Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=O)=[C:10]([CH3:20])[N:9]=1.O=S(Cl)[Cl:23]>C1COCC1.C(Cl)Cl>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][Cl:23])=[C:10]([CH3:20])[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(Cl)c2ccccc2c1C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc(Cl)c2ccccc2c1CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
LAH (3.6 ml of 1M in THF, 3.62 mmol) is added to a solution of 1-chloro-3-methyl-isoquinoline-4-carbaldehyde (744 mg, 3.62 mmol) in THF (10 ml) at 0° C. After stirring for 30 min at ambient temperature, the mixture is quenched with small amounts of saturated sodium sulfate and filtered through a pad of celite. The filtrate is concentrated in vacuo to give the crude alcohol. SOCl2 (13 ml of 2M in DCM, 25 mmol) is added to a solution of the crude alcohol in DCM (5 ml). After stirring for 1 h at room temperature, the mixture is concentrated in vacuo and the residue is chromatographed on silica gel to give 737 mg of 1-chloro-4-chloromethyl-3-methyl-isoquinoline. 1H NMR (CDCl3) 8.44 (d, 1H), 8.18 (d, 1H), 8.02 (t, 1H), 7.82 (t, 1H), 5.03 (s, 2H), 3.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH3:23][O:24][CH2:25][C:26]([OH:28])=[O:27]>>[OH:22][C@@:12]1([C@:13]2([CH3:14])[C@H:9]([C@H:8]3[C@H:17]([CH2:16][CH2:15]2)[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH2:20][CH2:19]2)=[CH:6][CH2:7]3)[CH2:10][CH2:11]1)[CH:25]([O:24][CH3:23])[C:26]([OH:28])=[O:27]
Reactant: COCC(=O)O
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Product: COC1=CC2=CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3CC[C@@]4(O)C(OC)C(=O)O)[C@@]2(C)CC1

Procedure:
Under the conditions described in Example 1, 15 g. of 3-methoxy-3,5-androstadien-17-one is reacted with the lithium enolate of the methyl ester of methoxyacetic acid. After recrystallization of the crude product from methylene chloride/ether, 17.8 g. of the methyl ester of 17β-hydroxy-3,20-dimethoxy-3,5-pregnadiene-21-oic acid is obtained, m.p. 182°-185°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[OH-].[K+].I[C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1ccccc1I
Reactant: Sc1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Sc1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
FIG. 2 is a flow chart for manufacturing the compound No. 1. First, 2,3-dichlorobenzenethiol (0.90 g, 5 mmol) is dissolved in 10 ml DMF solution, and 10 ml of 1N KOH(aq) is added thereinto. After stirring the mixture under room temperature for 10˜15 minutes, 2-iodobenzoic acid (1.24 g, 5 mmol) is dissolved in 10 ml of DMF solution. And then, 0.315 g of Cupper powder is added into the mixture, and the mixture is treated by a reverse flow under 120□ for 8 hours. After filtering the mixture, the filtrate is neutralized with 10 ml of 1N HCl(aq), and a precipitate will be produced. After filtering and washing the precipitate by water, 2-(2,3-dichlorophenylthio)benzoic acid is obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C@@H:10]2[CH2:20][OH:21])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C@@H:10]2[CH2:20][OH:21])=[CH:7][CH:8]=1)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of sulfide 18 (5 g, 16.7 mmol) in dichloromethane (200 mL) at −78° C. was added m-chloroperbenzoic acid (3.6 g, 16.7 mmol) in dichloromethane (150 mL) over a span of 10 minutes. The resulting mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with aqueous NaHCO3 at −78° C. Extraction with dichloromethane (3×200 mL) afforded 5.22 g of the desired sulfoxide as a white solid, upon concentration. 1H NMR (200 MHz, CDCl3) 2.72 (s, 3H), 3.80-3.90 (m, 1H), 4.05-4.15 (m, 1H), 4.20-4.30 (m, 1H), 5.61 (d, J=8 Hz, 1H), 7.35-7.55 (m, 5H), 7.68 (t, J=9 Hz, 2H), 8.0 (d, J=9 Hz, 2H).
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:22][C:23]1([CH3:31])[CH2:30][C:28](=O)[CH2:27][C:25](=[O:26])[CH2:24]1.C1(C)C=CC=CC=1>O>[NH2:17][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:28]3[CH2:30][C:23]([CH3:31])([CH3:22])[CH2:24][C:25](=[O:26])[CH:27]=3)[CH2:3][CH2:2]2)[N:16]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nc(N3CCN(C4=CC(=O)CC(C)(C)C4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 2.9 g (0.01 mol) of 2-piperazino-4-amino-6,7-dimethoxyquinazoline, 1.4 g (0.01 mol) of dimedone and 20 ml of toluene is heated at the boiling point under reflux for 4 hours, using a water separator. After cooling the solution, the reaction product precipitates. It is washed with petroleum ether and recrystallised from 220 ml of acetonitrile. 2.6 g of melting point 185°-187° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)O1>>[NH2:33][C:32]1[CH:34]=[CH:35][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:30][CH:31]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Yield: 14.1 %

