Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:8]=1.C[Si](C)(C)[O:26][C@@H:27]1[C@@H:32]([O:33][Si](C)(C)C)[C@H:31]([O:38][Si](C)(C)C)[C@@H:30]([CH2:43][O:44][Si](C)(C)C)[O:29][C:28]1=[O:49].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CO>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:28]2([O:49][CH3:2])[C@H:27]([OH:26])[C@@H:32]([OH:33])[C@H:31]([OH:38])[C@@H:30]([CH2:43][OH:44])[O:29]2)=[CH:8][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc(C2CC2)cc1
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC1(c2ccc(Cl)c(Cc3ccc(C4CC4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A cold solution of n-BuLi (2.5 M in hexane, 163 mL, 0.408 mol) precooled to −78° C. can be added dropwise under argon to a stirred solution of 4-bromo-1-chloro-2-((4-cyclopropylphenyl)methyl)benzene (100 g, 0.340 mol) in anhydrous THF/toluene (1:2 (v/v), 660 mL) at −78° C. at such a rate as to keep the internal temperature below −70° C. The mixture is then stirred for another 40 min after the addition. The reaction mixture is transferred by a cannula to a stirred solution of (3R,4S,5R,6R)-3,4,5-tris-(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (206 g, 0.442 mol) in toluene (660 mL) at −78° C. at a rate as to keep the internal temperature below −70° C. The reaction mixture is then stirred at −78° C. for 3 h until the starting materials are consumed before quenching slowly with a solution of hydrochloric acid (36˜38%, 62.3 mL, 0.747 mol) in methanol (440 mL), so the reaction temperature does not exceed −45° C. The reaction mixture is gradually warmed to room temperature and stirred overnight. The mixture is neutralized with aqueous solution of saturated sodium bicarbonate to pH 7.5. The organic layer is separated and the aqueous phase is extracted with ethyl acetate (2×1.2 L). The combined organic layers can be washed with brine (2×1.0 L), dried over sodium sulfate, and concentrated. The residue is then dissolved in hot toluene (200 mL), to which n-hexane (2.0 L) is poured in with rapid stirring. The mixture is stirred for another 1 h and filtered. The solid is dried under vacuum to give the crude product, which can be used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:6]2([C:19]([OH:21])=O)[CH2:18][CH:9]3[CH2:10][N:11]([C:13](=[O:17])[N:14]([CH3:16])[CH3:15])[CH2:12][CH:8]3[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>CC(C)=O.O>[CH:1]1([C:6]2([C:19]([N:35]=[N+:36]=[N-:37])=[O:21])[CH2:18][CH:9]3[CH2:10][N:11]([C:13](=[O:17])[N:14]([CH3:15])[CH3:16])[CH2:12][CH:8]3[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=O)N1CC2CC(C(=O)O)(C3CCCC3)CC2C1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CC2CC(C(=O)N=[N+]=[N-])(C3CCCC3)CC2C1
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
5-Cyclopentyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 16c (0.28 g, 6.95 mmol) was dissolved in 20 mL of acetone upon cooling by an ice-water bath, followed by addition of triethylamine (0.15 mL, 1.05 mmol) and a solution of 2 mL of ethyl chloroformate (0.1 mL, 1.05 mmol) in acetone at 0° C.˜−5° C. After the reaction mixture was stirred for 15 minutes, a solution of sodium azide (0.124 g, 1.9 mmol) in water was added dropwise. The reaction mixture was stirred for another 30 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated and the residue was diluted with 10 mL of water. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-cyclopentyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carbonyl azide 16d (0.287 g, yield 95%) as a yellow oil which was directly used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[H-].[Na+].[C:20]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[CH:57]=[CH:56][C:53]([CH2:54]Br)=[CH:52][CH:51]=2)=[N:42][N:41]=[N:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:54][C:53]3[CH:52]=[CH:51][C:50]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[C:43]4[N:39]([C:20]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:40]=[N:41][N:42]=4)=[CH:57][CH:56]=3)[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c2sc(CC)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
To a solution of ethyl 2-ethyl-4-hydroxy-thieno[2,3-b]pyridine-5-carboxylate (1.00 g, 4 mmol) in 20 ml of DMF) was added sodium hydride (60% dispersion in oil, 160 mg) and the mixture was stirred for 10 minutes. To the reaction mixture was added 4-[2'-(N-trityltetrazol-5-yl)phenyl]benzyl bromide (2.23 g, 4 mmol) and the mixture was heated at 90° C. for 1 hour with stirring. The reaction mixture was poured into water followed by extraction with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and evaporated to dryness. The resulting residue was purified by flash column chromatography on silica gel. The column was eluted with ethyl acetate/dichloromethane (1:1) to give 2.24 g (77%) of the title compound as white crystals.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15]C)[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:18]1C=CC(C(OC)=O)=C(C)C=1.C1(C[Mg]Br)CCC1.C1([Mg]Br)CCC1>>[CH:4]1([CH2:1][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:3][CH2:2][CH2:18]1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: CCc1cc(C2CCC2)ccc1C(=O)OC
Agent: Br[Mg]C1CCC1
Agent: Br[Mg]CC1CCC1
Product: COC(=O)c1ccc(CC2CCC2)cc1C
Yield: 84 %

