed by evaporation under reduced pressure, and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, dried (magnesium sulfate) and concentrated under vacuo, and the residue was flash chromatographed on silica gel using 2% ethanol in dichloromethane as eluant. The title compound was isolated as a foam (1.28 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH:10]=O)=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19].C([BH3-])#N.[Na+].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH2:10][NH:12][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:4][N:3]=1
Reactant: CNc1nc(Cl)ncc1C=O
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1nc(Cl)ncc1CNc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
A solution of 2-chloro-4-methylamino-pyrimidine-5-carbaldehyde (1.08 g, 6.3 mmol) and N-(3-amino-4-methyl-phenyl)-3-trifluoromethylbenzamide (2.04 g, 6.9 mmol) in MeOH (70 mL) is stirred for 2 hours at 45° C. and then treated with sodium cyanoborohydride (1.19 g, 18.9 mmol) and acetic acid (1 mL) sequentially. After stirring for 2 hours at room temperature, the reaction mixture is diluted with CHCl3 and washed with saturated NaHCO3 The organic layer is dried over MgSO4 and concentrated under reduced pressure. The residue is purified by flash column chromatography (SiO2, EtOAc/hexane=1/2) to give N-{3-[(2-chloro-4-methylaminopyrimidin-5-ylmethyl)amino]-4-methylphenyl}-3-trifluoromethylbenzamide (1.80 g, 64%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:21]=[CH:20][CH:19]=[CH:18][C:11]=2[C:12]([NH:14][CH2:15][C:16]#[CH:17])=[O:13])=[CH:5][CH:4]=1.[N:22]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=1)=[N+:23]=[N-:24].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1)[CH2:25][N:22]1[CH:17]=[C:16]([CH2:15][NH:14][C:12](=[O:13])[C:11]2[CH:18]=[CH:19][CH:20]=[N:21][C:10]=2[NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:24]=[N:23]1
Reactant: COc1cc(CN=[N+]=[N-])cc(OC)c1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(Nc2ncccc2C(=O)NCc2cn(Cc3cc(OC)cc(OC)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 78.3 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 102 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 6e (197 mg, 78%); mp: 147-149° C.; 1H NMR (300 MHz, CDCl3) δ 10.17 (s, 1H), 8.24 (dd, J=4.9, 1.7 Hz, 1H), 7.55-7.48 (dd, J=7.7, 1.7 Hz, 1H), 7.17 (t, J=5.0 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.62-6.57 (m, 1H), 6.42-6.39 (m, 3H), 5.42 (s, 2H), 4.66 (d, J=5.4 Hz, 2H), 3.79 (s, 3H), 3.75 ppm (s, 6H) MS (ESI m/z): 475 [M+H]+. Yield: 78%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40]([O:43][CH2:44][C:45](Cl)=[O:46])(=[O:42])[CH3:41]>ClCCl>[C:40]([O:43][CH2:44][C:45]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)=[CH:6][N:7]=1)=[O:46])(=[O:42])[CH3:41]
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(c2ccc(N)nc2)c2cc(Cl)ccc21
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C2=NC(Cc3ccc4ccccc4c3)C(=O)N(C)c3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
5-(6-Aminopyridin-3-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg, 0.11 mmol) was dissolved in dichloromethane (0.5 mL), and triethylamine (19 μL, 0.14 mmol) was added followed by acetoxyacetyl chloride (13 μL, 0.12 mmol). A slightly exothermic reaction occurred. This mixture as stirred at ambient temperature overnight. Additional triethylamine (46 μL, 0.33 mmol) was added followed by acetoxyacetyl chloride (30 μL, 0.22 mmol) and stirring continued at ambient temperature for 4 days. Concentration in the presence of silica, then column chromatography eluting with a step gradient of 20-80% ethyl acetate in hexanes in 5% increments every 3 minutes provided 2-(5-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)pyridin-2-ylamino)-2-oxoethyl acetate (45 mg, 73%). 1H NMR (300 MHz, d6-DMSO) δ 2.10 (s, 3H), 3.3 (s, 3H), 3.53 (d, 2H) 3.83 (t, 1H), 4.72 (s, 2H), 7.30 (m, 1H), 7.4-7.5 (m, 3H), 7.60 (m, 2H), 7.65 (m, 1H), 7.77-7.88 (m, 4H), 8.03 (m, 1H), 8.36, (m, 1H), 10.94 (s, 1H); ESI m/z measured 541.1646 [M+H]+. calculated 541.1643.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=O)=[N+:2]=[N-:3].S(Cl)([Cl:17])=O>CN(C)C=O.C(Cl)Cl>[N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([Cl:17])=[O:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccccc1CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCc1ccccc1CC(=O)Cl