Procedure:
Methyl 8-(4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (150 mg, 0.51 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (135 mg, 0.62 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (25 mg, 14%).
Reaction SMILES: [F:1][CH:2]([F:25])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>ClCCl>[F:25][CH:2]([F:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:35])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCc1noc(C2CNCC(c3ccc(CC(F)F)cc3)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 36.3 mg (0.061 mmol, purity 70%) of the compound from Example 61A in dichloromethane (2.0 ml) was admixed with 0.03 ml (21.6 mg, 0.21 mmol) of triethylamine and then 12.3 mg (0.061 mmol) of 4-nitrophenyl chloroformate were added at RT. The mixture was stirred at RT for 2 h and then the reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 56.2 mg (91% of theory, purity 60%)
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:31][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:30][CH2:29]1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: NC1CC1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC3CC3)c(=O)n12
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0,088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml of chloroform is dropped to the above mixture at a temperature between -10° C. and -17° C. during 25 minutes. After stirring for 5 minutes, 5.025 g (0.088 mol) of cyclopropylamine in 80 ml of chloroform are dropped to the above solution at the same temperature during 40 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 14.5 g (74.5%) of the named compound as light yellow crystals after recrystallization from ethanol, m.p.: 174°-176° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][C:15]1([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]2[OH:30])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13].Br[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[C:35]#[N:36]>>[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][C:15]1([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][N:27]([C:32]3[CH:33]=[C:34]([C:35]#[N:36])[CH:37]=[CH:38][C:39]=3[O:40][CH3:41])[CH2:26][C:25]2=[O:30])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:13]
Reactant: Cc1c(C(=O)NC2(C(=O)NC3CCNCC3O)CCCCC2)oc2ccccc12
Reactant: COc1ccc(C#N)cc1Br
Agent: Cl
Product: COc1ccc(C#N)cc1N1CCC(NC(=O)C2(NC(=O)c3oc4ccccc4c3C)CCCCC2)C(=O)C1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(3-methyl-benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 3-bromo-4-methoxybenzonitrile was used instead of 1-bromotoluene in Step 1 thereof, 270 mg of the titled compound was prepared.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)=O.Cl>O>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Clc1cnc(Cl)cn1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Clc1cnc(N2CCNCC2)cn1
Yield: 36.7 %

Procedure:
A mixture of 2,5-dichloropyrazine (14.9 g, 0.1 mol), piperazine (50.5 g, 0.59 mol), acetone (22.5 ml), water (20 ml) and concentrated aqueous HCl (1.8 ml) was heated at reflux for 3 hr. The reaction mixture was cooled, diluted with water, filtered and the acetone was removed by distillation. The aqueous solution was then extracted thrice with chloroform. The combined extracts were washed twice with water, dried (Na2SO4) and evaporated to dryness to afford 7.3 g of solid, m.p. 98°-102°. J. K. Boissier et al., J. Med. Chem., 6, 541 (1963) report a m.p. of 101° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([CH2:35][NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])=[CH:44][CH:43]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Oc2ccc(S(=O)(=O)CCN3CC[C@H](Cc4ccccc4)[C@H](O)C3)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of 500 mg (1.33 mmol) (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol in 10 ml methylenechloride were added 368 mg (1.46 mmol) 4-(tert-butoxycarbonylamino-methyl)-benzoic acid, 16.3 mg (0.133 mmol) DMAP und 511 mg (2.66 mmol) N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and the reaction mixture was stirred at 0° C. After 1 hour, 0.5 N HCl was added and the aqueous layer was extracted with methylenechloride. The combined organic layers were washed with 0.5N HCl solution and brine, dried over NaSO4, filtered and the solvent was removed under reduced pressure to give the crude product. Crystallization from diethylether yielded 280 mg (0.460 mmol, 35%) 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as colorless crystalls.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:35])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:34])[CH:17]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[N:23][O:24][C:25]=3[CH3:26])=[O:20])[C@H:5]2[S:4]1.[CH3:36][N:37]1[C:41]([SH:42])=[N:40][N:39]=[N:38]1>P([O-])([O-])([O-])=O.CC(C)=O>[CH3:36][N:37]1[C:41]([S:42][CH2:2][C:3]2([CH3:35])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]3[C:16](=[O:34])[CH:17]([NH:18][C:19]([C:21]4[C:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[Cl:33])=[N:23][O:24][C:25]=4[CH3:26])=[O:20])[C@H:5]3[S:4]2)=[N:40][N:39]=[N:38]1
Reactant: Cn1nnnc1S
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CBr)S[C@H]12
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CSc3nnnn3C)S[C@H]12

Procedure:
By treating in the similar manner as described in Example 11 using 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate and 1-methyl-IH-tetrazole-5-thiol in a mixture of pH 6.85 phosphate buffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl 2-(1-methyl-IH-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate. Infrared Absorption Spectrum (Nujol) 3300, 1780, 1770, 1665 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([O:19][C@@H:20]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:29][C@@H:21]1OC(=O)C(F)(F)F)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[CH2:12]([O:19][C@@H:20]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[O:29][C@H:21]1[C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[O:8][CH3:9])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(Br)c(OC)c1
Reactant: O=C(O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Br
Reaction time: 0.17 h

