Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([Cl:12])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[C:4]([CH:13]=O)=[C:3]1Cl.C([O-])([O-])=O.[K+].[K+].[SH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[C:10]2[C:5]=1[C:4]1[CH:13]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[S:22][C:3]=1[N:2]2[CH3:1]
Reactant: Cn1c(Cl)c(C=O)c2c(Cl)cc(Cl)cc21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3c(Cl)cc(Cl)cc3n(C)c2s1
Yield: 32.5 %

Procedure:
Prepared from (48) (6.5 g), K2CO3 (9.59 g) and methyl 2-mercaptoacetate (3.82 ml) yielding (53) 2.5 g (32.5%). M.p. 231°-232° C. The product was purified by chromatography on silicagel using toluene as eluent. The compound was crystallized by trituration with methanol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH3:22])[C:11]([NH:13][C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[NH:13][C:11]1[N:10]([CH3:22])[C:9]2[CH:23]=[CH:24][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[N:12]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(Nc1c(F)cccc1F)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(Nc2c(F)cccc2F)nc2cc(C(=O)O)ccc21

Procedure:
Prepared analogously to example 3b from 2-(2,6-difluoro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid ethyl ester and NaOH in ethanol and water.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[N:7]=[C:6]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])[CH:23]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2cccc(F)n2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a solution of 1,1-dimethylethyl(4RS,5RS)-5-(6-fluoropyridin-2-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (2.40 g, 4.91 mmol) in methanol (12 ml) was added a solution (11.8 ml, 5.90 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 10 min. To the reaction solution was added water (50 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.92 g, 84%).
Reaction SMILES: C([C@@H:4]1[CH2:7][C@H:6]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:5]1)(=O)C.O.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:42].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:42][C@@H:4]1[CH2:5][C@H:6]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:20][CH:21]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](C(C)=O)C2)c2ncnn12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](O)C2)c2ncnn12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a mixture of 4′-{[4-(cis-3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.2 g), 30% hydrogen peroxide water (5.9 g) and chloroform (30 mL) was gradually added trifluoroacetic acid anhydride (13 mL) at room temperature, and the reaction mixture was warmed to 60° C. and stirred for 24 hr. Saturated aqueous sodium hydrogen carbonate and sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 30 min. 1N Aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.58 g, 27%).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH3:32][N:33]([CH3:61])[C:34]([C:36]1[CH:37]=[CH:38][C:39]2[CH:43]=[C:42]([C:44]3[C:49]([CH3:50])=[CH:48][N:47]=[C:46]([NH:51][CH2:52][CH2:53][CH:54]4[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]4)[N:45]=3)[S:41][C:40]=2[CH:60]=1)=[O:35]>>[ClH:3].[ClH:1].[CH3:61][N:33]([CH3:32])[C:34]([C:36]1[CH:37]=[CH:38][C:39]2[CH:43]=[C:42]([C:44]3[C:49]([CH3:50])=[CH:48][N:47]=[C:46]([NH:51][CH2:52][CH2:53][CH:54]4[CH2:55][CH2:56][N:57]([CH3:4])[CH2:58][CH2:59]4)[N:45]=3)[S:41][C:40]=2[CH:60]=1)=[O:35]
Reactant: Cc1cnc(NCCC2CCNCC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: Cc1cnc(NCCC2CCN(C)CC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from crude product 2-[5-methyl-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-6-carboxylic acid dimethylamide and isolated as yellow foam (307 mg, 42% yield). ES+(m/z) 438 [M(free base)+H].
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:19][N+](C)(C)C)=[CH:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C-:24]#[N:25].[Na+]>CCO>[CH2:2]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:19][C:24]#[N:25])=[CH:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[N+](C)(C)Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: N#CCc1c[nH]c2cc(OCc3ccccc3)ccc12
Yield: 95.3 %

