Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[NH:16][CH:15]=[C:14]([I:17])[C:6]=2[N:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:9]=1.Cl[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:20][CH2:19][N:16]1[C:5]2[C:4]([Cl:3])=[N:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[N:7][C:6]=2[C:14]([I:17])=[CH:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCc1nc(Cl)c2[nH]cc(I)c2n1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c2c(n1)c(I)cn2COCc1ccccc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Sodium hydride (0.338 g, 60% in oil, 14.08 mmol) was added portionwise to a stirred solution of 4-chloro-7-iodo-2-butyl-5H-pyrrolo[3,2-d]pyrimidine (2.19 g, 6.53 mmol) in DMF (30 mL) cooled in an ice-bath. After 30 minutes benzyl chloromethyl ether (1.13 mL, 1.278 g, 8.16 mmol) was added and the reaction stirred at room temperature. The reaction mixture was quenched with water and the resultant mixture partitioned between ethyl acetate (150 mL) and water (150 mL). The organic phase was washed with water then saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and evaporated. The sample was dissolved in dichloromethane and purified by chromatography on silica (100 g) using a gradient of 0-100% ethyl acetate-cyclohexane over 30 minutes. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (2.82 g).
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[CH:44]=2)[C:37]1=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.B>>[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[CH:44]=2)[CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccc(CC2OCCN(Cc3ccccc3)C2=O)c1
Agent: B
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Product: Cc1cccc(CC2CN(Cc3ccccc3)CCO2)c1

Procedure:
N-Benzyl-2-(3-methylbenzyl)-morpholine was prepared as described for example 70, intermediate (a), but using N-benzyl-2-(3-methylbenzyl)-morpholin-3-one and borane and was isolated as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH:7](O)[C:6]=2[CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:11]=1
Reactant: OC1CSc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: Brc1ccc2sccc2c1
Yield: 96.9 %

Procedure:
To acetone (600 mL) solution of 300 g of 5-bromo-2,3-dihydro-1-benzothiophen-3-ol was added 12.4 g of p-toluenesulfonic acid monohydrate, which was then refluxed for 2 hours. To the reaction solution was added 15.0 g of activated carbon, which was then stirred. Insoluble matter was filtered off and washed with 300 mL of acetone. The filtrate and washings were combined, to which was dropwise added 2700 mL of water at 5 to 15° C. The precipitate was collected by filtration to provide 268 g of 5-bromo-1-benzothiophene as pale purple solid form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10](=[CH2:12])[CH3:11].C(Cl)Cl.FC(F)(F)S(O)(=O)=O>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]([CH3:12])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(C)C
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
4-Bromophenol(57.8 mmoles, 10.0 g) was added to a -30° C. solution of isobutylene (40 ml) and methylene chloride (50 ml) and then cooled to -78° C. Trifluoromethanesulfonic acid (4 mmoles, 0.35 ml) was added. The mixture was held at -78° C. for 4 hours and then allowed to warm to room temperature. Triethylamine (0.5 ml) was added; the solvent was removed. The residue was chromatographed over silica gel eluted with 1% ethyl acetate in hexane to yield 12.4 g. (MS)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1.C1(C)C=CC(S(O[CH2:27][C@@H:28]2[O:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][CH2:29]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:33]1[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[O:30][CH2:29][C@@H:28]1[CH2:27][NH:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1N1CCC(CN)CC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCC(CNC[C@H]2COc3ccccc3O2)CC1

Procedure:
A stirred mixture of 1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine (0.84 g, prepared in a similar manner to that described in Example 2), (R)-1,4-benzodioxan-2-ylmethyl toluene-4-sulphonate (1.2 g), potassium carbonate (1 g), and potassium iodide (catalytic amount) in acetonitrile (50 ml) was heated under reflux for 90 hours. The solvent was removed in vacuo and the residue diluted with ethyl acetate (100 ml). The product was extracted into hydrochloric acid (5M, 3×70 ml) and the extracts combined and basified by the addition of aqueous sodium hydroxide solution (5M). The product was extracted into ethyl acetate (3×150 ml), and the combined extracts were washed with water (2×100 ml), dried over magnesium sulphate and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using ethyl acetate as the eluant. Appropriate fractions were combined and the solvent removed in vacuo to leave a yellow oil which crystallised on standing. The product was then recrystallised from ethyl acetate to yield (S)-(-)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)-piperid-4-yl]methylamine as light brown crystals (0.41 g), m.p. 78°-79° C., [μ]D25 -27.0° (c=1.0, CH2Cl2)
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][C:5]([C:13]#[N:14])=[C:4]([C:15]#[N:16])[N:3]=1.[NH3:17].O.Cl>CN(C)C=O>[NH2:17][C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][C:5]([C:13]#[N:14])=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: CC(C)(C)Nc1nc(C#N)c(C#N)nc1Cl
Reactant: N
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Nc1nc(C#N)c(C#N)nc1N
Temperature: 25 °C
Yield: 69.4 %

