Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CC(N(C)C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Ic1ccc(N2CCNCC2)nc1
Temperature: 120 °C
Yield: 82 %

Procedure:
To a stirred solution of 2-chloro-5-iodo-pyridine (CAS number 69045-79-0, 10.52 g, 43.9 mmol) and diisopropylethylamine (11.5 mL, 65.9 mmol) in DMA (200 mL) was added piperazine (15.14 g, 0.176 mol). The mixture was the heated to 120° C. for 20 hours. The solid precipitate was then filtered off, and the filtrate evaporated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was then extracted with EtOAc (2×100 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo, to give 1-(5-iodopyridin-2-yl)piperazine as a yellow solid (10.42 g, 36 mmol, 82%).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][S:34][CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.I([O-])(=O)(=O)=[O:38].[Na+]>CO.O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][S:34](=[O:38])[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCSCC4)c3)cc2n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCS(=O)CC4)c3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (50 mg, 0.1 mmol) and sodium periodate (43 mg, 0.2 mmol) in MeOH/water (3:1, 4 mL) was stirred overnight at rt. The reaction was partitioned between EtOAc and brine and the organic phase dried, filtered and concentrated in vacuo to give 1-oxo-thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (30 mg, 58%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.37 (1H, s), 8.25 (1H, s), 8.17 (1H, d), 8.10 (1H, s), 7.96 (1H, t), 7.82 (1H, s), 7.71-7.74 (1H, m), 7.63 (1H, d), 7.23-7.32 (2H, m), 6.96-6.98 (1H, m), 6.67 (1H, t), 6.54 (1H, d), 4.45 (2H, d), 4.13 (3H, s), 3.99-4.04 (2H, m), 3.66-3.74 (2H, m), 2.84-2.93 (2H, m), 2.65-2.70 (2H, m); m/z (LC-ES+) 518 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[O:5][CH2:4][C@H:3]1[OH:13].C[C@]1(C(O)=O)C(C)(C)[C@@H](C(O)=O)CC1.C(#N)C>O>[NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[O:5][CH2:4][C@@H:3]1[OH:13]
Reactant: N[C@@H]1c2cc(Br)ccc2OC[C@H]1O
Agent: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Solvent: CC#N
Solvent: O
Product: N[C@H]1c2cc(Br)ccc2OC[C@@H]1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
Heat a mixture of racemic-trans-4-amino-6-bromochroman-3-ol (21.1 g, 86.4 mmol), D-(+)-camphoric acid (17.3 g, 86.4 mmol), acetonitrile (633 mL) and water (47.6 mL) to 70-75° C. and stir for 10 min. The solution is allowed to cool to ambient temperature over 4 hr. After 24 hr. at ambient temperature, the mixture is filtered. Rinse the solids with 7% H2O in acetonitrile (2×20 mL). Heat the filtrate to 50° C. and add 1N NaOH (216.1 mL). Concentrate the resulting mixture under reduced pressure to remove the acetonitrile. Add H2O (211 mL) and heat the solution to 70° C. Cool to ambient temperature and collect the precipitate by filtration. Wash with water (25 mL) and vacuum dry at 50° C. overnight to obtain the title compound as an off-white solid (9.8 g, 46.4% of 50% theoretical weight, 98.7% ee).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][CH:7]([CH3:10])[CH2:8][OH:9].N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][C:3]([O:9][CH2:8][CH:7]([CH3:10])[CH3:6])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)CO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)COC(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
A solution of chloroacetyl chloride (3.2 mL, 40 mmol) in anhydrous diethyl ether (20 mL) was added dropwise within 1 h to a solution of 2-methylpropanol (2.96 g, 40 mmol) and pyridine (3.25 mL, 40 mmol) in anhydrous diethyl ether (80 mL) at 0° C. After warming to RT, the white suspension was stirred for 3 h. The precipitate was removed by filtration and washed by diethyl ether (15 mL). The combined organic solution was washed with HCl (2 N, 30 mL), followed by sat. NaHCO3 (30 mL), sat. NaCl (30 mL) solutions and dried with Na2SO4. Removal of the solvent at about 60 mmHg/30° C. afford 2-Methylpropyl Chloroacetate (5.65 g, 94%) which was used without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH3:23])=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[CH:32])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:2]2[CH:3]=[C:4]([C:20]([NH:22][CH3:23])=[O:21])[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:7]=2[CH3:8])=[CH:27][CH:26]=1
Reactant: CNC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)c1cc(C#Cc2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 70 °C
Yield: 78 %

Procedure:
A mixture of 5-iodo-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (139 mg, 0.32 mmol), tetrakis(triphenylphosphine) palladium(0) (1.8 mg, 1.6 μmol), copper(I) iodide (0.6 mg 3.2 μmol), 1-chloro-4-ethynylbenzene (87 mg, 0.638 mmol) and DIEA (64 mg, 0.5 mmol) in acetonitrile (1.5 ml) was heated in a microwave oven to 70° C. for 0.5 h. After cooling, the reaction mixture was purified by flash chromatography to give 5-[(4-chlorophenyl)ethynyl]-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (111 mg, 78%).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].CC[N:15]([CH:19]([CH3:21])[CH3:20])C(C)C.ClS(N=C=O)(=O)=O.[C:29](O)(C)([CH3:31])[CH3:30]>ClCCCl.O.C(Cl)Cl>[S:2]([NH2:15])([NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])(=[O:4])=[O:3].[NH2:15][C:19]1[CH:20]=[CH:31][CH:29]=[CH:30][CH:21]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NS(N)(=O)=O