Procedure:
A mixture of (6-benzyloxy-1H-indol-3-ylmethyl)-trimethylammonium iodide (2.2 g, 5 mmol), sodium cyanide (500 mg, 10.2 mmol), and 95% EtOH (50 mL) was refluxed under nitrogen for 5 hours. The solvent was removed in vacuo, and the residue was taken in DCM, and washed with water, then dried with sodium sulfate, and evaporated in vacuo to afford a white solid, which was recrystallized from EtOH to give (6-benzyloxy-1H-indol-3-yl)-acetonitrile (1.25 g, 86%). MS (ES): 263 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:26]=[C:27]([F:29])[CH:28]=3)[C:21]([O:23]CC)=O)[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:38][NH2:39]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[N:9]2[CH2:10][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([CH:26]=[C:27]([F:29])[CH:28]=3)[C:21]([NH:38][NH2:39])=[O:23])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1
Solvent: CCO
Product: CC(C)(F)[C@H](c1cc(F)cc(C(=O)NN)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reaction time: 8 h

Procedure:
A mixture of 523 mg (0.41 mmol) of ethyl 3-(1-{l-[(4-chlorophenyl)(3-cyanophenyl)methyl] azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzoate (Preparation 17), 0.6 mL(1 6.36 mmol) of hydrazine, and 4 mL of EtOH was heated to reflux. After 8 h, the mixture was concentrated to remove solvents to afford the of title compound as an white solid. 1H-NMR(CDCl3) δ 1.20(d, 3H, J=21 Hz), 1.29(d, 3H, J=21 Hz), 2.32 (t, 3H, J=7.1 Hz), 2.85 (t, 1H, J=8 Hz), 2.94 (m, 1H), 3.06 (m, 1H), 3.20 (m, 1H), 3.51 (s, 2H), 3.63 (t, 1H, J=5 Hz), 4.26 (s, 1H), 7.06-7.71 (m, 11H); Mass Spectrum: m/e=509 (M+1, 35Cl), 511 (M+1, 37Cl).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[C:14]([C:31]([F:34])([F:33])[F:32])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[F:35].[CH2:36]([O:38][C:39]1[C:40]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)=[N:41][CH:42]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:44]=1)[CH3:37].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:22]([O:21][CH2:20][C:19]([CH3:30])([CH3:29])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:43]3[CH:42]=[N:41][C:40]([O:54][CH2:55][C:56]4[CH:57]=[CH:58][C:59]([O:62][CH3:63])=[CH:60][CH:61]=4)=[C:39]([O:38][CH2:36][CH3:37])[CH:44]=3)=[C:3]([F:35])[CH:4]=2)=[CH:13][C:14]=1[C:31]([F:34])([F:33])[F:32])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(NC(=O)Cc2ccc(Br)c(F)c2)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(C(F)(F)F)c3)cc2F)cnc1OCc1ccc(OC)cc1
Yield: 79.9 %

Procedure:
A solution of 2-(4-bromo-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (80 mg, 0.139 mmol), 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (53.5 mg, 0.139 mmol), Cs2CO3 (90 mg, 0.278 mmol), PdCl2(dppf) (10.15 mg, 0.014 mmol) in 1,4-dioxane (9 mL) and H2O (3 mL) was stirred at 110° C. for 15 min. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (60 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=2/1) to yield N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-fluorophenyl)acetamide (100 mg, 0.111 mmol, 80.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.84 (d, J=2.0 Hz, 1H), 7.77 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.34-7.30 (m, 5H), 7.17-7.15 (m, 2H), 6.83 (d, J=8.8 Hz, 2H), 5.27 (s, 2H), 4.04-3.99 (m, 4H), 3.70 (s, 3H), 3.66 (s, 2H), 3.24 (s, 2H), 2.69 (s, 2H), 1.31 (t, J=7.0 Hz, 3H), 0.86 (s, 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 755.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]CC)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:13]([C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17](Cl)[N:16]=1)[CH3:14]>C(O)C.CCN(CC)CC>[CH2:13]([C:15]1[N:20]=[C:19]([N:5]2[CH2:4][CH2:3][C:2]([CH3:1])([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]2)[CH:18]=[CH:17][N:16]=1)[CH3:14]
Reactant: CCc1nc(Cl)cc(Cl)n1
Reactant: CCOC(=O)C1(C)CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1nccc(N2CCC(C)(C(=O)O)CC2)n1
Reaction time: 20 h

