Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31]OS(C)(=O)=O)[C:6]=2[CH:37]=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][N:42]3[C:38](=[O:48])[C:39]4=[CH:47][CH:46]=[CH:45][CH:44]=[C:40]4[C:41]3=[O:43])[C:6]=2[CH:37]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCC(CCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Temperature: 110 °C
Reaction time: 3 h
Yield: 103.1 %

Procedure:
To a solution of 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.6 g) in dimethylformamide (30 ml) is added potassium phthalimide (0.58 g), and the mixture is stirred at 110° C. for 3 hours. The mixture is poured into ice-water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-phthalimidoethyl)-1-[6-(2-chlorobenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) as colorless amorphous.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH2:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[S:31]([NH2:35])(N)(=[O:33])=[O:32].[CH3:36][OH:37]>O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH:29][C:36]([N:35]=[S:31](=[O:33])=[O:32])=[O:37])=[CH:23][C:22]=3[F:30])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: NS(N)(=O)=O
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CN)cc3F)CC2)CC1
Reactant: CO
Solvent: O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CNC(=O)N=S(=O)=O)cc3F)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
25 mg of 16a and sulfamide (7 mg, 1.2 eq) were combined in 0.5 mL of water and 0.5 mL of methanol in a sealed vial. The mixture was stirred at 100° C. overnight then the mixture was evaporated, extracted with ethyl acetate and purified on preparative HPLC to give 17-1: LC-MS 504.2 (MH+-17), tR=5.06 (Method 5). EC50: 312 nM.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17][CH2:16][CH2:15]1)[CH:6]=[C:5]2[CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[CH:41]1([NH:44][C:45](=[O:63])[C:46]2[CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[C:49]([CH3:61])=[C:48]([F:62])[CH:47]=2)[CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:20]([O:19][CH2:18][C:14]1([CH2:13][N:7]2[CH:6]=[C:5]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:50]4[CH:51]=[C:46]([C:45](=[O:63])[NH:44][CH:41]5[CH2:42][CH2:43]5)[CH:47]=[C:48]([F:62])[C:49]=4[CH3:61])[CH:3]=3)[C:8]2=[O:12])[CH2:17][CH2:16][CH2:15]1)([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cn(CC3(CO[Si](C)(C)C(C)(C)C)CCC3)c(=O)c3ccc(Br)cc23)CC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO[Si](C)(C)C(C)(C)C)CCC3)cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of tert-butyl 4-[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]piperazine-1-carboxylate (Example 27c, 0.153 g) in DMF (4 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.077 g), Pd-118 (4.71 mg) and potassium carbonate (0.067 g) under nitrogen. The resulting mixture was stirred at 75° C. for 8 h. The reaction was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate (2×100 mL) before washing the organics with water (3×100 mL) and brine (3×100 mL). The organic was dried (MgSO4), filtered, and evaporated under reduced pressure to afford the crude product. The crude product was purified (SiO2 chromatography, elution with 30% ethyl acetate/isohexane) to afford the subtitle compound (0.099 g) as an oil.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:16][CH2:15]1.I.[NH2:27][C:28]1[C:29]([C:36]([NH:38][C:39](=[NH:42])SC)=[O:37])=[N:30][C:31]([Cl:35])=[C:32]([NH2:34])[N:33]=1>CN(C=O)C.CO>[NH3:8].[NH2:27][C:28]1[C:29]([C:36]([NH:38][C:39]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:39]([NH2:42])=[N:38][C:3]([C:2]3[C:28]([NH2:27])=[N:33][C:32]([NH2:34])=[C:31]([Cl:35])[N:30]=3)=[O:5])[CH2:15][CH2:16]2)=[NH:42])=[O:37])=[N:30][C:31]([Cl:35])=[C:32]([NH2:34])[N:33]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)C(F)(F)F
Reactant: NCCCCCN1CCN(CCCCCN)CC1
Agent: I
Solvent: CN(C)C=O
Solvent: CO
Product: N
Product: N=C(NCCCCCN1CCN(CCCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)CC1)NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 50 °C

Procedure:
5-[4-(5-Amino-pentyl)-piperazin-1-yl]pentylamine trifluoroacetate (Intermediate P) (172 mg, 0.24 mmol) is added to a stirring solution of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea hydroiodide (93 mg, 0.48 mmol) in DMF (1 mL). The resulting mixture is heated to 50° C. for 8 hours and then allowed to cool to RT. The reaction mixture is quenched with 5% citric acid solution and addition of DCM results in the formation of a gum. The gum is isolated and dissolved in MeOH (2 mL). The solution is passed through a “capture release” SCX-2 cartridge eluting with 1 N ammonia in MeOH followed by 1:1 MeOH:ammonia solution to afford the title compound.
Reaction SMILES: C(N1C[CH2:6][CH2:5][C:4]1=[O:8])=C.[C:9](OC(C)(C)C)(=[O:13])[C:10]([CH3:12])=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N>O>[C:9]([O:6][CH2:5][CH:4]=[CH2:8])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=CN1CCCC1=O
Reactant: C=C(C)C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: *CC(*)C
Solvent: O
Product: C=CCOC(=O)C(=C)C

Procedure:
The dimer of allyl methacrylate, which was prepared according to Example 1, was added to the mixture containing 70 wt.-% N-vinylpyrrolidone and 30 wt.-% tert-butyl methacrylate in the amount of 1 wt.-% on the whole mixture. The mixture was polymerized in a polypropylene mold at 60° C. for 16 h in the presence of 0.4 wt.-% azobisisobutyronitrile. The resulting gel was opalescent and contained, after swelling with water, 47 wt.-% water at G=1.238 MPa. The content of soluble extract was 3%.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15]4[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=4[N:13]=[CH:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CO>[C:21]1([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([N:11]4[C:15]5[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=5[N:13]=[CH:12]4)[CH:6]=3)[NH:2][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Reactant: O=C1CCCCC1
Agent: [Na]
Solvent: CO
Product: Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C3=CCCCC3)c2c1
Yield: 24.3 %