Procedure:
The title compound (4.00 g, yellow oil, 84%) was prepared using a procedure similar to that used for the preparation of compound 181.3 using compound 152.1 (5.00 g) and cyclobutylmethylmagnesium bromide in place of compound 181.2 and cyclobutylmagnesium bromide respectively.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=3[CH:23]=2)=[O:21])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([O:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=3[CH:23]=2)=[O:21])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])(=[O:38])[CH3:37]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)OCc4ccccc4)c(O)c3)ccc21
Reactant: CC(=O)Cl
Product: CC(=O)Oc1cc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)ccc1C(=O)OCc1ccccc1
Yield: 77.7 %

Procedure:
By reaction of 2.36 g (5 mmol) of benzyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate and 360 μl (5 mmol) of acetyl chloride in a manner analogous to Example 4(b), 2 g (80%) of the expected product which melts at 137°-138° C. are collected.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[C:39]2[CH:43]=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO.N1CCCCC1>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[C:39]2/[CH:43]=[C:7]1\[O:8][C:4]2[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1c[nH]c2c(OCc3ccccc3)cccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4c(OCc5ccccc5)cccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.050 g, 0.14 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 7-benzyloxy-1H-indole-3-carboxaldehyde (0.035 g, 0.14 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with a mixed solvent of chloroform and methanol to obtain tert-butyl (Z)-4-[(2-{[7-(benzyloxy)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.049 g, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[O:30])[C:21]3[C:20](=[O:31])[N:19]([CH3:32])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][OH:30])[C:21]3[C:20](=[O:31])[N:19]([CH3:32])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2CO)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
4-[7-(2-Formylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (27 mg) was dissolved in anhydrous tetrahydrofuran (0.5 ml) and ethanol (0.5 ml), and sodium borohydride (20 mg) was added thereto. The reaction solution was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 28 mg of 4-[7-(2-hydroxymethylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. This product (8 mg) was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 1.60 mg of 7-(2-hydroxymethylphenyl)-1,3-dimethyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione trifluoroacetate [MS m/e (ESI) 371(MH+—CF3COOH)] and 0.46 mg of 7-(2-trifluoroacetoxymethylphenyl)-1,3-dimethyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione trifluoroacetate [MS m/e (ESI) 467(MH+—CF3COOH)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17].[N+:25]([O-])([OH:27])=[O:26]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([N+:25]([O-:27])=[O:26])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1[nH]c2ccc(Br)c([N+](=O)[O-])c2c1S(=O)(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (56 mg, 0.13 mmol, 1.0 equiv) was dissolved in 3 mL of sulfuric acid and cooled to 0° C. A 1 mL aqueous solution of nitric acid (10 mg, 0.15 mmol, 1.15 equiv) was added dropwise and the reaction was stirred for 10 minutes at 0° C., after which an additional 1 mL aqueous solution of nitric acid (5 mg, 0.06 mmol, 0.5 equiv) was added dropwise. After stirring for 30 minutes, the reaction mixture was partitioned between ethyl acetate and water, which was extracted three times with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 15% ethyl acetate/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound ESI+MS: 462.0 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.C=O.[C:14]([BH3-])#[N:15].[Na+].[CH3:18]C(O)=O>C(#N)C>[CH3:18][N:15]([CH3:14])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: Nc1ccc2c(c1)COC2=O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc2c(c1)COC2=O
Temperature: 0 °C
Yield: 66 %

