Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:22]([I:23])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:24])[CH2:13][CH2:12]4)[C@@H:9]([O:25][C:26](=[O:28])[CH3:27])[CH2:8][C:7]=2[CH:6]=1)(=O)C.C(=O)(O)[O-].[Na+]>CO>[C:26]([O:25][C@H:9]1[CH2:8][C:7]2[CH:6]=[C:5]([OH:4])[C:22]([I:23])=[CH:21][C:20]=2[C@@H:19]2[C@@H:10]1[C@H:11]1[C@@:15]([CH2:17][CH2:18]2)([CH3:16])[C:14](=[O:24])[CH2:13][CH2:12]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Oc1cc2c(cc1I)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1[C@@H](OC(C)=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)O[C@H]1Cc2cc(O)c(I)cc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 8 h

Procedure:
700 mg (1.4 mmol) of 3,7β-diacetoxy-2-iodo-estra-1,3,5(10)-trien-17-one was dissolved in 30 ml of methanol, mixed with 1.0 g of sodium bicarbonate, and the reaction mixture was stirred overnight. Then, it was filtered, and the solution was concentrated by evaporation in a rotary evaporator. Flash chromatography (cyclohexane/ethyl acetate) yielded 402 mg (63%) of colorless crytstals.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C:9]([CH3:35])([CH3:34])[CH2:10][CH:11]1[CH2:15][NH:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[F:23])[C:12]21[C:31]1[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=1)[NH:25][C:24]2=[O:33])(C)(C)C.[C:38]([O-])(O)=[O:39].[Na+].C(Cl)(Cl)=O.CC1(C)[O:52][C@@H:51]([CH2:53][CH2:54][NH2:55])[CH2:50][O:49]1.Cl>ClCCl.O1CCCC1.C1(C)C=CC=CC=1>[OH:52][C@H:51]([CH2:50][OH:49])[CH2:53][CH2:54][NH:55][C:38]([N:14]1[CH2:15][CH:11]([CH2:10][C:9]([CH3:34])([CH3:35])[CH2:8][CH2:7][OH:6])[C:12]2([C:31]3[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=3)[NH:25][C:24]2=[O:33])[CH:13]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[F:23])=[O:39]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(CCO)CC1CN(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
To a solution of rac-(2′S,3′S,4′S)-4′-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 40 (70 mg, 0.12 mmol) in dichloromethane (5 mL) was added saturated aqueous NaHCO3 solution (5 mL). The temperature of the mixture was lowered to 0° C., and a toluene solution (Aldrich, 20%) of phosgene (0.12 mL, 0.22 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichlormethane twice. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated. The residue was dissolved into tetrahydrofuran (5 mL), and 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 7 (36 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. An aqueous HCl solution (1 N, 5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (15% MeOH in EtOAc) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(4-hydroxy-2,2-dimethyl-butyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (Yield 13 mg, 18%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([O-:33])=[O:32])=[C:29]3[C:24]([CH:25]4[CH2:34][CH:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH2:4]1)[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([OH:33])=[O:32])=[C:29]3[C:24]([C@H:25]4[CH2:34][C@H:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:18])=[O:19])[CH2:4]1)[CH3:2]
Reactant: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)[O-])OCC2CC32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OC[C@@H]2C[C@H]32)C1
Temperature: 100 °C
Yield: 45 %

Procedure:
A mixture of methyl (1aR,7bS))-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 221, 0.071 g) and lithium hydroxide monohydrate (0.059 g) was suspended in dioxane (5 mL) and water (2 mL) and the mixture was stirred and heated at 100° C. for 25 hours. Further lithium hydroxide monohydrate (0.116 g) was added and the mixture was heated at 100° C. for a further 18 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and saturated with sodium chloride. The mixture was extracted with DCM and the organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18), eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-60% to give (1aR,7bS)-5-[2-(1-ethyl-piperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.032 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[C:19]([C:25]([O:27][CH3:28])=[O:26])#[C:20][C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:24][O:23][C:21]([C:20]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]=1[C:25]([O:27][CH3:28])=[O:26])=[O:22]
Reactant: COc1ccccc1NCC(=O)c1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccccc2)cn(-c2ccccc2OC)c1C(=O)OC

