Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[Br:29][C:30]1[C:31]([CH3:38])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>O1CCCC1>[CH3:2][O:3]/[CH:4]=[CH:33]/[C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([Br:29])[C:31]=1[CH3:38]
Reactant: Cc1c(Br)cccc1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO/C=C/c1cccc(Br)c1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of [(methyloxy)methyl](triphenyl)phosphonium chloride (2.1 g, 6.13 mmol) in Tetrahydrofuran (THF) (40 mL) stirred under nitrogen at 0° C. was added BuLi (4.08 mL, 6.53 mmol) dropwise. The reaction mixture was stirred at −78° C. for 30 min. Then a solution of 3-bromo-2-methylbenzaldehyde (D93) (1 g, 5.02 mmol) in Tetrahydrofuran (THF) (40 mL) was added dropwise. The reaction mixture was continuously stirred overnight. The reaction was quenched with sat. aq. NH4Cl. The aqueous layers were separated and extracted with EA for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated, and purified by ISCO column chromatography (PE: EA=8:2) to afford (E)-2-(3-bromo-2-methylphenyl)ethenyl methyl ether (D94) (938 mg) as a yellow oil. MS (ES): C10H11BrO requires 255.9. found 227 (M+H+)
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([CH:31]([CH3:33])[CH3:32])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:30])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:29])[CH2:21][CH2:22][C@H:23]([O:25][C:26]([CH3:28])=[O:27])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7].C([O-])(O)=O.[Na+].CC1(C)N(Br)C(=O)N(Br)C1=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC1C=C(C)N=C(C)C=1>CCCCCCC.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC.O>[CH3:1][CH2:2][C@@H:3]([CH:31]([CH3:32])[CH3:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:30])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:29])[CH2:21][CH2:22][C@H:23]([O:25][C:26]([CH3:28])=[O:27])[CH2:24][C:19]4=[CH:18][CH:17]=[C:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: O
Solvent: CCCCCCC
Product: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A suspension of sitosterol acetate (5) (10 g, 21.89 mmol), anhydrous NaHCO3 (9.19 G, 109.45 mmol) and dibromantin in heptane (250 mL) was refluxed for 2 h under argon atmosphere. The reaction mixture was cooled to room temperature and filtered, and then the solvent was removed in vacuo. To the reaction flask, THF (50 mL) was added followed by tetrabutylammonium bromide (0.65 g, 2.02 mmol). The solution was stirred at room temperature for 30 minutes under argon atmosphere. To this reaction mixture tetrabutylammonium fluoride (112 mL, 1 M solution in THF) was added and followed by s-collidine (5 mL). Then the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with ether (1.5 L), then water (600 mL) was added. The crude reaction mixture was transferred to a separating funnel, the water layer was removed, the organic layer was washed with water (500 mL), 1 N HC1 (2×600 mL), water (600 mL), then brine (500 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford a dark brown viscous liquid. The crude reaction mixture was purified by column chromatography (silica gel, ethyl acetate-hexane 1:9 mixture as eluent) to afford 6.5 g, (75%) 7-dehydrositosterol acetate (6) as a pale brown viscous liquid.
Reaction SMILES: [CH2:1]([N:3]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:55])[NH:24][C:25]2[S:26][C:27]3[CH2:54][CH2:53][CH2:52][CH2:51][C:28]=3[C:29]=2[C:30](=[O:50])[NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([O:48]C)=[O:47])=[CH:42][CH:41]=3)=[CH:34][CH:33]=2)[CH:18]=1)(=[O:16])=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>CO>[C:46]([C:43]1[CH:44]=[CH:45][C:40]([CH2:39][CH2:38][C:35]2[CH:34]=[CH:33][C:32]([NH:31][C:30]([C:29]3[C:28]4[CH2:51][CH2:52][CH2:53][CH2:54][C:27]=4[S:26][C:25]=3[NH:24][C:23]([C:19]3[CH:18]=[C:17]([S:14]([N:3]([CH2:1][CH3:2])[C:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=4)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=3)=[O:55])=[O:50])=[CH:37][CH:36]=2)=[CH:41][CH:42]=1)([OH:48])=[O:47]
Reactant: CCN(c1ccc(C(=O)OC)cc1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(c1ccc(C(=O)O)cc1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 93.5 %

