Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[N:13]=2)=[N:6][CH:7]=1.[C:30](O)(=[O:36])[CH2:31][CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[NH2:21][C:14]1[N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:5]2[N:4]=[C:3]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:2]([N:1]3[C:33](=[O:34])[CH2:32][CH2:31][C:30]3=[O:36])=[CH:7][N:6]=2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(O)CCC(=O)O
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2ncc(N3C(=O)CCC3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine, and 2 mmol of succinic acid, 4 mmol of HBTU, and 5 mmol of N,N-diisopropylethylamine were added to solution and stirred for six hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography 5-10% methanol/methylene chloride to obtain 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]pyrrolidine-2,5-dione.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15]>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C(O)CCCCCBr
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A! Thionyl chloride (22.5 ml, 0.31 mole) was dropped at 0° C. in absolute ethanol (300 ml). At the end of the addition, 6-bromohexanoic acid (30 g, 0.153 mole) was added in small portions, then the mixture was stirred for 5 hours at room temperature and evaporated to dryness while taking it up in ethanol 2 times. The ethyl 6-bromohexanoate thus obtained was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CS(C)=O.C(OCC)C.Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of trans (4-hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (10.0 g, 43.7 mmol) in DCM (225 mL) was treated with dimethylsulfoxide (DMSO) (75 mL) and then cooled to 0° C. Diisopropylethylamine (30.4 mL, 0.17 mol) was added followed by dropwise addition of a fine suspension of sulphur trioxide pyridine complex (27.8 g, 0.17 mol) in DMSO (75 mL). The mixture was stirred at ambient temperature for 10 minutes and then diluted with diethyl ether and 1N aqueous hydrochloric acid with cooling in an ice bath. The phases were separated and the aqueous layer was extracted with ether (×2) and the combined organic phases were washed with 1N aqueous hydrochloric acid, and brine, dried with sodium sulfate and concentrated under vacuum. Trituration with pentane gave 9.36 g (94%) of trans (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ: 9.62 (d, 1H), 4.40 (br s, 1H), 3.51-3.28 (m, 1H), 2.20-1.99 (m, 4H), 1.44 (s, 9H), 1.38 (m, 2H), 1.16 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:9]1([C:15]#[C:16][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(I)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccccc2)cn1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (320 mg, 0.45 mmol) was dissolved in 50 ml THF and 2-amino-5-iodopyrdine (2.0 g, 9.1 mmol) and phenylacetylene (2.0 ml, 18.2 mmol) were added at room temperature. Et3N (3.8 ml, 27 3 mmol), triphenylphosphine (72 mg, 0.27 mmol) and copper(I)iodide (52 mg, 0.27 mmol) were added and the mixture was stirred for 2 hours at 65° C. The reaction mixture was cooled and extracted once with saturated NaHCO3 solution and three times with ethyl acetate. The organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. The crude product was suspended in 5 ml of dichloromethane, stirred for 15 minutes and filtered. The crystals were washed with a small volume of dichloromethane and dried for 1 hour at 50° C. and <20 mbar. The desired compound was obtained as a light yellow solid (1.1 g, 63%), MS: m/e=195.3 (M+H+).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (170 mg, 0.94 mmol) and N,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperature for 10 minutes and then a solution of 4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (190 mg, 0.628 mmol) in methylene chloride (4 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was used directly in the next step without purification (121 mg, 60%). LCMS calculated for C16H15Cl2N2O (M+H)+: m/z=321.0; Found: 321.0
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].[O:31]=[C:32]1[N:36]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[C:35]2[CH:43]=[CH:44][CH:45]=[CH:46][C:34]=2[NH:33]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(=O)([O-])O.[Na+]>ClCCl.O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:17]([N:40]1[CH2:39][CH2:38][CH:37]([N:36]2[C:35]3[CH:43]=[CH:44][CH:45]=[CH:46][C:34]=3[NH:33][C:32]2=[O:31])[CH2:42][CH2:41]1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(Cl)c(Cl)c1)C(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 56 %