Product: Nc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of chlorosulfonyl isocyanate (1.5 eq) in anhydrous 1,2-dichloroethane (0.1-0.5 M) at 0° C. was added 1.5 eq of tert-butanol as a solution in anhydrous 1,2-dichloroethane (0.5 M). The mixture was allowed to warm to room temperature while stirring and was then cooled to 0° C. again. A suspension of aniline-ester from general procedure E (1.0 eq) in 1,2-dichloroethane (0.3-0.5 M) and 2.5 eq DIEA was cooled to 0° C. and the chlorosulfonyl isocyanate-tert-butanol mixture was added drop-wise while stirring. The mixture was stirred at room temperature for 1 hour, then diluted with water/CH2Cl2 and the layers separated. The organic layers were combined and washed with water and brine. The organic phase was then dried over Na2SO4, filtered, and the filtrate was concentrated and purified by silica gel chromatography to afford the aniline N-Boc sulfamide derivative.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=O)[CH3:2].[H-].[Na+].Br[CH2:44]C#C.O>CN(C)C=O.C(OCC)(=O)C>[F:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:15][C:10]=1[N:9]1[C:5]([NH:4][CH2:1][C:2]#[CH:44])=[CH:6][C:7]([O:24][C:25]([F:39])([F:40])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:31])([F:32])[F:33])=[N:8]1
Reactant: C#CCBr
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
0.7 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole was dissolved in 5 mL of dimethylformamide, and under cooling with ice, the solution was dropwise added to a suspension having 50 mg of sodium hydride suspended in 10 mL of dimethylformamide, and after completion of the dropwise addition, stirring was carried out at room temperature for 30 minutes. The reaction solution was cooled with ice again, and 0.15 g of 1-bromo-2-propyne was added, followed by stirring at room temperature for 1 hour. Then, the reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in 20 mL of ethanol, and 20 mL of a 35mass % hydrochloric acid aqueous solution was added, followed by stirring under reflux with heating for 2 hours. The reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.3 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-(2-propynylamino)-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[NH2:11][CH:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]1=[O:29]>C(O)C>[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[NH2:11][C@H:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]1=[O:29]
Reactant: CCOC(=O)CN1C(=O)C(N)CCc2ccccc21
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Reaction time: 8 h

Procedure:
Tartaric acid (12.6 g) and racemic 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (22 g) were dissolved in hot ethanol (200 ml). This solution was cooled and allowed to stand overnight at room temperature. The solid which precepitated was collected by filtration and recrystallized twice from ethanol (200 ml) to give 3-(S)-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one tartrate salt. This was dissolved in H2O (100 ml) and the pH adjusted to 9 with dilute ammonium hydroxide and extracted with methylene chloride (2×50 ml). The combined extracts were washed with water (75 ml), dried (magnesium sulfate) and evaporated to give 3-(S)-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 104°-106°, [α]D =-285.5° (c=0.99 in ethanol).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CC(C)=O>[F:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CCN(S(=O)(=O)c2ccc(F)c(C(=O)O)c2)CC1
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A solution of 5-chlorosulphonyl-2-fluorobenzoic acid (47.72 g, 0.2 mol) in acetone (250 ml) was added to a mixture of N-methylpiperazine (22.04 g, 0.22 mol) and triethylamine (24.29 g, 0.24 mol) and the reaction was stirred at ambient for three hours. The mixture was filtered, the resulting solid was recrystallised from water to afford the title compound (14.63 g, 24.2%) as a white solid. δ (DMSO): 2.30 (3H, s), 2.58 (4H, m), 2.95 (4H, m), 7.52 (1H, m), 7.90 (1H, m), 8.10 m/z (Found: 303 [M+H]+, 100%, C12H16FN2O4S requires 303).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][NH2:43]>ClCCl.O>[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][NH:43][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:18][CH:17]=1
Reactant: CCCCCCC(CO)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CCCCCCC(CO)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-Hydroxymethyl-heptyl)-benzoic acid (500 mg, 2.00 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (362 mg, 2.06 mmol), and 4-methylmorpholine (230 μL, 2.10 mmol) are combined in anhydrous dichloromethane (10 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. Beta-alanine methyl ester hydrochloride (306 mg, 2.20 mmol) is added to the reaction mixture, followed by more 4-methyl morpholine (460 μL, 4.2 mmol), and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and after 4 h, the reaction is diluted with more dichloromethane. The reaction is diluted with water and rinsed with 1N HCl. Upon acidification, the two layers are separated. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue is purified by flash column chromatography with hexanes/ethyl acetate to provide the title compound. MS (ES): 334.2 [M+H]−.