Procedure:
To a stirred suspension of 5-aminophthalide (5.00 g, 33.5 mmol) in acetonitrile (120 ml), was added 37% formaldehyde aqueous solution (24.9 ml, 335 mmol) and sodium cyanoborohydride (8.42 g, 134 mmol). The mixture was cooled to 0° C., followed by addition of 10% AcOH aqueous solution (120 ml). The mixture was warmed to room temperature from 0° C. during 1.5 hour-period. The mixture was concentrated under reduced pressure to a smaller volume and was extracted with EtOAc (2×125 ml). The combined organic layers were washed with saturated NaHCO3 solution (125 ml) and brine (125 ml), dried over Na2SO4. Removal of the solvent produced a crude product. Recrystallization of the crude product from MeOH gave 5-dimethylamino-3H-isobenzofuran-1-one as an off-white solid (3.90 g, 66%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](C#N)=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]#[N:20].ClC(Cl)(Cl)C(O)=O.Cl>CCOCC.C(Cl)Cl>[CH3:12][N:13]1[C:17]([C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]#[N:20]
Reactant: Cc1ccc(C(=O)C#N)cc1
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Reaction time: 72 h
Yield: 30 %

Procedure:
A solution of 0.16 g (1.1 mmole) of 4-methylbenzoylcyanide, 0.13 g (1.1 mmole) of 1-methylpyrrole-2-acetonitrile and 4 mg of trichloroacetic acid in 0.4 ml of ether was allowed to stand in the dark under nitrogen at 25°. After three days, a small amount of hydrogen chloride gas was admitted to the vessel. The mixture was allowed to stand for 14 days. It was diluted with methylene chloride and the solution washed with sodium hydroxide. The solution was dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed on 37 ml of silica gel. The fractions eluted with a mixture of 1,1,1-trichloroethane:hexane, 1:1 were discarded. The fractions eluted with 1,1,1-trichloroethaneihexane 3:1 were collected. The solvent was evaporated to give 0.80 g of dark solid 1-methyl-5-(4-methylbenzoyl)pyrrole-2-acetonitrile (30 percent yield). It was recrystallized from 1,1,1-trichloroethaneihexane to give brown solid, mp 103°-104°, undepressed by admixture with authentic material.
Reaction SMILES: ClS(O)(=O)=O.ClC1C=CC(OC)=CC=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22]([N:29]([CH3:28])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:24])=[O:23])[CH:21]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: CNc1ccccc1
Agent: COc1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Product: COc1ccc(Cl)cc1S(=O)(=O)N(C)c1ccccc1
Temperature: 15 °C
Yield: 73.3 %

Procedure:
Freshly distilled chlorosulfonic acid (b.p. 150° C.) 13.2 g (~0.1 mole) is placed in a 50 mL round-bottomed flask. The liquid is cooled to 15° C. in an ice-water bath, and 27 mL of 4-chloroanisole (95 w/w %) is carefully added to chlorosulfonic acid. The mixture is stirred between additions and the temperature of the mixture is kept below 50° C. When the addition is complete, the mixture is refluxed on a steam bath for 2 hours. A homogeneous, viscous liquid is formed. The reaction mixture is then carefully poured into a 250 mL beaker of ice water. A white, solid mass of 5-chloro-2-methoxybenzenesulfonyl chloride is precipitated, filtered and dried (m.p. 88-89° C.). The 5-chloro-2-methoxybenzenesulfonyl chloride (15.7 g, ~0.07 mole) is added to 7.0 g (~0.07 mole) of N-methyl aniline by the procedure for making sulfonanilides as described previously. A light brown oil, 5-chloro-2-methoxy-N-methylbenzenesulfonanilide, (16 g, 80% yield) is obtained. 1H NMR (deuterioacetone): δ6.3-7.9 (m, 8 ArH), 3.8 (s, 3H, OCH3), 3.2 (s, 3H, N--CH3); ms:m/z 311 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[C@@H:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:19]=1.[Cl:20]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:20][C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][C:6]=3[C:7](=[O:18])[N:8]3[CH2:17][CH2:16][CH2:15][C@H:9]3[C:10]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2cc(Cl)ccc2-n2cncc2[C@@H]2CCCN12
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(Cl)ccc2-n2cnc(Cl)c2[C@@H]2CCCN12