Procedure:
To a mixture of 275 mg of methyl 4-(ethyl{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}amino)benzoate and 5.0 mL of methanol was added 2.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at 60° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, then to the residue was added 1 M hydrochloric acid, and the precipitate was collected by filtration. The obtained yellowish-white solid was solidified with methanol and the precipitate was collected by filtration to obtain 248 mg of 4-{[(3-{[3-({4-[2-(4-carboxyphenyl)ethyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}phenyl)sulfonyl](ethyl)amino}benzoic acid as yellowish-white crystal.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([OH:10])[CH2:8][OH:9].N1C=CC=CC=1.Cl>C(OCC)(=O)C.O1CCCC1>[Br:1][CH:2]([CH3:6])[C:3]([O:9][CH2:8][CH2:7][OH:10])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: OCCO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Br)C(=O)OCCO
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere, 2-bromopropionyl chloride (2 mL, 3.35 g, 19.5 mmol) is added dropwise slowly at 0° C. to a THF (tetrahydrofuran) solution (10 mL) of ethylene glycol (10.9 mL, 195 mmol) and pyridine (3 g, 39 mmol). The solution is stirred at that temperature for 2 hours. Dilute hydrochloric acid (20 mL) and ethyl acetate (30 mL) are added and the mixture is allowed to separate into two layers. The organic layer is washed with dilute hydrochloric acid and brine and dried over Na2SO4, and the volatile matter is then distilled off under reduced pressure to give a crude product (3.07 g). This crude product is distilled under reduced pressure (70˜73, 0.5 mmHg) to give hydroxyethyl 2-bromopropionate of the formula shown below (2.14 g, 56%):
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2>CN(C=O)C>[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:30]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Brc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc(Br)c4C3)c(F)cc2c1=O
Yield: 62.4 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 300 mg of 4-bromoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 162 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.[F:32][C:33]1[CH:34]=[N:35][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:37][CH:38]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:36]3[N:37]=[CH:38][C:33]([F:32])=[CH:34][N:35]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2ncc(F)cn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.064 g, 0.12 mmol, 1.3 eq), in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.026 g (50%). 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 2H), 7.99-7.95 (m, 2H), 7.80 (dd, J=2.0, 8.0 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.43-7.39 (m, 2H), 7.23-7.15 (m, 3H), 7.07 (bs, 1H), 6.18 (bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.27 (s, 3H), 1.81-1.78 (m, 2H), 1.55-1.53 (m, 2H). 19F NMR (376.47 MHz, CDCl3) δ−75.77 (TFA), −109.62, −119.26, −142.84 LCMS: (ES+) m/z=557.4 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2=[N:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13](Cl)=[C:4]2[CH:3]=1.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][SH:23].[OH-].[K+]>C(O)C>[NH2:19][CH2:20][CH2:21][CH2:22][S:23][C:13]1[C:12]2[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8][C:7]=2[N:6]=[C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=12
Reactant: NCCCS
Reactant: CN1CCc2nc3ccc(Cl)cc3c(Cl)c2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCc2nc3ccc(Cl)cc3c(SCCCN)c2C1
Yield: 52.9 %

Procedure:
A solution of 5.0 g (0.0188 mol) of the compound of Example 6, 3.3 g (0.02244 m) of 3-aminopropanethiol hydrochloride, 15 ml of 18.5% aqueous potassium hydroxide (0.05 m) and 30 ml of absolute ethanol is refluxed for one and a half hours. After evaporation of the solution, the residue is dissolved in methylene chloride and extracted with water. Evaporation of the methylene chloride solution gives the free base. Recrystallization of the product from hexane affords the title compound as a crystaline solid (3.2 g, 53%), m.p. 87°-89° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]3[CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]4[O:28][C:11]=3[CH:10]=2)O1.CC1C=CC(S(NCl)(=O)=O)=CC=1.[I-:42].[Na+]>C1COCC1.O>[I:42][C:9]1[CH:14]=[CH:13][C:12]2[CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]3[O:28][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC2C1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Reaction time: 20 h

Procedure:
Tert-butyl 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (20 g, 0.05 mol) was dissolved in THF (0.4 L) and a solution of Chloramine T (28.1 g, 0.1 mol) in H2O (0.2 L) was added, followed by a solution of sodium iodide (15 g, 0.1 mol) in H2O (0.2 L) over 20 min. After 20 h stirring, of chloramine T (2.8 g, 0.01 mol) and sodium iodide (1.5 g, 0.01 mol) were added. The reaction mixture was stirred for 20 h, the solvent was evaporated, ethyl acetate and H2O were added. The layers were separated, and the organic layer was washed with H2O.
Reaction SMILES: [F:1][CH2:2][CH:3]([NH2:8])[CH2:4][C:5]([CH3:7])=[CH2:6].C(N1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])(OCC)=O>C1C=CC=CC=1>[F:1][CH2:2][CH:3]([N:8]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)CC(N)CF
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: c1ccccc1
Product: C=C(C)CC(CF)N1C(=O)c2ccccc2C1=O
Yield: 84.5 %