Reaction SMILES: ClC1N=CN=C2N(C3C=CC=CC=3)N=CC=12.CCN(CC)CC.N[C@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][OH:27]>C(O)C>[C:29]1([CH2:28][CH2:25][CH2:26][OH:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N[C@@H](CO)Cc1ccccc1
Agent: Clc1ncnc2c1cnn2-c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCCCc1ccccc1
Yield: 74 %

Procedure:
First, 1.13 g of the starting material 4-chloro-1-phenylpyrazolo[3,4-d]pyrimidine was combined with 0.67 ml Et3N, 0.74 g of (R)-(+)-2-amino-3-phenyl-1-propanol in 60 ml absolute ethanol and heated in a steam bath for four hours. The solvent was then removed under vacuum and the residue was purified by flash chromatography (10-20% isopropyl alcohol/hexane) to yield 1.24 g of (R)-β-[1-phenyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl)amino]benzenepropanol (74% yield).
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-].C([O-])(=O)C>ClCCCl.C1C=CC=CC=1>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R, 3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.5 g) in 1,2-dichloroethane (10 ml) was added rhodiim(II) acetate (2 mg) under refluxing. After refluxing for 30 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in anhydrous benzene (10 ml) and then evaporated. This operation was repeated once again and the residue was dried in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in anhydrous acetonitrile (10 ml) and cooled to 0° C. under an atmosphere of nitrogen. To this solution were added N,N-diisopropyl-N-ethylanine (0.27 ml) and diphenyl phosphorochloridate (0.28 ml) successively, and the solution was stirred at 0° C. for 40 minutes. To the resulting solution were added dropwise a solution of (2S,4S)-2-(difluoromethyl)thiomethyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.54 g) in anhydrous acetonitrile (3 ml) and N,N-diisopropyl-N-ethylamine (0.29 ml) at 5° C. with stirring, and the stirring was continued at the same temperature for 2 hours. To the reaction mixture was added ethyl acetate (30 ml). The solution was washed twice with saturated aqueous sodium chloride (20 ml), dried over anhydrous magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (5:1,V/V) to give 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.58 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:22][CH2:23][CH:24]([OH:41])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:42]I>O1CCCC1>[C:3]([O:22][CH2:23][CH:24]([O:41][CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCCCCCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a stirred suspension of sodium hydride (2.40 g, 60% oil dispersion, washed with dry petroleum ether) in dry tetrahydrofuran (40 ml) was portionwise added (rac)-1-O-trityl-1,2-octadecanediol (12.2 g) at ambient temperature. After the mixture was stirred for 30 minutes at the same temperature, a solution of methyl iodide (13.1 g) in dry tetrahydrofuran (40 ml) was dropwise added during a period of 45 minutes. After stirring for 3.5 hours at the same temperature, the mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of diethyl ether and 0.5N aqueous sulfuric acid. The separated organic layer was dried and evaporated under reduced pressure. The residue was triturated in petroleum ether to remove impurities by filtration. The filtrate was evaporated to yield 9.8 g of (rac)-1-O-trityl-2-O-methyl-1,2-octadecanediol.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.CCN(CC)CC.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:36][C:37]1[C:38]2[C:43]([N:44]=[C:45]3[C:50]=1[CH:49]=[CH:48][CH:47]=[CH:46]3)=[CH:42][CH:41]=[CH:40][CH:39]=2>C(Cl)(Cl)Cl.CN(C=O)C>[CH:49]1[C:50]2[C:45](=[N:44][C:43]3[C:38]([C:37]=2[NH:36][C:27]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([N:5]([CH2:13][CH2:14][Cl:15])[CH2:4][CH2:3][Cl:2])=[CH:7][CH:8]=2)=[O:33])=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:46]=[CH:47][CH:48]=1