Procedure:
3 g (11 mmol) of (S)-7-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 30 ml of dimethylformamide are stirred at 90° for 30 minutes with 1.60 g of N-chlorosuccinimide. The solution is poured into water and extracted with chloroform. The chloroform extracts are washed several times with water, dried over magnesium sulphate and evaporated. By chromatography on a silica gel column and subsequent recrystallization from ethyl acetate there is obtained (S)-1,7-dichloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 209°-210°.
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([N:25]2[CH:29]([C:30]([O:32]CC)=[O:31])[CH2:28][S:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1.[C:37](=[O:40])([OH:39])[O-].[Na+].[CH3:42]C(C)=O>>[C:37]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]2[CH:29]([C:30]([OH:32])=[O:31])[CH2:28][S:27][CH2:26]2)=[O:24])=[CH:35][CH:36]=1)([O:39][CH3:42])=[O:40]
Reactant: CCOC(=O)C1CSCN1C(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: O=C([O-])O
Reactant: CC(C)=O
Agent: [Na+]
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)N2CSCC2C(=O)O)cc1

Procedure:
One-tenth mole of 4-(15-carbomethoxypentadecylamino)-benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile to yield 3-[4-(16-bromohexadecylamino)benzoyl]-4-carbethoxythiazolidine. By means of the alkaline hydrolysis method of Example 10, the ethyl ester is converted to the subject carboxylic acid. This acid is also prepared using the procedure of this Example except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](O)[N:5]2[CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[N:11]=[C:4]2[CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[N:5]2[CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[N:11]=[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)Cc1cn2c(O)nc(Cl)cc2n1
Product: CN(C)Cc1cn2c(Cl)nc(Cl)cc2n1

Procedure:
In analogy to Example 11A, 30 mg (18% of theory) of the product are obtained from 131 mg (0.58 mmol) of 7-chloro-2-[(dimethylamino)methyl]imidazo[1,2-c]pyrimidin-5-ol (Example 98A) by reaction with phosphoryl chloride.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]C)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:21][NH2:22])=[O:18])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NN
Reactant: CCCCCCOc1ccc(CCC(=O)OC)cc1
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(CCC(=O)NN)cc1

Procedure:
To a solution of methyl 3-(4-n-hexyloxyphenyl)propionate (1.18 g) in ethanol (10 ml) was added hydrazine monohydrate (1.08 ml) and the mixture was refluxed for 24 hours. After cooling, the solvent was removed under reduced pressure. Water was added and the precipitate was collected by filtration, washed with water and dried under reduced pressure to give 3-(4-n-hexyloxyphenyl)propionohydrazide (0.92 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[CH:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=[O:13]>C1COCC1>[OH:13][CH:12]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: Brc1nccs1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2nccs2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
2-Bromothiazole (2.72 ml, 30.5 mmol) was taken up in THF (60 ml) and cooled to −20° C. Isopropylmagnesium chloride (16.00 ml, 32.0 mmol) was added drop wise. After stirring for 1 h (−10° C. to 0° C.), the reaction was cooled to −78° C., and methyl 4-formylbenzoate (5.50 g, 33.5 mmol) in THF (10 ml) was added drop wise. The reaction was stirred for 30 min at −78° C., then warmed to room temperature. After 1 h at room temperature, the reaction was quenched with aqueous saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10-75% EtOAc/hexanes) to provide methyl 4-[hydroxy(1,3-thiazol-2-yl)methyl]benzoate (7.29 g, 29.2 mmol, 96% yield) as an off-white solid. MS ESI: [M+H]+ m/z 250.0.