Procedure:
2-Azidomethylphenylacetic acid (19.1 g., 0.1 mole) was dissolved in 800 ml. of methylene chloride. To this solution was added slowly thionyl chloride (26 g., 0.2 mole) and 0.5 ml. of dimethylformamide as catalyst. The reaction mixture was heated at reflux temperature under nitrogen atmosphere for 1 hour. The methylene chloride solution was concentrated with the aid of vacuum and the residue oil (checked by IR spectroscopy-carboxyl 1800 cm-1 and azido group at 2010 cm-1) was picked up in 100 ml. of acetone and placed into a dropping funnel for use directly in the subsequent acylation reaction.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].[Br:13]CC(C1N=CC2CCCCC=2C=1)=O>>[Br:13][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: O=C(CBr)c1cc2c(cn1)CCCC2
Product: O=C(CBr)c1ccc2c(c1)CCO2

Procedure:
*5-Bromoacetyl-2,3-dihydro-1-benzofuran was prepared from 5-acetyl-2,3-dihydro-1-benzofuran according to the procedure for preparing 3-bromoacetyl-5,6,7,8-tetrahydroisoquinoline described in Example 1.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:19])([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:6][CH2:5]2.[O:21]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:21][C:7]([CH3:19])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:20])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N(C)C)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)N(C)C)=C(C)C1=O
Yield: 95.4 %

Procedure:
Oxidation as described in protocol B, using 138.6 mg (0.50 mmol) of 6-hydroxy-N,N,2,5,7,8-hexamethylchroman-2-carboxamide and 560 mg CAN (1.02 mmol) yielded 139.9 mg of 2-hydroxy-N,N,2-trimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][C:15]#[N:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][NH2:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CCC1(c2ccc(F)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCC1(c2ccc(F)cc2)CCOCC1

Procedure:
To a solution of 2-[4-(4-fluorophenyl)oxan-4-yl]acetonitrile (450 mg, 2.05 mmol) in anhydrous ether (15 ml) at 0° C. was added dropwise LAH (1.0 M in Et2O, 4.1 ml, 4.11 mmol). After 2 h the reaction was quenched with 1 ml H2O, 0.1 ml 15% NaOH and then 1 ml H2O. The reaction mixture was extracted with Et2O (3×20 ml), dried over NA2SO4 and concentrated to give 2-[4-(4-fluorophenyl)oxan-4-yl]ethan-1-amine as an yellow oil, which used without further purification (450 mg, 94%, m/z: 223.1 [M+H]+ observed).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([OH:21])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[C:19](=[O:21])[CH2:18][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:4]=1[N+:1]([O-:3])=[O:2])[CH3:29]
Reactant: CCNCC
Reactant: O=C(O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN(CC)C(=O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]

Procedure:
2-[2-Nitro-3-(2-fluorophenoxy)phenyl]acetic acid (4 g.), phosphorus pentachloride (3.1 g.) and diethylamine (3 g.) were treated in a similar manner to that of the Preparation 33 to give the oily captioned compound (5.2 g.).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=2[N:6]=1
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1Cl
Temperature: 85 °C
Yield: 89 %