Procedure:
1-bromo-2,4-dimethoxybenzene (9.1 ml) was added to a solution of 2,3,4,6-tetra-O-benzyl-1-O-(trifluoroacetyl)-α-D-glucopyranose (20.0 g) in methylene chloride (100 ml) and the mixture was stirred for 10 minutes. Boron trifluoride-diethyl ether complex (3.9 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(5-bromo-2,4-dimethoxyphenyl)-D-glucitol (17.0 g).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1cccc(C(=O)O)c1O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (10 g, 66.7 mmol, 1.0 eq) in acetic acid (100 mL) was added bromine (10.66 g, 66.7 mmol, 1.0 eq) slowly over 5 min. The mixture was stirred at room temperature for 24 h, then water was added slowly and the mixture was stirred for a further 30 min. The precipitate was collected by filtration and was washed with water and dried to give the title compound as a white solid (13.7 g, 90%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]#[N:8].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17](F)[C:16]=1[F:25].Cl>C1COCC1>[F:25][C:16]1[C:15]([F:14])=[CH:20][CH:19]=[C:18]([N+:21]([O-:23])=[O:22])[C:17]=1[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]#[N:8]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: COc1cc(O)cc(C#N)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
NaH (2.05 g, 51.2 mmol) was added portionwise to a 0° C. solution of 3-hydroxy-5-(methyloxy)benzonitrile (7.63 g, 51.2 mmol) (prepared following the procedure in Magano et al. J. Org. Chem. 2006, 71, 7103) in THF (205 ml). When addition was complete, the thick suspension was stirred at this temperature for another 30 mins, and trifluoronitrobenzene (9.51 g, 53.7 mmol) was then added. The reaction mixture was stirred at RT for 3 h, dilute HCl was added and the solution was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-30% EtOAc/hexanes) to afford the title compound (14.44 g, 92%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.96 (ddd, J=9.36, 4.97, 2.24 Hz, 1H) 7.28-7.35 (m, 1H) 6.95 (d, J=0.73 Hz, 1H) 6.78 (t, J=2.15 Hz, 1H) 6.73 (s, 1H) 3.85 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:4].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>CC#N>[N:10]1([CH2:2][C:3]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)=[O:4])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)c1nccs1
Solvent: CC#N
Product: O=C(Cn1ccnc1)c1nccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-1-(thiazol-2-yl)-ethanone (2.5 g; 12 mmol) in CH3CN (70 ml) was added imidazole (1.65 g; 24 mmol). After stirring at room temperature for 1 hour, the mixture was evaporated to dryness and partitioned between CH2Cl2 and water. The organics were washed with saturated NaCl and evaporated to give 2-(imidazol-1-yl)-1-(thiazol-2-yl)-ethanone as a brown solid (1.17 g; 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:13]([O-:15])=[O:14].[CH3:16][N:17]([CH:19](N(C)C)OC(C)(C)C)[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:13]([O-:15])=[O:14])[C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)c([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: COc1ccc(C=CN(C)C)c([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
57.7 g of 4-methoxy-2,3-dinitrotoluene (J. Chem. Soc. 1927:580) is agitated with 150 ml of bisdimethylamino-tert-butoxymethane [Chem. Ber. 101:41 (1968)] for 6 hours at 80° C. After cooling, the precipitated solid material is filtered off, washed with diisopropyl ether, and dried with a water-jet aspirator, thus producing 54.6 g of β-dimethylamino4-methoxy-2,3-dinitrostyrene, mp 100°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:7]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5].[C:21](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:7]([N:11]([CH3:21])[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccccc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 78 h
Yield: 65.1 %

Procedure:
[2-(2-Chlorobenzoyl)-1H-pyrrol-1-yl]-carbamic acid, ethyl ester (22 g, 75.1 mmol), sodium carbonate (16.0 g, 0.112 mol) and methyl iodide (13 g, 0.122 mol) were added to 100 ml of dry DMF and the mixture stirred at ambient temperature for 78 hours. The reaction was quenched with 1 liter of H2O and extracted with five 200 ml portions of diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and evaporated to give 15 g of solid. This solid was purified by HPLC (silica gel, DCM) to give 13.1 g (57%) of crystals, m.p. 54°-56°.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>ClCCl>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12]2)=[O:19])=[CH:16][CH:15]=1
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)N1CCNC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
This compound could be made in the following manner: 500 mg of 2-phenylpiperazine would be dissolved in dichloromethane and cooled to 0° C. A solution of 0.5 equiv. of 4-bromobenzoyl chloride in dichloromethane would be added dropwise over 1 h at 0° C. The reaction would be stirred at 0° C. for 0.5 h, then allowed to warm to room temperature and stirred for a further 3 h until complete conversion. The reaction mixture would be diluted with dichloromethane, washed with 1M aqueous sodium hydroxide solution and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford (4-bromo-phenyl)-(3-phenyl-piperazin-1-yl)-methanone.