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c2ccccc2nc2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(N(CCCl)CCCl)cc1)Nc1c2ccccc2nc2ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (18, 0.306 g, 1.0 mmol) in dry CHCl3 (35 mL) containing Et3N (0.2 mL) was added dropwise a solution of triphosgene (115 mg, 0.4 mmol.) in an ice bath with vigorous stirring for 30 min. The reaction mixture was evaporated and the residue diluted with THF (20 mL), filtered through a pad of Celite, washed with THF (5 mL). The combined filtrate and washings (containing carbamoyl chloride 38) were then added dropwise into a solution of commercially available 9-aminoacridine hydrochloride (248 mg, 1.0 mmol) in dry DMF (10 mL) containing Et3N (0.5 mL) at room temperature. After being stirred for 16 h, the solvent was evaporated under reduced pressure and the residue was dissolved in a mixture of CHCl3/MeOH containing silica gel (5 g) and evaporated in vacuo to dryness. The residue was put on the top of a silica gel column (2×20 cm) using CHCl3/MeOH (50/1v/v) as eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness and residue was recrystallized from acetone to give 1-acridin-9-yl-3-{4-[bis(2-chloroethyl)amino]phenyl}urea (BO-1034); 273 mg (60%); mp 184-186° C.; 1HNMR (DMSO-d6) δ 3.71 (8H, s, 4×CH2), 6.73 (2H, d, J=9.1 Hz, 2×ArH), 7.10-7.13 (2H, m, 2×ArH), 7.28-7.53 (3H, m, 3×ArH), 7.58-7.60 (2H, m, 2×ArH), 7.84 (1H, brs, exchangeable, NH), 8.15 (2H, d, J=9.1 Hz, 2×ArH), 8.22 (1H, m, ArH), 9.37 (1H, brs, exchangeable, NH). Anal. Calcld. for (C24H22Cl2N4O); C, 63.58; H, 4.89; N, 12.36. Found: C, 63.35; H, 5.05; N, 12.09.
Reaction SMILES: Cl.[NH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13].[CH2:15]=O>C(O)C>[ClH:5].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH2:13][CH2:3][N:2]([CH3:15])[CH3:4]
Reactant: CC(=O)c1ccccc1Cl
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
At 0° C., concentrated HCl was added dropwise to Me2NH (40% in water, 5.57 mL, 1.1 equiv) to acidify the amine. After the addition, 1-(2-chlorophenyl)ethanone (6.18 g, 0.04 mol) and paraformaldehyde (1.68 g, 1.4 equiv) were added. The mixture was dissolved in ethanol (20 mL) and heated to reflux for 30 h. LC-MS found the starting material was gone. The reaction mixture was cooled to rt. The volatiles were removed in vacuo. EtOAc (30 mL) was added and the suspension was stirred for 15 min. The solid was collected by filtration and washed with EtOAc (2×5 mL). The white solid was dried under vacuum to afford 1-(2-chlorophenyl)-3-(dimethylamino)propan-1-one HCl salt (5.17 g, 61% yield). LC-MS (3 min) tR=0.72 min, m/z 212, 214(M+1).
Reaction SMILES: [Br:1][CH:2]([CH3:15])[C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:7]=2[CH:6]=1)=O.[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21].C(O)C>C(O)(=O)C>[BrH:1].[Cl:14][C:13]1[C:7]2[CH:6]=[C:5]([C:3]3[N:18]4[CH2:19][CH2:20][N:16]=[C:17]4[S:21][C:2]=3[CH3:15])[S:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: S=C1NCCN1
Reactant: CC(Br)C(=O)c1cc2c(Cl)cccc2s1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: CC1=C(c2cc3c(Cl)cccc3s2)N2CCN=C2S1
Temperature: 0 °C
Yield: 69.3 %

Procedure:
A mixture of 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl)propan-1-one (0.74 g), 2-imidazolidinethione (0.19 g) and ethanol (15 ml) was heated under reflux for 20 minutes. Acetic acid (7 ml) was added and the mixture was heated under reflux for 17 hours then cooled in ice-water. The resulting solid was collected by filtration and dried in vacuo at 60° C. to give 3-(4-chlorobenzo[b]thiophen-2-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (0.5 g) as a white solid, m.p. 246-248° C.