Procedure:
Triethylamine (0.28 mL, 0.20 g, 2 mmol) was added to a stirred, cooled (0° C.) mixture of (S)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionic acid (prepared according to the method of Sugano. H, and Miyoshi. M, J. Org. Chem 1976, 41, 2352) (364 mg, 1 mmol), 4-(2-keto-1-benzimidazolinyl)piperidine (217 mg, 1 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (305 mg, 2 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 1h. Aqueous sodium hydrogen carbonate (saturated, 40 mL) and water (10 mL) were added and the mixture was extracted with dichloromethane (3×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×50 mL), aqueous sodium hydrogen carbonate (saturated, 2×50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (99:1) to give the title compound as a colorless foam (318 mg, 56%). m/e (ES+) 563 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=2)[CH:14]=[C:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:8][CH:9]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:30]=[CH:29][CH:28]=[C:13]([CH:14]=[C:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:12]=2)=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl 4-(3-(5-ethoxypyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.6 g, 1.46 mmol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (1.1 mL, 14.6 mmol). The resulting mixture was stirred for 1 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 and the organic layer was dried over Na2SO4, and concentrated under reduced pressure to give the title compound (0.45 g, 99%); m/z (311.5, M+ H+).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][NH2:19])=[CH:15][CH:14]=1.Cl>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][NH:19][C:8](=[O:10])[CH2:7][N:6]2[C:2]([SH:1])=[N:3][N:4]=[N:5]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CON)cc1
Reactant: O=C(O)Cn1nnnc1S
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(CONC(=O)Cn2nnnc2S)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an ice cold solution of 5-mercapto-1H-tetrazole-1-acetic acid (4.4 g) in N,N-dimethylformamide (40 ml) is added N,N'-carbonyldiimidazole (4.86 g), and the mixture is stirred under nitrogen for 1 hour. To this solution is added a solution of p-methoxybenzyloxyamine (7.9 g) in N,N-dimethylformamide (10 ml), and the mixture is stirred under ice cooling for 45 minutes. The reaction mixture is poured onto ice water containing hydrochloric acid and extracted with ethyl acetate. The extract solution is washed with water, dried and concentrated under reduced pressure. The residue is crystallized from a mixture of acetone and ether to give the title compound (7.3 g). mp. 167°-168° C.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][C:7]1([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:19]2[CH:18]=[C:17]([C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][C:10]([C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:12]=2)C.[OH-].[Na+].Cl>O>[C:36]([CH2:35][CH2:34][C:7]1([CH2:6][CH2:5][C:4]([OH:41])=[O:3])[C:19]2[CH:18]=[C:17]([C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][C:10]([C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:12]=2)([OH:38])=[O:37]
Reactant: CCCCCC(=O)c1ccc2c(c1)C(CCC(=O)OCC)(CCC(=O)OCC)c1cc(C(=O)CCCCC)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(=O)c1ccc2c(c1)C(CCC(=O)O)(CCC(=O)O)c1cc(C(=O)CCCCC)ccc1-2
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A 2-neck 250-mL round bottom flask was equipped with a condenser, a nitrogen inlet, and a magnetic stirrer. The flask was charged with 3-[9-(2-ethoxycarbonyl-ethyl)-2,7-dihexanoyl-9H-fluoren-9-yl]-propionic acid ethyl ester (10.76 g), 100 mL of water and 5.0 g of sodium hydroxide. The mixture was then heated to reflux overnight. The reaction mixture was cooled to ambient temperature and acidified to pH=1 by addition of 6N hydrochloric acid solution. The resulting solid was isolated by filtration and washed with three portions of water. The solid was dried under vacuum at 70° C. to give 8.5 g of the title compound. 1H NMR (CDCl3, 300 MHz) δ 8.02-7.98 (m, 4H), 7.82 (m, 2H), 2.99 (t, J=7.6 Hz, 4H), 2.47 (m, 4H), 1.74 (m, 4H), 1.53 (m, 4H), 1.40-1.34 (m, 8H), 0.91 (m, 6H).
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[O:21]([C:17]1[CH:16]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)[CH:20]=[CH:19][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)n1nc(-c2cccc(Oc3ccccc3)c2)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: Nc1ncnc2[nH]nc(-c3cccc(Oc4ccccc4)c3)c12