Procedure:
A solution of 7,4 g of 2-(2-methoxyphenyl)amino-1-phenyl-ethan-1-one and 11,3 ml of dimethyl acetylenedicarboxylate in 150 ml of toluene is refluxed for 12 hours and then the solvent is eliminated in vacuo. The residue remaining is taken up in ethyl acetate and washed with water. After the organic phase has been dried the solvent is distilled off in vacuo and the residue remaining is chromatographed on silica gel (n-hexane:ethyl acetate 80:20). 9,4 g of 2,3-di(methoxycarbonyl)-1-(2-methoxyphenyl)-4-phenyl-pyrrole are obtained as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH2:18][OH:19]>O1CCCC1>[N+:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:16][CH2:17][CH2:18][OH:19])([O-:15])=[O:14]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CNCCO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a sealed tube, added 1-(chloromethyl)-2-nitro-4-(trifluoromethyl)benzene (2.0 g, 8.4 mmol), tetrahydrofuran (8.4 mL), and 2-aminoethanol (5.0 mL, 83.5 mmol). Stirred the mixture at room temperature for 45 minutes. Extracted the mixture into ethyl acetate, washed 2 times with water, 1 time with brine solution, dried over magnesium sulfate, filtered, concentrated to yield 2-(2-nitro-4-(trifluoromethyl)benzylamino)ethanol. MS (M+H)+=265; Calc'd 264.21 for C10H11F3N2O3.
Reaction SMILES: [Br:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])C=1C(OCC)=O.[C:22]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])([CH3:24])[CH3:23].CC(C)([O-])C.[K+]>>[Br:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[C:28]=1[C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:29]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(Br)c(Cl)c(C)n1COCC[Si](C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1c(Cl)c(Br)c(C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
Ethyl 3-bromo-4-chloro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate (Intermediate 266, 564 mg, 1.42 mmol), t-Butylacetate (330 mg, 2.84 mmol) and potassium t-butoxide (0.14 mmol) were mixed together and stirred at room temperature for 10 minutes, concentrated to an oil under vacuum. t-Butylacetate (330 mg, 2.84 mmol) and potassium t-butoxide (0.14 mmol) were added again into the reaction mixture, repeated the same procedure again. The resulting reaction crude was filtered through a short pass silica gel, washed with ethyl acetate, the combined filtrate was concentrated to an oil and purified by column chromatography (2% ethyl acetate in hexanses) to give the desired product as an oil (485 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:46])[C@H:22]([CH2:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[O:25])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:46])[C@H:22]([CH2:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N[C@@H](Cc2cccnc2)C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
N-(N-tert-Butoxycarbonyl-piperidine-4-carbonyl)-3-(3-pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (86) (1.30 g; 2.07 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 2 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.98 g) as a white solid. ESMS: MH+ 527.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CS(C)=O>[ClH:1].[ClH:23].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([CH2:20][CH2:21][CH2:22][Cl:23])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CCCN2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cl
Product: ClCCCN1CCN(CCCc2ccc(Cl)cc2)CC1
Yield: 104.9 %

Procedure:
The procedure described in Example 17(a) was followed, using 27.0 g of 3-(4-chlorophenyl)propyl piperazine, 22.0 g of potassium hydroxide, 250 ml of dimethyl sulfoxide and 17.7 g of 1-bromo-3-chloropropane to give 22.9 g (54% of theory) of 1-[3-(4-chlorophenyl)propyl]-4-(3-chloropropyl)piperazine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[CH:10]([NH2:13])[CH2:11][O:12][C:8]=2[CH:7]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[CH:10]([NH:13][C:24]([NH:23][CH2:21][CH3:22])=[O:25])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: CCN=C=O
Reactant: NC1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCNC(=O)NC1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-amine (146 mg) and THF (dry) (4.0 mL) was added ethyl isocyanate (0.048 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was poured into saturated aqueous NH4Cl at 0° C. and extracted with EtOAc. The organic layer was m washed with brine, dried over MgSO4, and concentrated in vacuo. The solid was washed with EtOH to give the title compound (74.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][OH:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH3:2].[C:39](Cl)(=[O:41])[CH3:40]>>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Product: CCOc1cc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1