Procedure:
1-(2-Ethylpyrimidin-4yl)-4-methyl-piperidine-4-carboxylic acid was prepared on a 3 mmol 4-methyl-4-ethoxycarbonyl-piperidine (as TFA salt) in 7 ml ethanol and 1 ml Et3N treated with a solution of 0.531 g 2-ethyl-4,6-dichloropyrimidine in 4 ml ethanol. After 20 hours at ambient temp. The ethanol was removed and the residue partitioned between water and ethanol, washed with sodium hydrogen carbonate solution and brine. Evaporated to give gum (88.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[OH:13][C:14]1[CH:19]=[C:18]([CH3:20])[O:17][C:16](=O)[CH:15]=1>>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[N:1]1[C:18]([CH3:20])=[CH:19][C:14]([OH:13])=[CH:15][C:16]1=[O:17]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Product: COC(=O)c1ccc(Cl)c(-n2c(C)cc(O)cc2=O)c1

Procedure:
A condensation reaction with methyl 3-amino-4-chlorobenzoate (14.5 g, 78.2 mmol) and 4-hydroxy-6-methyl pyranone under reaction condition similar to the one described in Example 465—step 3 gave 12.32 (53.8%) of desired product. Step 3—Preparation of methyl-4-chloro-3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([CH2:20][C:21]4[NH:22][CH:23]=[CH:24][N:25]=4)[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]3)=[CH:9][CH:8]=2)=[C:4]([CH3:28])[CH:3]=1.[H-].[Na+].[CH3:31]I>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([CH2:20][C:21]4[NH:25][CH:24]=[CH:23][N:22]=4)[O:17][CH:16]([CH2:18][O:19][CH3:31])[CH2:15][O:14]3)=[CH:9][CH:8]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Oc1ccc(C2(Cc3ncc[nH]3)OCC(CO)O2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COCC1COC(Cc2ncc[nH]2)(c2ccc(Oc3ccc(Cl)cc3C)cc2)O1
Temperature: 25 °C

Procedure:
16 parts of 2-[p-(4-chloro-2-methylphenoxy)phenyl]-2-(1-imidazolylmethyl)-4-hydroxymethyl-1,3-dioxolane are dissolved in 150 ml of N,,N-dimethyl formamide and then 1.9 parts of 55% sodium hydride dispersion are stirred in while introducing nitrogen. The mixture is heated for 2 hours to 80° C., then cooled to room temperature, treated dropwise, with stirring, with 6.3 parts of methyl iodide over 1 hour, then heated for 2 hours to 60° C., diluted with 800 ml of ice-water and extracted with three 300 ml portions of ethyl acetate. The combined extracts are washed with two 50 ml portions of water, dried over sodium sulfate, filtered, and the solvent is removed by evaporation. The residue is purified by column chromatography over silica gel with acetone/ethyl acetate (1:1). The eluant is then removed by evaporation and the mixture of diastereoisomers is crystallised by treatment with tiexane, giving beige-coloured crystals with a melting point of 92°-106° C.
Reaction SMILES: CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:10][C:11]1[S:12][C:13]([Cl:17])=[CH:14][C:15]=1[NH-:16].C1(=O)N([O:23][C:24]([C:26]2[C:30]([C:31](O)=[O:32])=[CH:29][S:28][CH:27]=2)=O)C(=O)CC1.Cl>>[Cl:17][C:13]1[S:12][C:11]([Cl:10])=[C:15]2[C:14]=1[C:24](=[O:23])[C:26]1=[CH:27][S:28][CH:29]=[C:30]1[C:31](=[O:32])[NH:16]2
Reactant: [NH-]c1cc(Cl)sc1Cl
Reactant: O=C(O)c1cscc1C(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(Cl)sc(Cl)c2c(=O)c2cscc12
Temperature: 0 °C
Yield: 94.2 %