Procedure:
1-tert-butyl-3-(3-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.16 mmol) was dissolved in a solution of formic acid (5 mL) and conc. HCl (0.1 mL) and heated to reflux for 2.5 hours. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 304.1, found 304.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[C:4]2[N:13]=[CH:12][N:11]([CH3:14])[C:5]2=[N:6][C:7]=1[C:8]([OH:10])=[O:9].[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1COCC1.CO>[CH3:17][O:9][C:8]([C:7]1[N:6]=[C:5]2[N:11]([CH3:14])[CH:12]=[N:13][C:4]2=[C:3]([F:15])[C:2]=1[Br:1])=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cn1cnc2c(F)c(Br)c(C(=O)O)nc21
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1nc2c(ncn2C)c(F)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.00 equivalent) in THF-MeOH at 0° C. is added TMSCHN2 (1.30 equivalents, 2 M solution in hexanes). The resulting mixture is warmed to room temperature and stirred for 2 hours. The reaction is quenched with AcOH. The reaction mixture is diluted with EtOAc. The organic layer is washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product that is used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C@H:14]([CH2:17][CH3:18])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:14]([CH2:17][CH3:18])[CH2:15][O:16][C:27]3=[O:29])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC[C@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
(2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}butan-1-ol (2.80 g, 8.56 mmol), prepared in the previous step, and triethylamine (10.5 mL, 60 mmol) in dry dichloromethane (75 mL) was cooled to 0° C. under a nitrogen atmosphere. Triphosgene (5.90 g, 20 mmol) in dry dichloromethane (25 mL) was then added drop wise. After 16 h, the mixture was washed with water and dried (anhydrous MgSO4). The crude product was recrystallized from diethyl ether to afford (4R)-3-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-4-ethyl-1,3-oxazolidin-2-one (1.46 g, 4.1 mmol). mp 134-135° C.; [α]D25=−46° (c=0.0107 g/mL, DMSO); MS (ES) m/z 353.0; HPLC purity 100% at 210-370 nm, 10.8 min; 100% at 270 nm, 10.8 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min. Anal. Calcd for C14H13BrN2O2S: C, 47.60; H, 3.71; N, 7.93. Found: C, 47.45; H, 3.43; N, 7.74.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].N(CCO)(CCO)CCO.[C:16]1(=[O:21])[O:20][CH2:19][CH2:18][CH2:17]1>>[OH:21][CH2:16][CH2:17][CH2:18][C:19]([NH:2][CH2:3][CH2:4][SH:5])=[O:20]
Reactant: NCCS
Reactant: O=C1CCCO1
Agent: Cl
Solvent: OCCN(CCO)CCO
Product: O=C(CCCO)NCCS
Reaction time: 3 h

Procedure:
In a reactor there are introduced, at ambient temperature and under an inert atmosphere, 11.4 g of cysteamine hydrochloride and then slowly, with stirring, 13.5 cm3 of triethanolamine. To the resulting mixture, brought to a temperature of about 60° C., 7.7 cm3 of γ-butyrolactone are slowly added. At the end of the introduction the whole is brought to a temperature of 90° C. for three hours, at the end of which time all the γ-butyrolactone is transformed (VPC verification). 32 g of 4-hydroxy N-(2-mercaptoethyl) butyramide are obtained containing one equivalent of triethanolamine hydrochloride in the form of a pasty white solid that is conditioned under an inert atmosphere.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20].[CH3:26]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: CO
Reactant: Cc1nc2c([N+](=O)[O-])c(Oc3ccc(CC(=O)O)cc3Cl)ccc2[nH]1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)nc3c2[N+](=O)[O-])c(Cl)c1
Temperature: 25 °C

Procedure:
Under an N2 atmosphere, 2-(3-chloro-4-(2-methyl-4-nitro-1H-benzo[d]imidazol-5-yloxy)phenyl)acetic acid (0.331 0.915 mmol) was dissolved in methanol and concentrated sulfuric acid (3 drops) was added. The reaction was heated to reflux for 2.5 h, cooled to room temperature and concentrated in vacuo. The residue was partitioned between saturated NaHCO3 (aq) and ethyl acetate. The layers were separated and the aqueous layer washed with additional ethyl acetate (2×). The organics were combined, dried (Na2SO4), and concentrated in vacuo. Flash column chromatography of the residue, eluting 0% to 3% methanol in dichloromethane, afforded title compound. LC-MS ESI (pos.) m/z: 376.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:3].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=O)[S:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.ClC(Cl)C>>[Br:17][C:18]1[CH:19]=[C:20]([CH2:23][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH:2]([CH3:1])[CH3:3])[CH2:16][CH2:15]2)[S:21][CH:22]=1
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Reactant: O=Cc1cc(Br)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)Oc1ccccc1N1CCN(Cc2cc(Br)cs2)CC1
Yield: 98.8 %