Procedure:
Prepared analogously to Example 37 from benzyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate with acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[S:12](=[O:14])(=[O:13])[N:11]([CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][CH2:17]Cl)[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)=[CH:4][CH:3]=1.[I-].[Na+].[CH3:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=3[N:11]([C@@H:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:16][CH2:17][NH:32][CH3:31])[S:12]2(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S1(=O)N(c2ccc(Cl)cc2)c2ccccc2N1C(CCCl)c1ccccc1
Reactant: CN
Agent: [I-]
Agent: [Na+]
Product: CNCC[C@H](c1ccccc1)N1c2ccccc2N(c2ccc(Cl)cc2)S1(=O)=O
Reaction time: 96 h

Procedure:
1-(4-Chloro-phenyl)-3-(3-chloro-1-phenyl-propyl)-1,3-dihydro-benzo[1,2,5]-thiadiazole 2,2-dioxide (0.12 g) was dissolved in methylamine (8M in ethanol, 20 mL), sodium iodide (58 mg, 0.39 mmol) was added and the mixture stirred for 96 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give (3R)-3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-3-phenylpropan-1-amine as a colorless oil. The freebase was dissolved in methanol (5 mL) and treated with 2N aqueous hydrochloric acid (1.0 equivalent) and concentrated. The residue was dissolved in water and lyophilized to give 130 mg (72%) (3R)-3-[3-(4-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-3-phenylpropan-1-amine as hydrochloride salt as a white powder. MS (ES) m/z 427.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][C:14](=O)CC(=O)C>CCO.Cl>[Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]2[N:9]=[C:13]([CH3:14])[NH:8][C:6]=2[CH:7]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1N
Agent: Cl
Solvent: CCO
Product: Cc1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 5-bromo-3-nitrobenzene-1,2-diamine (464 mg) and pentane-2,4-dione (400 mg) in EtOH (27 mL) and 5 N HCl (7.4 mL) was refluxed for 3 h. The mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution and brine. The organic layer was concentrated to afford the desired product as a solid (460 mg, 90%). 1H NMR (300 MHz, CDCl3) δ ppm 2.73 (s, 3H), 8.11 (d, 1H, J=1.8 Hz), 8.24 (d, 1H, J=1.8 Hz), 10.20 (s, 1H, s); LC-MS: m/e=256 [M+1]+
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:17]=[N:18][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[ClH:27]>C(O)C.[Pd]>[ClH:27].[C:19]1([C:15]2[C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[N:18]=[CH:17][N:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: c1ccc(CN2CCc3ncnc(-c4ccccc4)c3CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(-c2ncnc3c2CCNCC3)cc1
Temperature: 80 °C