Procedure:
109.5 g (116 ml; 1.50 moles) of dimethylformamide were added to 798 g (5.98 moles) of anhydrous aluminum chloride in the course of 15 minutes, while stirring, a highly exothermic reaction taking place. Thereafter, 250 g (0.596 mole) of thiophene-3,4-dicarboxylic acid succinimido ester [N-(2,5-dichlorothien-3-yl)]-amide were added to the stirred mixture at 80° C. in the course of 30 minutes. The reaction mixture was stirred for a further 3 hours at this temperature and then poured, in the warm state and while stirring, onto 4.5 kg of ice and 470 ml (561.2 g; 5.85 moles) of concentrated hydrochloric acid. The crystals precipitated during this procedure were filtered off under suction, washed in succession with 6 l of water, with twice 0.5 l of acetone and with twice 0.5 l of petroleum ether (boiling range 40°-60° C.) and dried at 50° C. in a drying oven under reduced pressure. 170.8 g (94%) of 1,3dichloro-4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione were isolated in the form of beige crystals of melting point 236.5°-239° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([C:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>O.O1CCOCC1>[CH2:12]([O:19][C:20]([C:22]1([NH:27][S:48]([C:45]2[CH:44]=[CH:43][C:42]([C:39]3[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=3)=[CH:47][CH:46]=2)(=[O:49])=[O:50])[CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-aminocyclopentanecarboxylic acid benzyl ester p-toluenesulfonic acid salt (12.1 grams, 30.9 mmol) and triethylamine (10.0 mL, 72 mmol) in water (150 mL) and 1,4-dioxane (150 mL) was added 4'-fluorobiphenyl-4-sulfonyl chloride (8.8 grams, 32.5 mmol). The mixture was stirred at room temperature for 16 hours and then most of the solvent was removed by evaporation under vacuum. The mixture was diluted with ethyl acetate and was washed successively with dilute hydrochloric acid solution, water, and brine. The solution was dried over magnesium sulfate and concentrated to leave 1-(4'-fluorobiphenyl-4-sulfonylamino)cyclopentanecarboxylic acid benzyl ester as a solid, 12.33 grams (76%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:38]/[O:39][CH2:40][S:41]([C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[C:46]([OH:51])[CH:45]=2)(=[O:43])=[O:42])/[C:8]([NH:10][C@@H:11]2[CH2:18][N:17]3[C@@H:12]2[S:13][C:14](=O)[C:15]([CH2:22][S:23][C:24]2[N:29]4[N:30]=[C:31]([C:33](=[O:35])[NH2:34])[N:32]=[C:28]4[N:27]=[C:26]([CH3:36])[CH:25]=2)=[C:16]3[C:19]([OH:21])=[O:20])=[O:9])[N:6]=1.[CH3:52][NH:53][CH2:54][C@@H:55]([C@H:57]([C@@H:59]([C@@H:61]([CH2:63][OH:64])[OH:62])[OH:60])[OH:58])[OH:56]>O>[CH3:52][NH:53][CH2:54][C@@H:55]([C@H:57]([C@@H:59]([C@@H:61]([CH2:63][OH:64])[OH:62])[OH:60])[OH:58])[OH:56].[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:38]/[O:39][CH2:40][S:41]([C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[C:46]([OH:51])[CH:45]=2)(=[O:42])=[O:43])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:56])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:22][S:23][C:24]2[N:29]4[N:30]=[C:31]([C:33](=[O:35])[NH2:34])[N:32]=[C:28]4[N:27]=[C:26]([CH3:36])[CH:25]=2)=[C:16]3[C:19]([OH:21])=[O:20])=[O:9])[N:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2=O)n2nc(C(N)=O)nc2n1
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1