Procedure:
2.0 g (0.008 mol) of 2-chloro-3-tert-butylamino-5,6-dicyanopyrazine was dissolved in 100 ml of dry N,N-dimethylformamide, and ammonia gas was blown into it under stirring at room temperature. Two hours later, the reaction solution was poured into 1 liter of water and neutralized with hydrochloric acid. The precipitated solid was collected by filtration and recrystallized from isobutyl alcohol to obtain 1.2 g of slightly yellow crystals (yield: 69.4%, melting point: at least 250° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1N)([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[C:5]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Clc1ccc(Cl)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccc(Cl)cc1-c1cc(Cl)ccc1Cl

Procedure:
2,5,5'-Trichloro-2'-nitrobiphenyl was prepared according to the procedure in Example 2A from 2-nitro-5-chloroaniline (2.6 g, 15 mmol) and 1,4-dichlorobenzene (29.5 g, 200 mmol). Purification was by filtration through silica gel (see Example 1A) eluting with hexanes/methylene chloride 80:20 yielding the title compound (830 mg). Mass spectrum: m/z at 301 for C12H6Cl3NO2.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30](=[O:32])[NH2:31])[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:31])=[O:32])[CH:28]=4)[NH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(C(N)=O)cc34)n2)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc2[nH]cc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Temperature: 50 °C
Yield: 20.1 %

Procedure:
To a mixture of tert-butyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-carbamoyl-1H-indole-1-carboxylate (200 mg, 0.37 mmol) in chloroform was added TFA at 0° C. The reaction mixture was heated at 50° C. for 12 h. After removal of TFA the crude product was purified by preparative HPLC to obtain title compound (25 mg, 20%) as a brown solid. MS (ESI, pos. ion) m/z: 337.1 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:7]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH:2]=[CH2:3].C>C(O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH2:19][CH3:20])[C:7]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH2:2][CH3:3]
Reactant: C=CCc1cc(CC=C)c2oc(C(=O)O)cc(=O)c2c1
Solvent: CCO
Product: CCCc1cc(CCC)c2oc(C(=O)O)cc(=O)c2c1

Procedure:
A solution of 6.2 parts of 6,8-diallyl-4-oxo-4H-1-benzopyran-2-carboxylic acid in 100 parts of ethanol was hydrogenated at room temperature for 45 minutes at a pressure of 45 p.s.i. at the presence of 5% palladised charcoal. The solution was filtered and evaporated to afford 6.1 parts of 6,8-di-n-propyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, melting point 183°-184° C after recrystallisation from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: O=C(CO)NC1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][N:12]([CH3:47])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]3[C:25](=O)[C:26]([CH3:29])([CH3:28])[O:27][C:23]=3[C:22]([CH3:31])=[C:21]([CH3:32])[C:20]=2[N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:35][CH2:34]2)=[CH:15][CH:14]=1.[OH-].[Na+]>O.C1COCC1>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([N:36]2[CH2:35][CH2:34][N:33]([C:20]3[C:21]([CH3:32])=[C:22]([CH3:31])[C:23]4[O:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]=4[C:19]=3[C:16]3[CH:15]=[CH:14][C:13]([N:12]([CH3:11])[CH3:47])=[CH:18][CH:17]=3)[CH2:38][CH2:37]2)=[CH:44][CH:43]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3-c3ccc(N(C)C)cc3)C(=O)C(C)(C)O4)CC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3-c3ccc(N(C)C)cc3)CC(C)(C)O4)CC2)cc1
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To the THF (15 mL) suspension of lithium aluminum hydride (342 mg, 9.00 mmol), aluminum chloride (1.20 g, 9.00 mmol) was added under ice cooling, and then the mixture was stirred for 10 minutes and added with the THF (25 mL) solution of 4-[4-(dimethylamino)phenyl]-5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (1.50 g, 3.00 mmol) synthesized in Reference example 31, followed by further stirring for 2.5 hours under reflux. After cooling the mixture solution on ice, water was added dropwise thereto and 0.5 N aqueous solution of sodium hydroxide was further added. The mixture was stirred for 10 minutes at room temperature. Undissolved residues were removed by filtration. The filtrate was extracted with the mixture solvent of ethyl acetate-ether (1:1). After washing with the saturated brine, the extract solution was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate 96:4-85:15) and crystallized from ethyl acetate and hexane to obtain the title compound 1.01 g (yield 69%). Melting point was 177 to 179° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](N2CCCC2)=[O:9])=[N:6][C:5]([Cl:15])=[CH:4][N:3]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O1CCCC1>O>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)nc1C(=O)N1CCCC1
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(Cl)nc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-5-chloropyrazine-3-carboxylic acid pyrrolidide (9 g. or 0.04 mol) was added to a freshly prepared solution of 36.2 g. (0.2 mol) of phenylmagnesium bromide in 300 ml. of tetrahydrofuran cooled to 20°. After addition, the reaction mixture was stirred for 3 hours at room temperature and was then hydrolyzed by addition of 150 ml. of water. The organic layer was separated, dried over alumina, filtered and evaporated. Crystallization of the oil obtained from ether yielded 2 g. (50%) of the above-named product as yellow crystals, m.p. 158°-161°. The analytical sample was recrystallized from ethyl acetate, m.p. 160°-161°.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of 4-nitroaniline (10.0 g, 72.4 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (14.60 g, 6.35 mL, 72.4 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 16.92 g (90%) of the title compound as a greenish yellow solid, mp 175°-178° C.: 1H NMR (DMSO-d6) δ10.98 (s, 1H), 8.24 (d, J=9.2, 2H), 7.83 (d, J=9.2, 2H), 4.10 (s, 2H); 13C NMR (DMSO-d6) δ165.77, 144.67, 142.62, 125.05, 119.01, 30.15; MS (EI, m/z) 285 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:7])=[CH:4][CH:3]=1
Reactant: NCCCCCC(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
4-Methylbenzoyl chloride (1.46 g, 9.5 mmol) was added dropwise to a mixture of 6-aminohexanoic acid (1.31 g, 10 mmol) and DMAP (1.22 g, 10 mmol) in THF (100 mL) at 0° C. The mixture was warmed to room temperature and stirred overnight. THF was evaporated, and dichloromethane (100 mL) was added. The mixture was washed with water and brine, dried over Na2SO4, and evaporated. The residue was purified by chromatography on silica gel to give the title compound (1.03 g, 41.5%).
Reaction SMILES: CC1(C)[O:7][C@@H:6]2[C@H:8]3[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:9]3[O:10][C@@H:5]2[CH2:4][O:3]1.O=C[C@@H]([C@H]([C@@H](CO)O)O)O>OS(O)(=O)=O>[CH3:14][C:12]1([CH3:15])[O:11][C@@H:9]2[C@@H:8]([C@@H:6]([OH:7])[C@@H:5]([CH2:4][OH:3])[O:10]2)[O:13]1
Reactant: CC1(C)OC[C@H]2O[C@@H]3OC(C)(C)O[C@@H]3[C@H]2O1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Product: CC1(C)O[C@H]2O[C@H](CO)[C@H](O)[C@H]2O1
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
1,2:3,5-Di-O-isopropylidene-D-xylofuranose (70.66 g, 0.30 mol) is treated with H2SO4 (0.1 M, 300 mL). Upon stirring, the xylose slowly dissolves. After 30 minutes, the reaction is quenched with NH4OH (pH 9.0) and half of the water removed at reduced pressure. The aqueous layer is diluted with brine (100 mL) and extracted with ethyl acetate (3×200 mL). A normal work-up provides an oil. Kugelrohr distillation provides 1,2-O-isopropylidene-D-xylofuranose (40 g, 68.5%); b.p. 120-135° C./0.4 mm Hg.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH2:22][C:23]([OH:25])=O)[CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:9].C(N(CC)CC)C.[CH3:33][CH:34]([CH3:50])[CH2:35][C@H:36]([NH2:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>C1(C)C=CC=CC=1.CCCCCC>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH2:22][C:23]([NH:49][C@H:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N:43]2[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]2)[CH2:35][CH:34]([CH3:50])[CH3:33])=[O:25])[CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:9]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 30 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Pivaloyl chloride (5.4 g, 45 mmol) was added to a mixture of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid (10.0 g, 40 mmol), toluene (50 ml) and triethylamine (5.0 g, 49 mmol) at −5° C. and stirred for 1 hour. A solution of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (9.8 g, 40 mmol) in toluene (20 ml) was then added at below 10° C. The temperature of the reaction mixture was raised to 30° C. and the mixture stirred overnight. It was then washed with water and saturated sodium bicarbonate solution. Toluene was distilled off under reduced pressure to get the crude product. The crude product was dissolved in toluene (35 ml), hexane (200 ml) was added and the mixture cooled at 0° C. The solid product so obtained was filtered and dried to give 14.0 g of the title compound (Yield: 73%, HPLC Purity 99%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:35][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)=[O:24])[C:20](=[O:21])[N:13]3[CH:12]([C:36](O)=[O:37])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:61][CH:62]([CH2:77][C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C:63](=[O:76])[CH2:64][O:65][C:66](=[O:75])[C:67]1[C:72]([CH3:73])=[CH:71][CH:70]=[CH:69][C:68]=1[CH3:74].C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([N:10]2[CH2:35][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)=[O:24])[C:20](=[O:21])[N:13]3[CH:12]([C:36]([NH:61][CH:62]([CH2:77][C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C:63](=[O:76])[CH2:64][O:65][C:66](=[O:75])[C:67]3[C:72]([CH3:73])=[CH:71][CH:70]=[CH:69][C:68]=3[CH3:74])=[O:37])[CH2:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(C)c1C(=O)OCC(=O)C(N)CC(=O)OC(C)(C)C
Reactant: O=C(NC1CCCCC2CN(S(=O)(=O)c3ccccc3)CC(C(=O)O)N2C1=O)c1nccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)C1CN(S(=O)(=O)c2ccccc2)CC2CCCCC(NC(=O)c3nccc4ccccc34)C(=O)N21

Procedure:
To a solution of 2-benzenesulfonyl-6-[(isoquinoline-1-carbonyl)-amino]-5-oxo-decahydro-2,4a-diaza-benzocyclooctene-4-carboxylic acid, 111, (124 mg, 0.23 mmol) in dichloromethane is added EDCl (191 mg, 1 mmol), HOBt (135 mg, 1 mmol), 2,6-dimethyl-benzoic acid 3-amino-4-tert-butoxycarbonyl-2-oxo-butyl ester (200 mg, 0.62 mmol), and triethylamine (0.15 mL, 1 mmol). After consumption of the starting material, the reaction is diluted with EtOAc and washed with water, 1N HCl, saturated NaHCO3, and brine. The organic layer is concentrated in vacuo and the crude residue obtained is used directly in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:19]2[CH:20]=[CH:21][C:22]([C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][C:5]3[N:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=3)=[CH:23][C:18]=2[F:17])=[CH:34][N:35]=1
Reactant: N#Cc1ccc(Oc2ccccc2Br)nc1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: N#Cc1ccc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 6-(2-bromophenoxy)nicotinonitrile and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H14FN5O, 383.12; m/z found, 384.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J=2.3, 0.8, 1H), 8.44 (d, J=1.6, 2H), 8.26 (dd, J=8.6, 2.3, 1H), 7.59 (dd, J=7.6, 1.8, 1H), 7.56-7.48 (m, 2H), 7.45-7.39 (m, 1H), 7.36-7.27 (m, 3H), 7.21 (dd, J=8.7, 0.7, 1H), 6.89 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH:40][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=5)=[N:9][C:10]=34)=[O:23])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 580.2 [(M+H)+]; mp 251° C.
Reaction SMILES: [CH3:1][CH:2]([NH:4][S:5](Cl)(=[O:7])=[O:6])[CH3:3].[CH2:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10].C(N(CC)CC)C>ClCCl>[CH2:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:5]([NH:4][CH:2]([CH3:3])[CH3:1])(=[O:7])=[O:6])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10]
Reactant: CC(C)NS(=O)(=O)Cl
Reactant: CCS(=O)(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(NS(=O)(=O)NC(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(1-Methylethyl)sulfamoyl chloride (6.63 g, 0.034 mol) was added dropwise to a solution of 4-(ethylsulfonyl)benzene amine (6 g, 0.032 mol) and triethylamine (4.87 ml, 0.035 mol) in dry dichloromethane (100 ml) at 0° C. under a nitrogen atmosphere. After addition, the resultant mixture was allowed to warm to room temperature and was stirred for 6 hr. The reaction mixture was then washed with water (2×50 ml). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to yield N-(4-ethylsulfonylphenyl)-N′-(1-methylethyl)sulfamide as a white solid. δ(1H NMR, DMSO, ppm): 1.05 (6H, d), 1.10 (3H, t), 3.25 (2H, q), 3.40 (1H, m), 7.40 (2H, d), 7.80 (3H, m).