Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:22](=O)[NH2:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:22][NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C(N)=O)c2ccccc2Cl)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Yield: 41.7 %

Procedure:
To 4-[Carbamoyl-(2-chloro-phenyl)-methyl]-piperazine-1-carboxylic acid tert-butyl ester 462(0.45 g, 1.27 mmol) in THF (10 mL) at 0° C. was added 1.0M BH3 in THF (5.1 mL). The reaction was allowed to stir at reflux for 18 h. MeOH (5.0 mL) was added to the reaction mixture and mixture was then concentrated to dryness. The resulting residue was taken up in MeOH (10 mL) and allowed to reflux for 1 h. The reaction mixture was concentrated to dryness and the resulting residue was taken up in EtOAc (30 mL) and washed with sat. NaHCO3 (30 mL) and brine (30 mL). The organic phase was concentrated to dryness yielding 0.18 g (43%) product.
Reaction SMILES: [CH2:1]([SiH:9]([Cl:11])[Cl:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:12]1([Si:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([Cl:11])[Cl:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1=CCCCC1
Reactant: Cl[SiH](Cl)CCc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: Cl[Si](Cl)(CCc1ccccc1)C1CCCCC1
Reaction time: 17.5 h
Yield: 60.7 %

Procedure:
Then into a 100 ml pressure-proof stainless steel reactor; 6.21 g (30.3 millimol) of the above-mentioned phenethyldichlorosilane, 4.47 g (54.4 millimol) of cylcohexene and 0.1 ml of a chloroplatinic acid solution in isopropanol (0.03 mol % relative to phenethyldichlorosilane) were charged and sealed. Reaction was carried out in an oil bath at 100° C. with stirring for 17.5 hours. After completion of reaction, the reacted solution was subjected to vacuum distillation to obtain 5.30 g (18.4 millimol) of cyclohexylphenethyldichlorosilane. This cyclohexylphenethyldichlorosilane had a boiling point of 112.8°~115.4° C./2.0 mmHg. The infrared spectrum of this compound is shown in FIG. 4. There is no characteristic absorption of Si-H at 2100 cm-1. The NMR spectrum is shown in FIG. 9. There are signals of δ value at 1.0~2.0 ppm (Si--CH2 and C--CH2 --); 2.4~3.0 ppm (--CH2 --C6H5) and 7.15 ppm (--C6H 5). The integral ratio thereof was 14:2:5. In the mass spectrum analysis, parent ion was M+ 286.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1Cc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 3-neck 500 mL round-bottomed flask fitted with a condenser and an addition funnel was charged with 2.62 g (0.11 mol) of Mg turnings and 20 mL of anhydrous Et2O. Slow addition of a solution of 25.10 g (0.09 mol) of 3,5-bis(trifluoromethyl) bromobenzene in Et2O (100 mL), followed by refluxing for 30 min, gave a brown-grey solution of the aryl Grignard reagent. The solution was cooled to room temperature, filtered over a plug of Celite and evacuated to yield a brown oil. Toluene (40 mL) was added and the suspension cooled to 0° C. whereupon a solution of 2-indanone (9.22 g, 0.07 mol) in toluene (60 mL) was added dropwise to give a tan-brown slurry. This mixture was warmed to room temperature and stirred for an additional 3 hours. After cooling to a 0° C. it was quenched with 150 mL of water. Hexane (200 mL) was added and the reaction mixture neutralized with 5M HCl. The organic layer was separated, and the aqueous layer was extracted with two 50-mL portions of hexane. The combined organic layers were washed with two 50-mL portions of brine and dried over anhydrous magnesium sulfate. After filtration over Celite, the solvent was removed under vacuo yielding 21.5 g (89% based on 2-indanone) of 2-(bis-3,5-(trifluoromethyl)phenyl)indanol as an off-white solid. 1H NMR (DCDl3, 23° C., 400 Mhz): d 8.05 (s, 2H), 7.80 (s, 1H), 7.5-7.0 (M, 4H), 3.41 (m, 4H), 2.21 (s, 1H, OH). Under argon, this alcohol (21.5 g, 0.06 mol) and p-toluene-sulfonic acid monohydrate (800 mg) were dissolved in toluene (250 mL) and the solution was heated to reflux for 6 hours to afford 14.4 g, (70%) of 2-(bis-3,5-(trifluoromethyl)-phenyl) indene upon recrystallization from diethyl ether/hexane at -18° C. 1H NMR (CDCl3, 23° C., 400 Mhz): d 8.01 (s, 2H), Arf), 7.75 (s, 1H, Arf), 7.52 (d, J=7 Hz, 1H), 7.47 (d, J=7 Hz, 1H), 7.43 (s, 1H), 7.33 (dd, 2J=7 Hz, 1H), 7.27 (dd, 2J- 7 Hz, 1H), 2.83 (s, 2H). 13C NMR (CDCl3, 23° C., 100 Mhz): d 144.3 (s), 143.1 (s), 138.0 (s), 132.1 (q 2JC-F =33 Hz), 130.1 (d, JC-H =167 Hz), 127.0 (dd), JC-H =160 Hz, 2JC-H =7 Hz), 126.0 (dd, JC-H =159 Hz, 2JC-H =7 Hz)m 125.2 (brd, JC-H =162 Hz), 123.9 (dd, JC-H =156 Hz, 2JC-H =9 Hz), 123.4 (q, JC-F =273 Hz, CF3), 121.8 (dd, JC-H =160 Hz, 2JC-H =8 Hz), 120.6 (brd, JC-H =167 Hz), 38.9 (td, JC-H =127 Hz, 2JC-H =7 Hz, CH2). C,H analysis: Anal. Found (Calcd): C, 62.45 (62.20); H 3.01 (3.07).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49]>C(N(CC)CC)C>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])[CH2:19][CH2:20]3)[N:14]=1)[CH2:4]2
Reactant: NCC(N)=O
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: NC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and glycinamide hydrochloride (18 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 559.8 (M+H)+
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrCCCCCC1CCCCC1.[Mg].BrCCBr.[CH3:31][Si:32]([CH3:41])([CH3:40])[C:33]1[O:37][CH:36]=[C:35]([CH:38]=[O:39])[CH:34]=1.S(=O)(=O)(O)O>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:38]([C:35]2[CH:34]=[C:33]([Si:32]([CH3:41])([CH3:40])[CH3:31])[O:37][CH:36]=2)[OH:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: Br[Mg]CCCCCC1CCCCC1
Agent: BrCCCCCC1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)CCCCCC2CCCCC2)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-cyclohexylpentyl-magnesium bromide (1.32 mmol, prepared from 0.31 g., 1.32 mmol 1-bromo-5-cyclohexylpentane and 2.88 mmol magnesium, with a catalytic amount of 1,2-dibromoethane as initiator), in 2.5 ml anhydrous tetrahydrofuran at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.23 g., 1.40 mmol) in 2.5 ml tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for one hour, and then poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a colorless oil (0.173 g.). This material was purified by flash chromatography (silica, 90% petroleum ether/ethyl ether) to give the desired alcohol.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29](O)=[O:30]>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:29]([C:19]3[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:21][O:22][C:18]=3[CH3:17])=[O:30])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1C(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 5-methyl-3-phenylisoxazole-4-carboxlic acid by the same method as described for the title compound of Example 2 to afford a white solid, m.p. 235°-236° C. [α]D =-29.6° (c=0.46, MeOH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.FC(F)(F)S(O[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)(=O)=O.[F-].[K+].C(Cl)Cl>CN(C=O)C>[NH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=3)=[CH:11][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Nc1nc2cc(Br)ccc2o1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3oc(N)nc3c2)CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 44.7 %

Procedure:
5-Bromobenzo[d]oxazol-2-amine (824 mg, 3.9 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (1.8 g, 5.8 mmol), Potassium fluoride (674 mg, 11.61 mmol) were dissolved in DMF under N2 atmosphere. This mixture was purged with N2 for 30 mins Pd(dppf)2Cl2.CH2Cl2 (252 mg, 0.3 mmol) was added to the above mixture and again purged with N2 for 30 mins. The reaction mixture was stirred at 90° C. for 12 h. Work up (EtOAc/H2O) followed by column purification on combiflash using a gradient mixture of EtOAc and Petether (1:1) as eluent afforded the titled compound (550 mg) as an off-white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.38-7.36 (m, 2H), 7.26-7.22 (m, 2H), 7.02 (d, J 7.9, 1H), 6.05 (s, 1H), 4.01-3.90 (m, 2H), 3.49-3.55 (m, 2H), 2.50-2.40 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:23]=[CH:22][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Yield: 95.5 %

Procedure:
10.8 g of t-butyl N-[2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl]carbamate was dissolved in 300 ml of ethanol, 2 g of 10% palladium-carbon was added thereto, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give 8.2 g of the title compound.
Reaction SMILES: Cl.[C:2]([C:5]1[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[NH:4])[NH2:3].Br[CH2:18][C:19]([C@@H:21]1[CH2:25][CH2:24][CH2:23][O:22]1)=O.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:15][C:8]1[CH:7]=[C:6]([CH3:16])[C:5]([C:2]2[NH:3][C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][O:22]3)=[CH:18][N:4]=2)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Reactant: O=C(CBr)[C@@H]1CCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ncc([C@@H]3CCCO3)[nH]2)c(C)cc1C
Temperature: 75 °C
Reaction time: 72 h
Yield: 24.9 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 1.30 g) in CH3CN (30 mL). (S)-2-bromo-1-(tetrahydrofuran-2-yl)ethanone (compound 257.2, 1.92 g, 9.95 mmol) and potassium carbonate (4.20 g, 30.4 mmol) were added to the reaction. The resulting solution was stirred for 3 days at 75° C. under nitrogen. After cooling to ambient temperature, the solids were removed by filtration. The filtrate was concentrated in vacuo and diluted with 30 mL of H2O. The aqueous phase was extracted with 3×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, then concentrated in vacuo. The mixture was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:2) as eluent to yield 400 mg (25%) of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as a light yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([C:48]([CH3:54])=[CH:49][CH:50]=[CH:51][CH:52]=[CH2:53])=[CH:29][C:30]=1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:34](=[O:47])[CH2:33]1)=[O:25]>ClCCCl>[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([C:48]([CH3:54])=[CH:49][CH:50]=[CH:51][CH:52]=[CH2:53])=[CH:29][C:30]=1[N:31]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C:34](=[O:47])[CH2:33]1)[C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]1)=[O:10])=[O:25]
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C=CC=CC=C(C)c1cc(NC2CCN(Cc3ccc(OC)cc3)C(=O)C2)c(C(=O)OC)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=CC=CC=C(C)c1cc(N(C(=O)C2CCC(C)CC2)C2CCN(Cc3ccc(OC)cc3)C(=O)C2)c(C(=O)OC)s1
Yield: 10.8 %

Procedure:
A solution of trans 4-methylcyclohexane carboxylic acid (56 mg, 0.399 mmol, 1.2 eq) in 1,2-dichloroethane (1 ml) at 0°, under N2, was treated with oxalyl chloride (2.0M solution in CH2Cl2) (231 μl, 0.46 mmol, 1.4 eq), followed by dimethylformamide (8 μl, 7 mg, 0.1 mmol, 30 mol %). After 1 h the reaction was treated with a solution of 3-[1-(4-Methoxy-benzyl)-2-oxo-piperidin-4-ylamino]-5-(1-methyl-hexa-1,3,5-trienyl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.33 mmol) in DCE (2 ml). The reaction was then placed in bath at 90° and left at reflux overnight for 21 h. The reaction was stripped-off solvent and the residue (212 mg) was purified by bond elute chromatography using (Hexane:CH2Cl2:EtOAc=1:1:1) as eluent to give 3-[[1-(4-Methoxy-benzyl)-2-oxo-piperidin-4-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(1-methyl-hexa-1,3,5-trienyl)-thiophene-2-carboxylic acid methyl ester (21 mg, 11%) as a yellow foam; (300 MHz, CDCl3) 0.55-0.73 (m, 1H), 0.77 (d, J=5.4 Hz, 3H), 1.26-1.30 (m, 12H), 1.94-2.12 (m, 1H), 2.14-2.19 (m, 1H), 2.40 (dd, J=9.0 Hz, J=12.0 Hz, 1H), 2.64-2.70 and 2.80 and 2.84 (m, 1H), 3.10-3.15 (m, 3H), 3.79-3.82 (m, 1H), 3.78 (s, 3H), 3.83 and 3.87 (s, 3H), 4.32 (t, J=12.0 Hz, 1H), 4.62 (dd, J=5.7 Hz, J=10.8 Hz, 1H)′ 4.50-5.0 (m, 1H), 6.79-6.83 (m, 2H), 6.99-7.14 (m, 2H), 7.26-7.48 (m, 3H), 7.61-7.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:15])[CH2:6][CH2:5]2.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CC(C)=O>[CH2:16]([NH:23][S:11]([C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:15])=[CH:3][C:2]=1[Cl:1])(=[O:13])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCc2cc(Cl)c(S(=O)(=O)Cl)cc21
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1CCc2cc(Cl)c(S(=O)(=O)NCc3ccccc3)cc21

Procedure:
According to Example 2(a), 13.26 g (50 mmoles) of 5-chloro-6-chlorosulfonyl-1-indanone, 5.89 g (55 mmoles) of benzylamine and 5.05 g (50 mmoes) of triethylamine in a total of 100 ml of acetone yield 6-benzylsulfamoyl-5-chloro-1-indanone having a melting point of 203° to 205° C., from which the pure product is obtained after a recrystallization from ethanol, said product having a melting point of 228° to 231° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]1[SH:20])[CH3:8].CI>CN(C=O)C>[CH2:7]([N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]=[C:10]1[S:20][CH3:1])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCn1c(S)nc(C(F)(F)F)cc1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1c(SC)nc(C(F)(F)F)cc1=O
Yield: 94.2 %

Procedure:
Next, potassium carbonate (8.15 g, 59.0 mmol) was added to DMF (100 ml) solution of 3-ethyl-2-mercapto-6-trifluoromethyl-4(3H)-pyrimidinone (11.0 g, 49.0 mmol), methyl iodide (3.68 ml, 59.0 mmol) was added with stirring under ice-cooling, followed by stirring for 4 hours while gradually returning to room temperature. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added to the thus obtained residue to separate the organic layer, and then the aqueous layer was extracted with ethyl acetate (50 ml×3). The organic layers were combined, washed with water (100 ml×3) and saturated brine (300 ml) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the resulting filtrate was concentrated under a reduced pressure to obtain 3-ethyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (11.0 g, 94%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:21]([O:22]C(=O)C)[C@H:20]([O:26]C(=O)C)[CH2:19][S:18][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[C:16]#[N:17])(=O)C>C(Cl)Cl.CO>[S:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[C:16]#[N:17])[C@@H:6]1[S:18][CH2:19][C@@H:20]([OH:26])[C@H:21]([OH:22])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2C#N)SC[C@H]1OC(C)=O
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(S[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)c(C#N)c1
Yield: 67 %

Procedure:
If the procedure described in Preparation V is followed, except that the reaction is carried out at 0° C., starting from 1.5 g (34.10-3 mol) of 2,4-dicyanophenyl 2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 16a), 0.71 g (yield: 67%) of the expected product is obtained after chromatography on silica using a CH2Cl2 /CH3OH mixture (8/1 v/v) as the eluent.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[N:21]=[C:20]2[NH:22][N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1.[CH3:33][O:34][CH2:35][CH:36](O)[CH2:37][O:38][CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:15][C:16]1[N:21]=[C:20]2[N:22]([CH:36]([CH2:37][O:38][CH3:39])[CH2:35][O:34][CH3:33])[N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1
Reactant: COCC(O)COC
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Yield: 126 %

Procedure:
Diisopropyl azodicarboxylate (1.1 mL, 5.4 mmol) was added in drops to a suspension of 3-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.1 g, 4.1 mmol), 1,3-dimethoxypropan-2-ol (0.65 g, 5.4 mmol), and triphenylphosphine (1.4 g, 5.4 mmol) in tetrahydrofuran (33 mL). When this Mitsunobu reaction was deemed to be complete by LC/MS analysis, the mixture was adsorbed onto flash silica gel and purified by automated flash chromatography (methanol/chloroform) to provide 3-(6-chloro-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane as an amber glass (1.9 g, >100%) contaminated with triphenylphosphine oxide. MS (ES+): 368.2, 370.2 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[NH:20][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[CH:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][CH:9]=2)[C:4]([C:12]2[NH:20][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[CH:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-ylamine [52.4 mg, Example 18] in dichloromethane (5 mL) was treated with triethylamine (30 μl) followed by methane sulfonyl chloride (17 μl). After stirring at ambient temperature for 16 hours the reaction mixture was diluted with dichloromethane (10 mL), then washed with water (10 mL), then washed with brine (10 mL), then dried over magnesium sulfate and then evaporated. The residual solid was triturated with diethyl ether to give the title compound as a yellow solid, m.p. 223-224° C. MS: 341 (MH+).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2([CH3:12])[CH2:11][CH2:10]2)=[N:5][N:4]=[C:3]1[SH:13].[CH3:14]O.CI>[OH-].[Na+]>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2([CH3:12])[CH2:10][CH2:11]2)=[N:5][N:4]=[C:3]1[S:13][CH3:14]
Reactant: CO
Reactant: CC1(c2nnc(S)n(N)c2=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSc1nnc(C2(C)CC2)c(=O)n1N
Reaction time: 6 h
Yield: 82.3 %

Procedure:
198 g of compound obtained according to (b) is dissolved in 500 ml of 2 N NaOH, and 500 ml of methanol and 150 g of methyl iodide are added. The reaction mixture is stirred at 20° to 30° C. for 6 hours. The crystals which have formed are filtered off with suction, washed and dried to yield 174.5 g of final product (dried in vacuo at 40° C.); white crystals; melting point 115° to 116° C.; yield 82.3% of theory.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: Fc1ccccn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccn2)cn1
Yield: 23 %

Procedure:
As described for Example 12, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 2-fluoropyridine instead of 4-fluoroacetophenone was converted to the title compound (31 mg, 23%) which was obtained as an off-white solid. MS: m/e=303.1 [M+H]+.
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH3:22][N:23]([CH3:28])[CH:24](C)[CH2:25]N.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CN(C=O)C>[CH3:22][N:23]([CH3:28])[CH:24]([CH3:25])[CH2:20][N:2]1[C:12]2[C:11](=[CH:16][C:15]([I:17])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: CC(CN)N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(C)N(C)C)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
(Z)-Ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (0.500 g, 1.28 mmol, Intermediate 24), N2,N2-dimethylpropane-1,2-diamine hydrochloride (0.177 g, 1.28 mmol), and potassium carbonate (0.194 g, 1.41 mmol) were combined in THF (10.0 mL). The reaction was heated at 60° C. for 2 hrs. After 2 h, DMF (5.0 mL) was added followed by potassium carbonate (0.530 g, 3.83 mmol). The reaction was heated at 90° C. for 6 h. The reaction mixture was cooled to 0° C. and 1N HCl was slowly added until pH was around 4. The resulting precipitate was filtered, washed with water and dried overnight to yield a light yellow solid (0.428 g).