Procedure:
A suspension of 373 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)-thio]methyl]-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 7 ml of water was treated portionwise while stirring with 91 mg of N-methyl-D-glucamine. The resulting clear solution was lyophilized. There was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-methyl-D-glucamine salt as a white powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C@H:5]1[CH2:20][C:9]2=[CH:10][NH:11][C:12]3=[CH:13][CH:14]=[C:15]([C:16]([NH:18][NH2:19])=[O:17])[C:7](=[C:8]23)[CH2:6]1)[CH2:2][CH3:3]>COC(OC)(OC)C1C=CC=CC=1.C(Cl)Cl>[C:7]1([C:15]2[O:17][C:16]([C:15]3[CH:14]=[CH:13][C:12]4[NH:11][CH:10]=[C:9]5[CH2:20][C@H:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:21][CH2:22][CH3:23])[CH2:6][C:7]=3[C:8]=45)=[N:18][N:19]=2)[CH:8]=[CH:9][CH:20]=[CH:5][CH:6]=1
Reactant: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(C(=O)NN)c(c23)C1
Agent: COC(OC)(OC)c1ccccc1
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4nnc(-c5ccccc5)o4)c(c23)C1
Yield: 163.9 %

Procedure:
A solution of 0.20 g (0.64 mmol) of (4R)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxylic hydrazide in 2.0 ml of trimethylorthobenzoate was heated at 135° C. under nitrogen for 5 hours. After cooling, the semisolid mixture was dissolved in methylene chloride and the product was extracted into aqueous tartaric acid. The aqueous solution was basified with sodium carbonate and the product was extracted into methylene chloride. Evaporation of the methylene chloride left crystalline product which was then chromatographed over 3 g of silica gel using ethyl acetate as eluent. The product from the column was recrystallized from toluene to give 0.21 g of title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH3:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20](B(O)O)[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH3:10])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[C:19]([OH:25])=[CH:20][CH:21]=1
Reactant: CCSc1ccc(Br)c(C(F)(F)F)c1
Reactant: OB(O)c1cc(Cl)ccc1O
Product: CCSc1ccc(-c2cc(Cl)ccc2O)c(C(F)(F)F)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.26 g
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=O.[CH3:18][S:19]([CH2:22][C:23](=O)[CH3:24])(=[O:21])=[O:20].[Na]>CC(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:23]([CH3:24])[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1
Reactant: CC(=O)CS(C)(=O)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Yield: 18.9 %

Procedure:
(2-Amino-5-bromo-phenyl)-(4-chloro-phenyl)-methanone (compound of example A.2) (4 g, 12.9 mmol), methanesulfonylacetone (2.63 g, 19.3 mmol) and sodium tetrachloroaureate(III) dihydrate (0.26 g, 0.64 mmol) were heated at reflux in 2-propanol (50 ml) for 4 days. The resulting mixture was evaporated to dryness and the residue extracted with dichloromethane (2×), 1 N NaOH (2×) and sat. NaCl (1×). The crude product was purified by chromatography on silica gel in dichloromethane. The product was crystallized from dichloromethane/heptane by evaporation of dichloromethane. One obtained a light yellow solid (1 g, 19%). MS: m/z=410 (M).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[C:11]([O:14][CH3:15])=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=2[O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]1[O:13][C:12]2[C:11]([O:14][CH3:15])=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1cc(OC)c2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)cc2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
Methyl ester 5 (11.9 g, 57 mmol) in THF (50 ml) was added (slowly) dropwise to a stirred grey suspension of lithium aluminum hydride (3.4 g, 90 mmol) in THF (50 ml) at 0° C. under Ar. After stirring for 3 h at rt, the suspension was cooled to 0° C. and the reduction terminated by careful addition of Na2SO4 (sat., aq) until effervescence ceased. The precipitate was collected and the filtrant dried and concentrated in vacuo to afford benzyl alcohol 6 (9.3 g, 91%) as a colorless powder, m.p. 66–67° C. (lit. mp 66–67° C., Pettit and Singh, 1987); 1H-NMR (300 MHz):1.59 (1H, bs, —OH), 3.91 (3H, s, —OCH3) 4.59 (2H, bs, —ArCH2O—), 5.97 (2H, s, —OCH2O—), 6.56 (2H, d, J=2.1 Hz, ArH).