Procedure:
A mixture of 1-fluoro-2-amino-4-methyl-4-pentene (52.5 g, 450 mmoles) prepared as in step A above, N-carbethoxyphthalimide (98.55 g, 450 mmoles), and benzene (600 mL) is kept overnight at room temperature. The solution is concentrated under vacuum, the oily residue is dissolved in methylene chloride (500 mL) and treated with 50 g of triethylamine during 4 hours at room temperature. After extraction with 2 N hydrochloric acid (6×500 mL), the organic layer is dried over sodium sulfate and discoloured by filtration through a layer of silica gel and another of carbon black. The oily residue obtained after concentration (110 g) is extracted several times with petroleum ether to remove some insoluble N-carbethoxyphthalimide. Evaporation of the petroleum ether affords a yellow oil (94 g) which is crystallized from pentane at low temperature (85 g, 77%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S(OC)(O[CH3:26])(=O)=O.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])[CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution at 0° C. of N-(5-methoxy-2-nitrophenyl)carbamic acid t-butyl ester (5.5 g) in dimethylformamide (35 ml) was added sodium hydride (0.9 g, 60% dispersion in mineral oil) and the mixture was stirred at 0° C. for 1 hour. A solution of dimethyl sulfate (2.2 ml) in dimethylformamide (5.5 ml) was slowly added dropwise at 0° C. and the mixture was stirred at the same temperature for 0.5 hours. At the end of this time, to the reaction mixture was slowly added water (55 ml) and the mixture was extracted with toluene (66 ml). The extract was washed with water and concentrated in vacuo to give the desired compound (5.8 g, yield 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:19])[C:9]([O:11][C:12]2([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[S-:20][C:21]#[N:22].[K+].BrBr.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[NH2:22][C:21]1[S:20][C:7]2[CH:6]=[C:5]([CH:8]([CH3:19])[C:9]([O:11][C:12]3([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C(=O)OC1(C)CCCCC1)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C(=O)OC1(C)CCCCC1)c1ccc2nc(N)sc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A stirred mixture of 20.9 g of 1-methylcyclohexyl 2-(p-aminophenyl)-propionate and 31.0 g of potassium thiocyanate in 150 ml of glacial acetic acid was heated in an oil bath at 50° C. and a solution of 25.6 g of Br2 in 15 ml of glacial acetic acid was added dropwise over 30 minutes. The mixture was stirred at 50° C. for an extra 30 minutes, then was cooled and poured into 1,000 ml of 3:2 water/ethyl acetate mixture. The resulting mixture was neutralized to pH 5-6 with solid Na2CO3 and filtered through celite, and the organic layer was then separated, washed with water, dried over MgSO4 and finally evaporated to dryness. Trituration of the residual oil with petroleum ether gave 18.62 g (73% yield) of 1-methylcyclohexyl 2-amino-α-methylbenzothiazole-6-acetate as creamy white crystals melting at 165°-167° C.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.C(O)CCC.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27]>O>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1)[CH3:27]
Reactant: CCOC(=O)CN
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Agent: Cl
Solvent: O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(N)nc2c1CCCC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
To a mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100 mg, 0.545 mmol), triethylamine (221 mg, 2.18 mmol) and butanol (3 ml) was added glycine ethyl ester hydrochloride (152 mg, 1.10 mmol) at room temperature. After the mixture was stirred for 4 hours at 90° C., the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the solvent in the filtrate was removed in vacuo. The residue was purified by silica gel chromatography (3% MeOH/CHCl3) to give the object compound (98.3 mg, 72.1%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1
Reactant: CCOC(=O)Cc1cccc(I)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2Cl)c1
Yield: 49.6 %

Procedure:
Ethyl 3-iodophenylacetate (2.90 g), 2-chloro-4-(trifluoromethyl)phenyl boronic acid (3.3 g), 2M aqueous sodium carbonate solution (5 mL), dioxane (10 mL) and dichloro-bis(triphenylphosphine)palladium(II) (350 mg) were heated at 80° C. for 30 min with stirring. The reaction mixture was then cooled, poured into water, extracted with ethyl acetate, and the organic layer was separated and concentrated under vacuum in the presence of Celite® to a solid residue. This solid residue was purified by medium pressure liquid chromatography on silica gel eluting with a gradient of ethyl acetate in hexanes to yield 1.7 g of the title compound. 1H NMR (CDCl3) δ 7.14 (s, 1H), 7.56 (d, 1H) 7.30-7.45 (m, 5H), 4.77 (q, 2H), 3.67 (s, 2H), 1.26 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[CH:22]([CH3:24])[CH3:23]>>[CH3:23][CH:22]([O:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2)CC1
Product: CC(C)Oc1cccc(N2CCNCC2)c1