Procedure:
A mixture of 1-[2-(methylethoxy)phenyl]piperazine (6.30 g, 0.029 mol), prepared as described by Martin and Scott, et al., J. Med. Chem., 1989, 32, 1052-1056, 4-bromo-2-thiophenecarboxaldehyde (5.50 g, 0.029 mol), NaBH(OAc)3 (8.00 g, 0.038 mol), acetic acid (1.70 g, 0.029 mol), and dichloroethane was stirred for several hours at room temperature. The reaction was then partitioned between diethyl ether/aqueous 10% Na2CO3 and the ether layer was separated, washed with saturated NaCl solution, dried over anhydrous K2CO3, filtered, and evaporated to give 1-[(4-bromo-2-thienyl) methyl]-4-[2-(1-methylethoxy)phenyl]piperazine (11.33 g) as a crude oil. Treatment of this material with HCl diethyl ether-isopropanol gave a crystalline solid which was recrystallized from methanol to give 1-[(4-bromo-2-thienyl)methyl]-4-[2-(1-methylethoxy) phenyl]piperazine monohydrochloride (10 g, 77%). A 2.0 g sample of this was recrystallized twice from methanol, and chromatographed on flash silica (99:1/CHCl3 :MeOH with 1% NH4OH as eluant). The resulting oil was converted to the hydrochloride salt, as described previously, and was recrystallized from methanol , and dried to give 1-[(4-bromo-2-thienyl) methyl]-4-[2-(1-methylethoxy) phenyl]piperazine monohydrochloride, m.p. (darkens 240° C.) 243°-249.5° C. 1H NMR and CI MS support the structure.
Reaction SMILES: C[O:2][C:3]1[CH:29]=[N:28][C:6]2[N:7]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:5]=2[CH:4]=1.I>C(O)(=O)C>[OH:2][C:3]1[CH:29]=[N:28][C:6]2[N:7]([CH2:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: COc1cnc2c(c1)N=C(c1ccccc1)c1ccccc1N2CCCN(C)C
Agent: I
Solvent: CC(=O)O
Product: CN(C)CCCN1c2ccccc2C(c2ccccc2)=Nc2cc(O)cnc21

Procedure:
The title compound is prepared by reacting 3-methoxy-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine with hydrogen iodide and glacial acetic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH:18]2[NH:22][C:21](=[O:23])[NH:20][C:19]2=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].N1CCOCC1.C=O.O1CCN(CN2[C:44](=O)[CH:43]([CH2:46][CH2:47][C:48]3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)[CH:49]=3)NC2=O)CC1.BrCCCCCC>>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][CH:18]2[N:22]([CH2:44][CH2:43][CH2:46][CH2:47][CH2:48][CH3:49])[C:21](=[O:23])[NH:20][C:19]2=[O:24])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(CCC2NC(=O)NC2=O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(CCC2NC(=O)N(CN3CCOCC3)C2=O)cc(C(C)(C)C)c1O
Agent: C=O
Solvent: CCCCCCBr
Solvent: C1COCCN1
Product: CCCCCCN1C(=O)NC(=O)C1CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
5-(3',5' -di-tert-butyl-4'-hydroxyphenylethyl)hydantoin is treated with morpholine and formaldehyde according to the procedure of O. O Orazi and R. A. Corral, Tetrahedron, 15, 93 (1961) to prepare the corresponding 3-N-morpholinomethyl-5-(3',5' -di-tert-butyl-4'-hydroxyphenylethyl)hydantoin. This material is then alkylated in the 1-position with 1-bromohexane as described in Example 25. The morpholinomethyl group is removed by subsequent hydrolysis according to the procedure of O. O. Orazi and R. A. Corral, Experientia, 21, 508 (1965) to give 5-(3',5' -di-tert-butyl-4'-hydroxyphenylethyl)-1-n-hexylhydantoin.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(OC(NCC1C=C(CCC(O)=O)C=CC=1)=O)(C)(C)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(=O)NCc1cccc(CCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(OCC(=O)O)cc1

Procedure:
1 g of methyl 2-(4-tert-butoxycarbonylaminomethyl-phenoxy)acetate (starting material D3) is saponified with 4.1 ml 1N aqueous sodium hydroxide solution in 10 ml tetrahydrofurane as described for starting material C2. Yield: 0.7g; the mass spectrum shows the molecular peak MNa+ at 304 Da.