Procedure:
To 5-chloro-6-nitro-1,3-dihydro-benzoimidazol-2-one (5.63 g, 26.35 mmol) was added phosphorus oxychloride (35 mL) and the reaction mixture was heated to 85° C. for 36 h. The reaction mixture was concentrated and the residue triturated with cold saturated aqueous sodium bicarbonate (to pH 8, 0.8 L). The resulting precipitate was collected and dried to yield the titled compound (5.43 g, 89% yield). MS (ESI/CI): mass calcd. for C7H3Cl2N3O2, 231.0; m/z found, 232.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:3]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][O:10][N:11]=[C:7]2[CH:6]=1)=[O:4].Cl.[NH2:22][OH:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:23][N:22]=[C:17]1[CH2:18][CH2:19][CH:14]([N:2]([CH3:1])[C:3]([C:5]2[CH:13]=[CH:12][C:8]3=[N:9][O:10][N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:15][CH2:16]1
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C(=O)c1ccc2nonc2c1)C1CCC(=NO)CC1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
N-Methyl-N-(4-oxocyclohexyl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.41 g, 1.5 mmol) was dissolved in chloroform (10 ml), hydroxylamine hydrochloride (0.63 g) and triethylamine (1.6 ml) were added, and the mixture stirred overnight. Evaporation of the solvent and to chromatography of the residue on silica gel, eluting with chloroform/ethyl acetate (3:2), gave a white solid (0.37 g). Mp=197-198° C., NMR (300 MHz, CDCl3) δ 8.49 (s, 1H); 7.93 (d, J=9.0 Hz, 1H); 7.86 (m, 1H); 7.43 (d, J=9.0 Hz, 1H); 4.90-4.70 and 3.80-3.35 (m, 1H); 2.99 and 2.88 (s+s, 3H); 2.80-1.50 ppm (s, 8H).
Reaction SMILES: [C:1]1([CH:7]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCOCC1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([NH:13][S:10]([C:8]([CH3:9])=[CH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])=[O:12])=[O:24]
Reactant: CC(=Cc1ccccc1)S(N)(=O)=O
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=Cc1ccccc1)S(=O)(=O)NC(=O)c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 18.5 h

Procedure:
Phenyl-propene-2-sulfonic acid amide is dissolved in dioxane followed by the addition of potassium carbonate and 2,4-dichlorobenzoyl chloride. The resulting solution is stirred in a sealed tube at 100° C. for 18.5 h, cooled to room temperature (RT) and partitioned between 1M HCl and ethyl acetate. The aqueous phase is separated and extracted with further portions of ethyl acetate. The organic fractions are combined, washed with brine, dried over MgSO4 and concentrated in vacuo. After flash column chromatography (dichloromethane) 1-phenyl-propene-2-sulfonic acid 2,4-dichlorobenzoylamide can be isolated as a colourless oil. Yield 55 mg (56%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:35]([O:37]CC)=[O:36])[CH2:26][C:25]3[C:20](=[C:21]([O:33][CH3:34])[C:22]([O:31][CH3:32])=[C:23]([O:29][CH3:30])[C:24]=3[O:27][CH3:28])[CH2:19]2)=[CH:14][CH:13]=1)=[O:7])C>C(O)C>[C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:35]([OH:37])=[O:36])[CH2:26][C:25]3[C:20](=[C:21]([O:33][CH3:34])[C:22]([O:31][CH3:32])=[C:23]([O:29][CH3:30])[C:24]=3[O:27][CH3:28])[CH2:19]2)=[CH:16][CH:17]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)CCCOc1ccc(C2(C(=O)OCC)Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c2c(c(OC)c(OC)c1OC)CC(C(=O)O)(c1ccc(OCCCC(=O)O)cc1)C2
Yield: 98.4 %

Procedure:
An aqueous sodium hydroxide solution (3 N, 0.440 ml, 1.32 mmols) was added to an ethanol (4 ml) solution of ethyl 2-[4-(4-ethoxycarbonyl-1-oxabutyl)phenyl]-4,5,6,7-tetramethoxy-2-indancarboxylate (342 mg, 0.662 mmols), and heated under reflux for 6 hours. The reaction mixture was concentrated in vacuo, diluted with water, made acidic by adding 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (300 mg) as crystals.
Reaction SMILES: [CH:1]([CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=[S:13])[NH:11][CH3:12])=[O:2].[BH4-].[Na+].C(OCC)(=O)C.O>CO>[OH:2][CH2:1][CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=[S:13])[NH:11][CH3:12]
Reactant: CNC(=S)C1(c2cnc3ccccc3c2)CCCCC1=CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=S)C1(c2cnc3ccccc3c2)CCCCC1=CCO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.4 %