Procedure:
Prepared from 1,1-dimethylethyl 4-(3-hydroxyphenyl)-1-piperazinecarboxylate (Description 21) and 2-iodopropane according to the method of Description 22. 1H NMR (250 MHz, CDCl3) δ1.34 (6H, d, J 6 Hz), 3.63-3.78 (8H, m), 4.51-4.60 (1H, m), 6.78-6.84 (2H, m), and 7.30-7.37 (1H, m).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].NC([C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)CC.[BH4-].[Na+]>C(#N)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:24][CH2:25][CH2:26][CH2:28][N:24]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=[CH:23]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: CCC(N)c1nc2ccccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: OC(CNCCCn1cnc2ccccc21)c1ccc(OCc2ccccc2)cc1

Procedure:
30.5 gm of 2-bromo-p-benzyloxyacetophenone and 35 gm of 1-aminopropyl-benzimidazole were stirred for 1 hour at 30°-40° C. in 150 ml of acetonitrile. After separation of the hydrobromide, the mother liquor was acidified with 12 gm of maleic acid, and the precipitated α-[3-(1-benzimidazolyl)-propylamino]-4-benzyloxyacetophenone maleate (m.p. 145°-148° C.) was collected by suction of filtiation. Aqueous ammonia was used to prepare the base, which was reduced in 200 ml of alcohol with sodium borohydride to form 1-(4-benzyloxyphenyl)-2-[3-(1-benzimidazolyl)-propylamino]-ethanol (m.p. 83°-85° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[CH:13]1(/[CH:19]=[C:20](\B2OC(C)(C)C(C)(C)O2)/[CH2:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:12][C:4]1[CH:3]=[C:2](/[C:20](/[CH2:21][OH:22])=[CH:19]\[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Reactant: NS(=O)(=O)c1ccc(Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1Cl
Yield: 109.8 %

Procedure:
According to example 26b, reaction of 4-bromo-2-chloro-benzenesulfonamide (1.0 g, 3.7 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (271 mg, 0.37 mmol), (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.5 g, 5.5 mmol) and aqueous sodium carbonat solution (2 M, 3.60 mL, 7.40 mmol) in 15 mL DMF at 80° C. and purification via column chromatography on silica gel, eluting with a gradient from 70:30 to 50:50 hexane:ethyl acetate affords the title compound as an oil (1.34 g). MS (m/e): 312 [(M−H2O)+H].
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:3].C(O)C.[OH-].[K+].Cl>CCOCC>[ClH:1].[ClH:1].[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH:5]([NH:4][CH2:2][CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCNC(Cc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCNC(Cc1ccccc1N)c1ccccc1
Reaction time: 3 h

Procedure:
3.00 g of N-Ethyl-2-nitro-α-phenylphenethylamine hydrochloride is treated with 100 ml of hot 95% ethanol containing 1.10 g of potassium hydroxide for 15 minutes, after which the mixture is filtered and placed in a Paar flask. 0.15 g of 10% palladium on charcoal is added and the mixture is hydrogenated at room temperature and 50 psia for 3 hours, after which the catalyst is removed. The ethanol is evaporated from the filtrate and the resulting yellow oil is poured onto 100 ml of water. The biphasic aqueous mixture is extracted with methylene chloride (2×100 ml). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride evaporated to afford a colorless oil. The oil is dissolved in 50 ml of ether. Ethereal hydrogen chloride (100 ml) is added precipitating the hydrochloride acid salt as an oil. The ethanol is evaporated and the oil is dissolved in 20 ml of i-propanol with heating. Upon cooling, white crystals, mp >248° C. dec, fell from solution providing 2-amino-N-ethyl-α-phenylphenethylamine dihydrochloride.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=2)[CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1.C(N(CC)CC)C.ClC1[C:38]2[C:45]([CH3:46])=[CH:44][S:43][C:39]=2[N:40]=[CH:41][N:42]=1>C(O)C.C(O)(=O)C>[CH3:21][O:20][C:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6]1[C:38]3[C:45]([CH3:46])=[CH:44][S:43][C:39]=3[N:40]=[CH:41][N:42]=1)[CH2:17]2)=[O:19]
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: COC(=O)c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)CC(Nc1ncnc3scc(C)c13)C2
Yield: 44.8 %

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-methoxycarbonylindan (60 mg, 0.21 mmol) synthesized in the above Reference Production Example 3, 4N hydrochloric acid-dioxane (1.0 ml) and acetic acid (3.0 ml), and then ethanol (1 ml), triethylamine (88 μl, 0.63 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (39 mg, 0.21 mmol), a similar procedure to Production Example 213 was carried out. The product obtained was purified by silica gel chromatography (methylene chloride:ethyl acetate=6:1) to obtain the title compound (32 mg, 0.094 mmol) having the following physical properties: