Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: CCOc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CCOc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-ethoxyaniline were reacted to yield N2-(4-ethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.88 (bs, 1H), 7.40 (bd, 2H, J=8.7 Hz), 7.27 (bd, 2H, J=6.3 Hz), 6.95 (dd, 1H, J=3 and 9 Hz), 6.86-6.77 (m, 3H), 6.58 (s, 1H), 4.28 (bs, 4H), 4.01 (q, 2H, J=6.9 Hz), 1.40 (t, 3H, J=6.9 Hz); LCMS: ret. time: 24.46 min.; purity: 90%; MS (m/e): 383 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].CI.[C:13](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 4-bromo-3,5-dimethylphenol (4) (25.0 g, 124.3 mmol), methyl iodide (35.3 g, 248.6 mmol), and potassium carbonate (34.4 g, 248.6 mmol) in 62.5 mL of DMF was stirred for 2 hours at room temperature. The reaction mixture was diluted with 300 mL of ether and washed with 250 mL of water and 5×100 mL of brine. The organic portion was dried (MgSO4), filtered, and evaporated to give an oil, which was purified by flash column chromatography (silica gel, 90:10 hexane/ethylacetate) to give 4-bromo-3,5-dimethylanisole (5) (26 g, 120.8 mmol, 97%); 1HNMR (CDCl3) δ 2.39 (s, 6H), 3.76 (s, 3H), 6.67 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[S:26][C:27]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=4[N:29]=3)=[CH:23][CH:24]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(Br)c([N+](=O)[O-])c4)cc3)sc2c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 4-bromo-3-nitrobenzoic acid (0.24 g, 0.976 mmol) and thionyl chloride (5 ml) was heated under reflux for 3 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride, 2-(4-aminophenyl)-6-methoxybenzothiazole (0.25 g, 0.976 mmol) and Hunig's base (0.151 g, 1.17 mmol) in dry THF (10 ml) to give the title compound (0.368 g, 78%) as small yellow crystals after work-up and recrystallisation from DMF.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[C:12]([C:14]1[N:15]([CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][N:18]=1)#[N:13].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CCOCC.C(O)C.O1CCCC1>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[NH2:13][CH2:12][C:14]1[N:15]([CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][N:18]=1
Reactant: N#Cc1nccn1Cc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1nccn1Cc1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.9 Grams of lithium aluminum hydride was added to about 50 ml of dry tetrahydrofuran. Then 1.3 ml of sulfuric acid was added by means of a syringe with cooling. The resulting slurry was stirred at room temperature for 1 hour and then a tetrahydrofuran solution of 3.0 g of 2-cyano-1-(2-thienylmethyl)-1H-imidazole was added and the mixture was stirred for 16 hours. The reaction mixture was quenched with 1.9 ml of water, 1.9 ml of 15% aqueous sodium hydroxide solution, and 5.7 ml of water. The mixture was then filtered and the solid was washed with ethyl acetate. The filtrate was then partitioned between water and ethyl acetate. The ethyl acetate layer was separated, dried over sodium sulfate and concentrated to give a yellow oil. A solution of 0.7 g of this oil in 300 ml of ether was prepared and a solution of 3.6 g of 4-toluenesulfonic acid in ethanol was added. The solid which formed was separated by filtration and dried to give 2-aminomethyl-1-(2-thienylmethyl)-1H-imidazole 4-toluenesulfonate melting at about 129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 99 %

Procedure:
To a suspension of 4′-chloro-p-toluenesulfonanilide (1100 g (3.90 mol) in acetic acid (2200 ml), fuming nitric acid (273.9 g (4.22 mol) was added dropwise over a period of 40 minutes with stirring at 50° C. After completion of the addition, the reaction mixture was stirred at the same temperature to complete the reaction. After being left to cool to room temperature, the reaction mixture was treated with 7000 ml of water to bring about precipitation of crystals. The crystals were filtered and washed with water to give 1261 g (99%) of 4′-chloro-2′-nitro-p-toluenesulfonanilide as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][NH:7][C:8](=[O:23])[CH2:9][N:10]1[C:16](=[O:17])[C:15]2[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:14]=2[O:13][CH2:12][CH2:11]1)[CH3:2].[CH2:25]([N:32]=[C:33]=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][NH:7][C:8](=[O:23])[CH2:9][N:10]1[C:16](=[O:17])[C:15]2[CH:18]=[C:19]([NH:22][C:33]([NH:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH:20]=[CH:21][C:14]=2[O:13][CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)CN1CCOc2ccc(N)cc2C1=O
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)CCNC(=O)CN1CCOc2ccc(NC(=O)NCc3ccccc3)cc2C1=O

Procedure:
Treatment of 3-[2-(7-amino-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-propionic acid ethyl ester (0.17 g, 0.5 mmol) with benzylisocyanate as described in Example 1 d) yielded 3-{2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-propionic acid ethyl ester (0.2 g, 0.42 mmol): mp. 70-75° C.; MS (ISP): 469 (M+1)+.
Reaction SMILES: [C:1](=[O:9])([O:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8])[NH2:2].[C:10](Cl)(Cl)=[O:11]>CCCCCCCCCCCCCCCCCCCNC=O.ClC1C=CC=CC=1>[Cl:8][CH2:7][CH2:6][CH2:5][CH2:4][O:3][C:1]([N:2]=[C:10]=[O:11])=[O:9]
Reactant: O=C(Cl)Cl
Reactant: NC(=O)OCCCCCl
Agent: CCCCCCCCCCCCCCCCCCCNC=O
Solvent: Clc1ccccc1
Product: O=C=NC(=O)OCCCCCl
Reaction time: 6 h
Yield: 44 %

Procedure:
45 5 g of δ-chlorobutyl carbamate were initially introduced as a melt and 63 g of phosgene were passed into the melt at 80° C. within 6 hours. 150 g of chlorobenzene and 0.36 g (=0.4 mol %) of methylstearylformamide were then added and a further 159 g of phosgene were passed into the mixture at 130° C. over a further 16 hours. Excess phosgene was subsequently driven out using nitrogen. 23.7 g of δ-chlorobutyloxycarbonyl isocyanate having a boiling point of 86° to 109° C. at 20 mbar were obtained on subsequent distillation, corresponding to a yield of 44% of theory.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](Cl)=[O:24])=[CH:20][CH:21]=2)[C:16]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:15]1)(=O)C>N1C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([C:23]([NH:1][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[O:24])[CH:18]=3)[NH:14][N:15]=2)=[CH:31][CH:30]=1
Reactant: NCCCN1CCOCC1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Solvent: c1ccncc1
Product: O=C(NCCCN1CCOCC1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a flask containing a solution of 4-(3-Aminopropyl)-morpholine (117 μl, 0.79 mmol) in pyridine (1 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (230 mg, 0.72 mmol) dissolved in pyridine (5 mL). The reaction was allowed to stir under a nitrogen atmosphere overnight. The reaction was not complete so an additional equivalent of 4-(3-Aminopropyl)-morpholine (100 μl, 0.72 mmol) was added. The reaction was allowed to stir at room temperature overnight. LCMS showed the product formation. Solvent was removed by rotary evaporation. The reaction was treated with water and the product was extracted with ethyl acetate and dichloromethane. The organic layers were combined and washed with saturated aqueous sodium carbonate solution and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the product. This was purified by semi-preparative HPLC. The product was washed with a sodium bicarbonate solution to remove the TFA salt to yield the title compound (37.3 mg, 13.5% yield). 1H NMR (DMSO-d6) δ 8.6 (m, 1H), 8.5 (m, 1H), 8.0 (m, 2H), 7.9 (m, 1H), 7.7 (m, 1H), 7.4 (m, 2H), 3.3 (m, 4H), 3.1 (m, 2H), 2.3 (m, 6H), 1.6 (m, 2H) ES-MS m/z 383 [M+1]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[C:34]([NH2:46])[CH:33]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH2:39][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)=[C:34]([NH:46][C:7](=[O:9])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: COC(=O)c1ccc(NCC2CCCCC2)c(N)c1
Reactant: O=C(O)Cc1cccs1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCC2CCCCC2)c(NC(=O)Cc2cccs2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 99.6 %

Procedure:
To a solution of 8.94 g of thiophen-2-yl-acetic acid in 130 ml of dry DMF 8.56 g of HOAT, 12.06 g of EDC and 30 ml of DIPEA were added at 0° C. After 30 min 15.00 g of 3-Amino-4-(cyclohexylmethyl-amino)-benzoic acid methyl ester were added and the reaction was stirred at 80° C. for 48 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The crude product was purified by chromatography (silica, ethyl acetate/heptane) to yield 22.00 g (100%) of 4-(Cyclohexylmethyl-amino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9](=[O:28])(=[O:27])[CH2:10][C:11]3[C:15]([C:16]([O:18]CC)=[O:17])=[N:14][N:13]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[OH-:29].[Na+].OO>CCO>[NH2:2][C:1]([C:3]1[C:8]2[S:9](=[O:28])(=[O:27])[CH2:10][C:11]3[C:15]([C:16]([OH:18])=[O:17])=[N:14][N:13]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:29]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1c(C#N)cccc1-2
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc2c1S(=O)(=O)Cc1c(C(=O)O)nn(-c3ccccc3)c1-2
Reaction time: 2 h

Procedure:
To a solution of Ethyl 6-cyano-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (100 mg, 0.254 mmol) in EtOH (10 mL) is added an aq. solution of NaOH (10%, 1 mL) and 30% hydrogen peroxide (2 mL) at 100° C. and the heating is continued for another 2 h. The reaction mixture is evaporated under vacuum, acidified with HCl (1.5 N) and extracted with EtOAc. The organic layer is separated, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound. MS (ESI+): 384.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccc(F)cc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and 4-fluorobenzenesulfonyl chloride (68 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 445.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([OH:9])=O)[C:2]=1[C:10]([OH:12])=[O:11].C(OC(=O)C)(=O)C>>[N:4]1[CH:5]=[CH:6][N:1]=[C:2]2[C:10]([O:12][C:7](=[O:9])[C:3]=12)=[O:11]
Reactant: O=C(O)c1nccnc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2nccnc21
Temperature: 115 °C

Procedure:
In a clean 500 ml R. B. flask charged pyrazine-2,3-dicaroxylic acid (50 gms) and acetic anhydride (162 gms). The reaction mass was heated to 110-120° C. till the completion of reaction to get pyrazine-2,3-dicarboxylic acid anhydride. After completion of the reaction, excess acetic anhydride was distilled out under vacuum and furthermore charged with methylene dichloride (315 ml) and 2-amino-5-chloropyridine (40 gms) in a lot wise manner at room temperature for 30 min. Further, the reaction mixture was stirred for 2 hours at room temperature. The reaction mass was cooled to 5 to 10° C. for one hour, the product was filtered and washed with chilled methylene dichloride. The solid was charged with methylene dichloride (235 ml), triethylamine (40.9 ml) at a temp. of 0-5° C. followed by ethyl chloroformate (28.1 ml). The reaction mass was stirred at 0-5° C. for 1 hr, water (200 ml) was added to the reaction mixture and the mass stirred at room temperature for 1 hr to obtain the solids. The title compound thus separated was isolated by filtration.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14](O)[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1.O>C(OC(=O)C)(=O)C>[C:1]([O:4][CH:14]([C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[Cl:6])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)(=[O:3])[CH3:2]
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 10 h
Yield: 43 %

Procedure:
A pinch of sodium acetate was added to 25.8 g (0.1 mol) of 1-(2,4-dichlorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)-ethane in 100 ml of acetic anhydride and the mixture was then kept for 10 hours at a temperature of 100° C. Thereafter the solution was cooled and stirred into 1,000 ml of water. A smeary, crystalline mass precipitated, which was taken up in chloroform. The chloroform solution was washed with sodium bicarbonate and water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue crystallized on adding petroleum ether. 13 g (43% of theory) of 1-acetoxy-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethane of melting point 92°-96° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>COCCOC>[F:16][C:5]1[C:6]([NH:26][CH2:25][CH2:24][O:23][CH3:22])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1
Reactant: COCCN
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Solvent: COCCOC
Product: COCCNc1nc(N)nc(-c2ccco2)c1F

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester and 2-methoxyethylamine in DME. ES-MS m/e (%): 253 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:6]=2[CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:6]=2[CH:5]=1
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc2cc(N)ccc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
In a 250 ml round-bottomed flask fitted with a Teflon stirrer and a reflux condenser, methyl 5-nitrobenzo[b]thiophene-2-carboxylate (10 g, 42.18 mmole) was dissolved in ethanol (100 ml). Tin (II) chloride dihydrate (5 equivalents, 47.60 g, 211 mmole) was added in one lot and the resulting slurry was reluxed for 18 hours while being stirred. The reaction mixture was cooled to room temperature, transferred to a 2000 ml Erlenmeyer flask, and carefully quenched with 5% sodium bicarbonate solution (aprroximately 700 ml) until effervescense was no longer detected. The resulting precipitate was filtered off and air-dried. The dried solid was dissolved in hot ethanol (500 ml), and filtered to remove undissolved material. The filtrate was evaporated in vacuo to give 8.564 g (96%) of methyl 5-aminobenzo[b]thiophene-2-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[O:6][CH:7]=1.[OH:21][C:22]1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO>>[OH:1][C:2]1[C:3](=[O:20])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[O:6][C:7]=1[CH2:22][OH:21]
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(O)co2)cc1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(O)c(CO)o2)cc1
Yield: 45.34 %

Procedure:
N-(5-Hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (9-06) (7.0 g, 45.34%) was synthesized as a white solid from N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (8-06) (14.0 g, 47.45 mmol) following the procedure described for N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-01).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([C:13]([CH3:32])([CH3:31])[CH2:14][C:15]([CH2:21][C:22]2[NH:30][C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:11][CH:12]=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[F:19][C:16]([F:17])([F:18])[C:15]([OH:20])([CH2:21][C:22]1[NH:30][C:25]2=[CH:26][N:27]=[CH:28][CH:29]=[C:24]2[CH:23]=1)[CH2:14][C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:2]=[O:1])([CH3:31])[CH3:32]
Reactant: CC(C)(CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F)c1cccc(C2OCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: CC(C)(CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.3 %

Procedure:
A mixture of 4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol (160 mg, 0.36 mmol), 2 mL of ethanol, 1 mL of water, and pyridinium p-toluenesulfonic acid (200 mg, 0.8 mmol) was stirred at room temperature for 14 hours and then concentrated in vacuo to remove ethanol. The residue was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with aqueous saturated sodium bicarbonate solution and brine, and dried over sodium sulfate. Removal of the solvent in vacuo afforded 134 mg (95% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc(F)c1
Yield: 88.4 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.32 ml (0.0027 mol) of 3-fluoro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.72 g (88%) of 1-benzyl-piperidin-4-yl 3-fluoro-benzoate was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:25].CC(O)C>>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:25])[C:6]=12
Reactant: FC(F)(F)c1nnc2n1CCC(c1nc(Br)c3c(Cl)nccn13)C2
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCn4c(nnc4C(F)(F)F)C3)nc(Br)c12
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 7-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine (335 mg, 0.978 mmol) in NH3-iPrOH (50 mL) was heated at 100° C. for 24 hours in a sealed tube. The reaction was completed by LC-MS, then cooled to room temperature. Remove the solvent in vacuo to give 1-bromo-3-(3-(trifluoro methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)imidazo[1,5-a]pyrazin-8-amine as a yellow solid (0.39 g, yield 99%).