Procedure:
A solution of (±)-2 -formylmethylene-N-methyl-1-(quinolin-3 -yl)cyclohexane carbothioamide (150 mg, 0.46 mmol) at room temperature in methanol (5 ml) was treated with sodium borohydride (20 mg, 0.5 mmol). The mixture was stirred at room temperature for 45 mins. Ethyl acetate (20 ml) and then water (20 ml) were added to the reaction mixture. The layers were separated and the organic extract was dried over magnesium sulphate. Concentration in vacuo yielded a crude solid which was purified by flash chromatography over silica gel, eluting with a 1:1 (v/v) mixture of ethyl acetate/hexane to yield (±)-2 -hydroxyethylidene-N-methyl-1-(quinolin-3-yl) cyclohexane carbothioamide (100 mg, 0.31 mmol) as a white solid, m.p. 104°-110° C.;
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39]C)=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:41][CH2:42][NH:43][S:44]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=1)(=[O:46])=[O:45])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:15]1[CH2:41][CH2:42][NH:43][S:44]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=1)(=[O:46])=[O:45])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino} ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (step 13, 1.0 eq) was dissolved in THF:MeOH (1:1) (0.1M), then added 1N NaOH. The mixture was kept stirred overnight at room temperature. The solvent was stripped off and the residue was dissolved in water to form a basic solution, which was neutralized with diluted HCl solution to precipitate the product. The solid was collected by filtration, washed with water, rinsed with hexane, then dried to give the desired product in 86% yield. HRMS calc for [C41H37Cl3N2O6S2+H] 823.12314 found 823.12292.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([OH:29])[CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1.[CH3:30]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([O:29][CH3:30])[CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 35.7 %

Procedure:
Sodium hydride (60% in oil, 50.8 mg, 1.27 mmol) was added to a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butan-1-ol (250 mg, 1.06 mmol) in N,N-dimethylformamide (3.0 mL) at room temperature. After stirring 5 min, methyl iodide (226 mg, 1.59 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (166 mg, 0.378 mmol, 36%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)=O.[F:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>C(O)C>[F:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][N:30]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C@@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)=[CH:5][CH:4]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C=O)cc2)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C=NNC(=O)c3ccc(F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
(S)-tert-Butyl 2-(4-formylphenyl)morpholine-4-carboxylate (120 mg, 0.41 mmol) and 4-fluorobenzohydrazide (64 mg, 0.41 mmol) were dissolved in ethanol (2 ml) and stirred for 2 h at room temperature. The solvent was evaporated and ether/ethanol (3:1) was added to precipitate the product. The crystals were filtered off to yield a white solid (101 mg, 58%). MS (ISP): 327.1 ([M-tBu+H]+).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:32])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH:29]([OH:31])[CH3:30])[CH:20]=[CH:19][C:18]1=2>>[CH3:32][C:17]1([CH3:16])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH:29]([O:31][C:11]([C:10]3[CH:14]=[CH:15][C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:8][CH:9]=3)=[O:12])[CH3:30])[CH:20]=[CH:19][C:18]1=2
Reactant: CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C=CCOC(=O)c1ccc(C(=O)O)cc1
Product: C=CCOC(=O)c1ccc(C(=O)OC(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2.1 g (10 mmol) of 4-(allyloxycarbonyl)benzoic acid with 2.3 g (10 mmol) of 1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethanol, 3.2 g (76%) of the expected allyl ester are obtained in the form of a colorless oil.
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[CH3:12][C:13]1[CH:17]=[C:16](CC(O)=O)[O:15][N:14]=1>ClCCl>[CH3:12][C:13]1[CH:17]=[C:16]([CH2:6][C:7]([Cl:9])=[O:8])[O:15][N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(CC(=O)O)on1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(CC(=O)Cl)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Dimethylformamide (few drops), followed by oxalyl chloride (9.5 mL, 106 mmol) were added dropwise to a cooled (10° C.) solution of (3-methyl-isoxazol-5-yl)-acetic acid (5 g, 35.4 mmol) in dichloromethane (50 mL), and the solution was allowed to warm to room temperature. The reaction was stirred for a further 3 hours, then concentrated under reduced pressure. The residue was azeotroped with toluene to afford the title compound.