Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CS(C)=O.Cl.[NH+]1C=CC=CC=1>O>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4]1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
4-(6-Methoxypyridin-3-yl)benzoic acid (3.34 g, 14.6 mmol), dimethylsulfoxide (6 mL), and pyridinium hydrochloride (8.43 g, 72.9 mmol) were heated together, with stirring, at 160° C. for 15 minutes. The reaction mixture was cooled to ˜90° C., and water added slowly (100 mL). The solution/suspension was cooled to 0° C., the precipitate filtered off and washed with water. The wet product was dried by azeotroping off the residual water with methanol to give the product as a white solid (2.38 g, 11.1 mmol). 1H NMR (DMSO) δ 7.93 (d, 2H), 7.91-7.78 (m, 2H), 7.68 (d, 2H), 6.43 (d, 1H). ESI MS (M+1)+: 216.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[CH:17]=[C:16]1B(O)O)(OC(C)(C)C)=O>>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[C:16]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[NH:15]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Reactant: Brc1cccnc1
Product: Clc1ccc2cc(-c3cccnc3)[nH]c2c1

Procedure:
3-Bromopyridine and N-Boc-6-chloro-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 6-chloro-2-pyridin-3-yl-1H-indole. (ESI) m/z 229.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:35][NH:36][S:37](CC(C)C)(=[O:39])=[O:38])=[N:15][C:16]=2[NH:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-:44].[K+:45]>C(O)(C)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:35][N:36]([CH2:21][CH:22]([CH3:29])[CH3:23])[S:37]([O-:38])(=[O:44])=[O:39])=[N:15][C:16]=2[NH:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+:45]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](O)[C@@H]1O
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN(CC(C)C)S(=O)(=O)[O-])nc32)[C@H](O)[C@@H]1O
Yield: 145.1 %

Procedure:
N-({9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulfonamide (example 15) (1.9 g, 3.11 mmol) was dissolved into isopropyl alcohol (20 ml) and a 4 molar solution of potassium hydroxide (0.9 ml, 3.11 mmol) added. The isopropyl alcohol was removed by evaporation under reduced pressure and more isopropyl alcohol (20 ml) added to the residue, then the solvent removed under reduced pressure again. The residue was suspended in isopropyl alcohol (160 ml) and then the suspension heated under reflux for 1 hr. The resulting suspension was allowed to cool and then filtered. The white solid was washed with a little isopropyl alcohol and then dried. This gave the title compound (1.5 g) as a white crystalline solid m.p. 231° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[BrH:11]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:11])=[CH:4][CH:3]=1
Reactant: Br
Reactant: OCCc1ccc(O)cc1
Product: Oc1ccc(CCBr)cc1
Temperature: 20 °C
Yield: 96.2 %

Procedure:
500 g 2-(4-hydroxyphenyl) ethanol was placed in a 5 L round bottom flask, to which 2960 g of 48% aq. HBr was added with stirring. The reaction mixture was placed in a bath at 75° C. After 2.5 h agitation 5 g of A11 seed crystals was added. The reaction mixture was stirred at this temperature for another 24 h. The reaction mixture was slowly cooled to 20° C. The precipitate was isolated by filtration and washed with 10% aq. sodium bicarbonate solution to give 700 g (96% yield) of the title product. 1H NMR (CDCl3); δ 3.10 (2H, t, J=7.8 Hz), 3.53 (2H, t, J=7.5 Hz), 6.80 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([OH:17])[CH2:12]1>>[CH3:7][N:6]1[C:2]([N:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([OH:17])[CH2:12]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1C[C@H](O)[C@@H](O)C1
Yield: 91 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (3S,4S)-pyrrolidine-3,4-diol gave (3S,4S)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidine-3,4-diol as a bright yellow solid (258 mg, 91%). 1H NMR (400 MHz, d4-MeOD) δ 8.04 (s, 1H), 4.27-4.22 (m, 2H), 3.98 (dd, J=10.0, 4.4 Hz, 2H), 3.84 (s, 3H), 3.31-3.25 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:8][C:9](=[O:14])[CH2:10][C:11]2([CH3:12])[CH3:13]
Reactant: CC(C)=CC(=O)Oc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CC(=O)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A solution of 3-methyl-but-2-enoic acid 4-bromo-phenyl ester (7 g, 27.6 mmol) in anhydrous dichloromethane (200 mL) was cooled (ice bath) and treated with aluminum chloride (6.6 g, 49.6 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with diethyl ether (×2). The combined organic extract was washed woth brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil which was purified by flash column chromatography over silica gel (230-400 mesh) using 2.5% ethyl acetate in hexane as the eluent to afford the title compound (4.2 g, 57%).
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](O)(=[O:9])[CH3:8].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:7]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: CC(N)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)C(=O)O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
134 g (1.50 mol) of DL-alanine are introduced into acetic acid and treated dropwise with 230 g (2.25 mol) of acetic anhydride. The mixture is additionally stirred at 100° C. for 2 h to complete the reaction and the solvent is then stripped off in vacuo. The solid obtained is suspended in ethyl acetate and filtered off with suction. For purification, the solid is washed several times with diethyl ether.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.Cl.[NH2:27][N:28]1[CH2:35][CH:34]2[CH:30]([CH2:31][CH2:32][CH2:33]2)[CH2:29]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:27][N:28]3[CH2:35][CH:34]4[CH2:33][CH2:32][CH2:31][CH:30]4[CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NN1CC2CCCC2C1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncnc(NN3CC4CCCC4C3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6](=O)[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:29][CH2:28]1)=[O:26])[CH3:23].C(N(CC)CC)C>CO>[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][N:43]3[C:4]([C:1](=[O:3])[CH3:2])=[C:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=4)[C:6]3=[O:5])=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:29][CH2:28]1)=[O:26])[CH3:23]
Reactant: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Cn3c(C(C)=O)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
[Step 3] To a solution of 3-acetyl-6-bromo-4-phenylisochromen-1-one (343 mg) in methanol (20 ml) were added 1-(4-aminomethylbenzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (979 mg) and triethylamine (1.4 ml), and the mixture was stirred at room temperature for 72 hrs. The solvent was evaporated under reduced pressure, and partitioned between 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3→2/3) to give the title compound (91 mg, 14%). 1H-NMR (CDCl3) δ: 1.21 (3H, t, J=7.0 Hz), 1.37 (3H, s), 1.65-2.01 (4H, m), 2.11 (1H, m), 2.38-2.56 (2H, m), 3.50-3.66 (2H, m), 4.09 (2H, q, J=7.0 Hz), 5.47 (2H, s), 7.24-7.50 (8H, m), 7.67-7.76 (3H, m), 8.41 (1H, d, J=8.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:27][N:28]([CH3:33])[S:29](Cl)(=[O:31])=[O:30].O>CN(C=O)C>[CH3:24][C:19]1[C:18]([C:10]2[N:11]([S:29]([N:28]([CH3:33])[CH3:27])(=[O:31])=[O:30])[C:12]3[C:17]([C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)[nH]c3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(-c3c(C)noc3C)n(S(=O)(=O)N(C)C)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole (the intermediate product of step (d) from Example 1, 35 mg, 0.11 mmol) was added to a suspension of NaH (25 mg, 60% in heptane) in DMF (dry, 0.7 ml) at 0° C. under nitrogen. The mixture was stirred at rt for 30 min and was then cooled to 0° C. again. Dimethylsulfamoyl chloride (2 eq) was added drop wise. The mixture was stirred at rt for 2 h, cooled to 0° C. and water was added to quench the reaction. Extraction with DCM using isolute phase separator and concentration of the combined organic layers afforded 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-N,N-dimethyl-1H-indole-1-sulfonamide in quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si](C(C)(C)C)(C)C)[CH2:8][C@H:7]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:5])[CH3:2].N1C=CC=CC=1.[Na]>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([OH:11])[CH2:8][C@H:7]1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COc1ccc(Cl)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1CC(O)C[C@H]1COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a cold (ice bath) solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(4-chloro-phenoxymethyl)-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, 529 mg) in tetrahydrofuran (20 mL) was slowly added pyridine (8.1 g) and a pyridine-hydrofluoric acid complex (70% HF w/w, 9.07 g). The mixture was stirred 3 h at room temperature then solid sodium hydrogenocarbonate an aqueous saturated solution of sodium hydrogenocarbonate were added to adjust the pH to 7. The mixture was extracted with dichloromethane and the combined organic layers were washed with an aqueous saturated solution of sodium hydrogenocarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethylacetate (6:1 to 1:1 v/v) as eluant to afford the title compound (0.346 g, 90%) as a light yellow oil. MS (EI): 299.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>C(OCC)C>[CH2:35]([O:34][C:32]([NH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH3:23])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])=[CH:13][CH:14]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(c1ccccc1)c1ccc(OC[C@H]2CCC[C@H]2N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)N[C@@H]1CCC[C@@H]1COc1ccc(C(C)(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of (±) cis-1-amino-2-[4-(1-methyl-1-phenylethyl)phenoxymethyl] cyclopentane (0.35 g, 1.13 mmol) in dry diethyl ether (30 ml) containing triethylamine (0.31 ml, 2.26 mmol) was added a solution of ethyl chloroformate (0.18 g, 1.70 mmol) in diethyl ether (5 ml). The reaction was stirred at room temperature for 2 h and then poured into ice-water. The pH of the aqueous phase was adjusted to approximately 7 by the addition of dilute hydrochloric acid. The aqueous layer was separated and extracted with diethyl ether (2×30 ml). The combined organic layers were washed with water followed by brine, then dried over sodium sulfate and concentrated in vacuo to give an oil (0.41 g) which was used in the next stage without purification.
Reaction SMILES: CS(O)(=O)=O.[O:6]=[C:7]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:19][C:11]2[C:12]3[CH:13]=[N:14][NH:15][C:16]=3[CH:17]=[CH:18][C:10]=2[CH2:9][C@H:8]1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.[C:45](OC(=O)C)(=[O:47])[CH3:46].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:45]([N:24]1[CH2:25][CH2:26][CH:21]([N:20]2[C:7](=[O:6])[C@H:8]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:9][C:10]3[CH:18]=[CH:17][C:16]4[NH:15][N:14]=[CH:13][C:12]=4[C:11]=3[CH2:19]2)[CH2:22][CH2:23]1)(=[O:47])[CH3:46]
Reactant: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(C2CCNCC2)C1=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
(R)-benzyl 8-oxo-9-(piperidin-4-yl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate methanesulfonate (100 mg, 0.19 mmol) was dissolved in a mixture of dichloromethane (4 mL) and triethylamine (500 μL, 3.6 mmol). Acetic anhydride (500 μL, 5.3 mmol) was added to the mixture. Reaction stirred at room temperature overnight. Reaction mixture was washed successively 1× water, 2×1N hydrochloric acid, 2×1N sodium hydroxide, and 1× brine. Organic was dried (magnesium sulfate), and filtered. Filtrate was concentrated in vacuo. Residue was treated with methanol (3 mL). Potassium carbonate (40 mg, 0.29 mmol) was added to the mixture. Reaction stirred at room temperature for 2 hours. Reaction was quenched with 1N hydrochloric acid (6 mL). Methanol was removed from the mixture in vacuo. Remaining aqueous mixture was made basic with sodium bicarbonate. Mixture was extracted with ethyl acetate. Organic layer was dried (magnesium sulfate), filtered and concentrated. Title compound was obtained as yellow solid in 43% yield. MS m/e (M+H)+=476.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1OC
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3scc(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]CS([O-])(=O)=O)[CH:5]=[CH:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:27][CH:24]2[CH2:23][CH2:22][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:26][CH2:25]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=S(=O)([O-])CCc1ccnc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccnc(Cl)c2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42 using (2-chloropyridin-4-yl)methylmethanesulfonate (Intermediate-4) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.215 g, 29%); MS: 327.2 (M+1).
Reaction SMILES: [C:1]([C:9]1[C:18]([CH3:19])=[N+:17]([O-:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22]Br>CO>[C:1]([C:9]1[C:18]([CH2:19][Br:22])=[N+:17]([O-:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: BrBr
Solvent: CO
Product: O=C(c1ccccc1)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred suspension of 28 g. (0.10 mol.) of 2-benzoyl-3-methylquinoxaline 1,4-dioxide in 1,000 ml. of methanol was added 5.6 ml. (0.11 mol.) of bromine. The reaction mixture was refluxed for 2 hours and then an additional 5.6 ml. (0.11 mol.) of bromine was added. The mixture was refluxed for an additional 2 hours and then it was cooled to 25° C. The solid which had precipitated was collected by filtration, washed with methanol, and dried to affored 30.4 g. (85% yield) of 2-benzoyl-3-bromomethylquinoxaline 1,4-dioxide, m.p. 183°-185° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1.[NH3:18]>ClCCl>[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:18])=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1
Reactant: N
Reactant: O=C(O)c1ccc(SC2CC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionylchloride (342 μL, 4.7 mmol) is added to a solution of 4-cyclopropylsulfanyl-benzoic acid (prepared as described in WO07003960, 190 mg, 0.98 mmol) in dichloro-methane (1.9 mL). The mixture is heated at reflux for 30 min and concentrated under reduced pressure. The residue is treated with toluene, and all volatiles are evaporated. The residue is dissolved in chloroform (1.9 mL) and treated with concentrated aqueous ammonia (770 μL, 9.8 mmol). The mixture is stirred at room temperature for 1 h and then extracted with water. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 137 mg (72% of theory); ESI mass spectrum: [M+H]+=194; Retention time HPLC: 0.45 min (X011_S03).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=O)[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28]([CH:30]1[CH2:32][NH:31]1)#[N:29]>O1CCCC1>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[CH2:5][CH2:6][C:7]([N:31]1[CH2:32][CH:30]1[C:28]#[N:29])=[O:9])[CH3:12]
Reactant: CCN(CC)C(=O)CCC(=O)O
Reactant: N#CC1CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCC(=O)N1CC1C#N
Reaction time: 2 h

Procedure:
3.46 g. N,N-Diethylsuccinic acid monoamide and 4.3 g. dicyclohexylcarbodiimide are dissolved in 35 ml. tetrahydrofuran and 1.36 g. 2-cyanoaziridine is added to the resultant suspension. After subsequently stirring for 2 hours in an ice bath and leaving to stand overnight at ambient temperature, the dicyclohexylurea is separated off and the filtrate evaporated. There are thus obtained 2.9 g. 1-(N,N-diethylsuccinamoyl)-2-cyanoaziridine in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Al].Cl[CH:16](Cl)[CH2:17][Si:18]([Cl:21])([Cl:20])[Cl:19]>C(=S)=S.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:16]([CH2:17][Si:18]([Cl:21])([Cl:20])[Cl:19])[C:6]=2[CH:7]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Agent: [Al]
Solvent: S=C=S
Solvent: CCCCCC
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2ccc(Br)cc21
Yield: 15 %

Procedure:
In the same apparatus and procedures as Example 1 above, 5.0 g (21.7 mmol) of 4-bromobiphenyl and 0.08 g (11.1 mmol) of aluminum foil were alkylated in CS2 (50 ml) solution with (2,2-dichloroethyl)-trichlorosilane 6.68 g (21.7 mmol) for 24 hr. at reflux temperature. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and CS2 were distilled, the reaction products were vacuum distilled to give 1.28 g of 2-bromo-9-(trichlorosilyl)methylfluorene (yield; 15%).
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:28][N:29]([C:37]2([CH2:40][OH:41])[CH2:39][CH2:38]2)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:9]=1[Br:42].F[B-](F)(F)F.[CH3:58][O+](C)C>C(Cl)Cl>[CH3:52][Si:2]([CH3:1])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:49])([CH3:48])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:28][N:29]([C:37]2([CH2:40][O:41][CH3:58])[CH2:39][CH2:38]2)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:9]=1[Br:42]
Reactant: C[O+](C)C
Reactant: CC(C)(C)OC(=O)N(Cc1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C1(CO)CC1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(N(Cc2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
To tert-butyl (7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl(1-(hydroxymethyl)cyclopropyl)carbamate (0.19 g, 0.23 mmol) in DCM (2.5 ml) was added protonsponge (70 mg, 0.33 mmol) followed by trimethyloxoniumtetrafluoroborate (48.2 mg, 0.33 mmol) at room temperature and the resulting mixture was stirred at room temperature for 16 h, at which time LC/MS confirmed full conversion of starting material to product. Reaction mixture was quenched with sat. NH4Cl and diluted with DCM (25 ml). Organics were separated and washed with brine (5 ml) and dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with DCM/MeOH (0-50%) gave slightly impure desired tert-butyl (7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl(1-(methoxymethyl)cyclopropyl)carbamate (97 mg, 50%).