Procedure:
Palladium charcoal was added to 17 g 7-benzyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine in 250 mL ethanol and 54 mL 1 mol/L HCl solution. The reaction was stirred at 80° C. and 5 bar hydrogen. The mixture was filtered and evaporated to give 13.15 g of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C.Cl[C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])O.[Na+]>ClCCl>[CH3:23][O:22][C:20](=[O:21])[NH:1][CH2:2][CH2:3][CH:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH3:7]
Reactant: CC(C)=CC(O)CCN
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NCCC(O)C=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
(±)-1-Amino-5-methyl-hex-4-en-3-ol (28.5 g, 219 mmol) and diisopropyl ethylamine (45.9 mL, 263 mmol) were dissolved in dichloromethane (400 mL) and cooled on an ice bath. Methyl chloroformate (17 mL, 219 mmol) in dichloromethane (20 mL) was added slowly. The mixture was stirred for 2 h. at 0° C. A saturated aqueous solution of sodium hydrogencarbonate was added and the phases separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were dried, filtered and evaporated to give (±)-(3-hydroxy-5-methyl-hex-4-enyl)carbamic acid methyl ester (38.9 g, 100%) as a yellow oil.
Reaction SMILES: CN(C)[C:3](=[O:5])[CH3:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH2:30])[CH:24]=1.N1C(C)=CC(C)=CC=1C>ClCCCl>[Br:22][C:23]1[CH:24]=[C:25]([CH:29]2[CH2:30][C:3](=[O:5])[CH2:4]2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)N(C)C
Reactant: C=Cc1cccc(Br)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: Cc1cc(C)nc(C)c1
Product: O=C1CC(c2cccc(Br)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
N,N-Dimethylacetamide (9.0 g, 103 mmol) was dissolved in 1,2-dichloroethane (200 mL). The solution was cooled to 0° C. before trifluoromethanesulfonic anhydride (63 g, 223 mmol) was added. The reaction was stirred for an additional 60 min at 0° C. Then 1-bromo-3-vinylbenzene (15 g, 81.9 mmol) and 2,4,6-collidine (10.5 g, 86.6 mmol) were added. The reaction was heated to reflux overnight, quenched by addition of water (300 mL) and stirred for 2 hr at rt. The mixture was extracted with DCM (300 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by CC (EA/PE=1:20) gave the title compound 2a (5.0 g, 27%) as a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][S:6][CH2:7][C:8]1([OH:26])[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([O:15][CH3:16])[CH:9]1[C:17]1([CH3:25])[O:24][CH:18]1[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].[Cl:31][CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34].O>ClCCl>[Cl:31][CH2:32][C:33]([NH:35][C:36]([O:14][CH:11]1[CH2:12][CH2:13][C:8]([CH2:7][S:6][CH2:5][C:4]2[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=2[CH2:2][Cl:1])([OH:26])[CH:9]([C:17]2([CH3:25])[O:24][CH:18]2[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:10]1[O:15][CH3:16])=[O:37])=[O:34]
Reactant: O=C=NC(=O)CCl
Reactant: COC1C(O)CCC(O)(CSCc2ccccc2CCl)C1C1(C)OC1CC=C(C)C
Solvent: ClCCl
Solvent: O
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CSCc2ccccc2CCl)C1C1(C)OC1CC=C(C)C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
In dichloromethane (1.5 ml) was dissolved 1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (300 mg). To the solution was added dropwise, under ice-cooling, chloroacetylisocyanate (84 μl). The mixture was stirred for 15 minutes, to which was added water to suspend the reaction. The product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent : methyl acetate - hexane=1:2) to give 4-(N-chloroacetylcarbamoyloxy)-1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol (302 mg: yield 79%) as colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([SH:12])[N:3]=1.[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>C(O)C.O>[F:10][C:8]([F:9])([F:11])[C:6]1[N:5]=[C:4]([S:12][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:3]=[C:2]([OH:1])[CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CSc2nc(O)cc(C(F)(F)F)n2)cc1

Procedure:
4-hydroxy-6-trifluoromethyl-2-pyrimidinethiol (Cpd #264; 4.90 g, 25.0 mmol) in ethanol (8 ml) is treated with 3.25 N NaOH (8 ml, 26.0 mmol) followed by 4-methoxybenzyl chloride (3.5 ml, 25.7 mmol). After refluxing for 1 hr, the reaction is diluted with water and filtered. The solid is recrystallized from ethanol: 4.63 g (14.6 mmol, 58%), mp 169-170° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:35][NH:36][NH2:37]>C(O)C>[CH:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([N:36]([CH3:35])[NH2:37])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:32])=[CH:25][CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: CNN
Solvent: CCO
Product: CN(N)C(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Yield: 9 %

Procedure:
A solution of 2,2,2-trichloro-1-[(10-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-1-ethanone of Example 7 (2.32 g) in absolute ethanol (50 mL) was treated with methylhydrazine (0.626 g). The mixture was refluxed for four hours and then all volatiles were removed in vacuo. The residue was treated with water and extracted with dichloromethane. The extracts were filtered through a short column of Magnesol®. The eluate was evaporated to dryness to provide the title compound as an amorphous yellow solid (0.18 g).
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O:23][CH:24](OCC)[C:25]#[CH:26])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(=O)CCCCC1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:26][C:25]([CH:24]=[O:23])=[C:6]2[N:7]1[CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccsc1-2
Reactant: C#CC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [OH-]
Solvent: O=C1CCCCC1
Product: O=Cc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
A mixture of 0.855 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) and 0.65 ml of 3,3-diethoxypropyne in 30 ml of cyclohexanone was stirred with a few crystals of p-toluenesulfonic acid at 130° for 3 hours under an inert gas and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with 10 percent potassium bicarbonate soluttion and saturated sodium chloride solution, dried over magnesium sulfate, concentrated and chromatographed on silica gel with toluene/acetonitrile (19:1). By crystallization from dioxane, there is obtained 4,5-dihydro-7-oxo-8-phenyl -7H-thieno[2,3-a]quinolizine-10-carboxaldehyde of m p. 213°-215°.