Procedure:
To a stirred solution of sodium (0.325 g, 14.2 mmol, 7.0 equivalents) in absolute methanol (10 mL) was added 1-(indol-5-yl)-5-methylbenzimidazole (0.500 g, 2.02 mmol) and cyclohexanone (0.84 mL, 8.08 mmol, 4.0 equivalents), and the resulting reaction solution was heated at reflux under nitrogen for 12 hours. The resulting mixture was evaporated under reduced pressure, and the residue was column chromatographed using silica gel (approximately 25 g) and eluted with 20% ethyl acetate in methylene chloride to afford the title compound (0.160 g, 0.49 mmol, 24%) as a pale yellow foam. Mp, 101.0°-102.0° C.; Rf =0.75 in 5% MeOH in methylene chloride; 1H NMR (CD3OD) d 8.25 (s, 1H), 7.88 (s, 1H), 7.53-7.50 (m, 2H), 7.35-7.33 (m, 2H), 7.21 (br d, J=8.5 Hz, 1H), 7.12 (d, J=8.2 Hz, 1Hz), 6.14 (br m, 1H), 4.90 (s, 1 exchangeable H), 2.46 (s, 3H), 2.19 (br m, 2H), 1.86-1.75 (m, 2H), 1.75-1.63 (m, 2H); IR (KBr) 2929, 2859, 1615, 1579, 1494, 1447 cm-1.
Reaction SMILES: C(O)[C@H]1O[C@H]([O:8][C@:9]2(CO)[O:13][C@H:12](CO)[C@@H:11](O)[C@@H:10]2[OH:17])[C@H](O)[C@@H](O)[C@@H]1O.O.[CH3:25][C:26]1([CH3:40])[O:31][C:30](=O)[CH:29]=[C:28]([CH2:33][C:34](=[O:39])[CH2:35][N:36]=[N+:37]=[N-:38])[O:27]1>C(OCC)(=O)C>[CH3:25][C:26]1([CH3:40])[O:31][CH2:30][CH:29]=[C:28]([CH2:33][CH:34]([OH:39])[CH2:35][N:36]=[N+:37]=[N-:38])[O:27]1.[O:13]1[CH:12]=[CH:11][C:10](=[O:17])[O:8][CH2:9]1
Reactant: CC1(C)OC(=O)C=C(CC(=O)CN=[N+]=[N-])O1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OCC=C(CC(O)CN=[N+]=[N-])O1
Product: O=C1C=COCO1
Temperature: 32 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
30 g of baker's yeast (made by Oriental Yeast Co., Ltd.) and 15 g of saccharose were added in 30 ml of tap water, and the solution was then stirred at 32° C. for 30 minutes. Afterward, 300 mg of 2,2-dimethyl-6-(3-azido-2-oxopropyl)-1,3-dioxin-4-one were added thereto, and the solution was then stirred overnight at the same temperature. 7.5 g of saccharose were further added thereto, followed by stirring overnight. Water of the reaction solution was then distilled off under reduced pressure, and the residue was extracted with dichloromethane and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off, and the resultant residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 67 mg (yield 22%) of (+)-2,2-dimethyl-6-(3-azido-2-hydroxypropyl)-1,3-dioxin-1,3-dioxin-4-one [a compound having the formula (1) in which n is 1, X is N3, Y is a hydrogen atom, and the substituent is present at the 6-position].
Reaction SMILES: CN.Cl.Cl.[CH2:5]([N:7]([CH2:30][CH3:31])[CH2:8][CH2:9][NH:10][C:11](=[O:29])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)[CH3:6].[C:32]([BH3-])#[N:33].[Na+]>CO>[ClH:20].[CH2:5]([N:7]([CH2:30][CH3:31])[CH2:8][CH2:9][NH:10][C:11]([C:12]1[N:33]([CH3:32])[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]2[C:14]=1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16]2)=[O:29])[CH3:6]
Reactant: [BH3-]C#N
Reactant: CCN(CC)CCNC(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.45 g. of methylamine in 120 ml. of methanol is treated with 12 ml. of 6.65-N methanolic hydrochloric acid. Thereafter, there are successively added under an atmosphere of argon at 20°-25° C. 17.0 g. of o-benzoyl-p-chlorophenylglyoxylic acid [2-(diethylamino)ethyl]amide hydrochloride and 1.6 g. of sodium cyanoborohydride and the mixture is stirred at room temperature for an addition 2 hours. The mixture is made acidic with concentrated hydrochloric acid while cooling with ice, stirred at room temperature for an additional 0.5 hour and evaporated to dryness under reduced pressure. The residue is made alkaline with 2-N ammonium hydroxide with the addition of ice and extracted with diethyl ether. After drying over sodium sulfate, the extract is concentrated to dryness and the oily residue triturated with hexane to crystallize the product. The product is removed by filtration, dissolved in 30 ml. of methanol and the solution treated with excess ethereal hydrochloric acid. After dilution with diethyl ether to a ten-fold volume, the hydrochloride which crystallizes out is removed by filtration and washed with diethyl ether. Recrystallization from methanol/diethyl ether yields 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [2-(diethylamino)ethyl]amide hydrochloride in the form of almost colorless crystals having a melting point of 211°-214° C. (decomposition).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]([OH:14])([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12]>>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:13])=[O:5].[CH2:12]([OH:5])[CH2:11][CH2:10][CH2:9][CH2:8][OH:14]
Reactant: CCCCC(O)O
Reactant: O=C1C=CC(=O)O1
Product: O=C(O)/C=C\C(=O)O
Product: OCCCCCO
Temperature: 160 °C

Procedure:
Ninety-eight grams (1 mol) of maleic anhydride were weighed into a 500 ml. round-bottom flask fitted with a separatory funnel, thermometer and reflux condenser. One hundred and two grams (1 mol) of 1, 5 - pentanediol were introduced into the separatory funnel. The maleic anhydride was heated to 140° C by means of a heating mantle and the pentanediol was added dropwise over a period of 60 minutes. The reactants were stirred with a magnetic stirrer. The temperature was raised gradually to 160° C. After the addition of the pentanediol was complete, the mixtures was heated an additional 30 minutes, then allowed to cool. The monoester was a moderately viscous liquid of 1400 - 1500 centipoise and an acid value of 216.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(Cl)cc1)N1CCCOCC1
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chlorophenyl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]1.[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1>O1CCCC1.CCOCC>[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]([CH2:6][N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]2)([OH:20])[CH2:15]1
Reactant: Cc1ccnn1C
Reactant: CC1(C)CCCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccnn1CC1(O)CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of nBuLi (12.48 mL) in tetrahydrofuran (40 mL) was added a solution of 1,5-dimethyl-1H-pyrazole (3.0 g) in tetrahydrofuran (3 mL) dropwise. After stirring for 1 hour, a solution of 3,3-dimethylcyclohexanone (3.94 g) in tetrahydrofuran (3 mL) was added dropwise, and the reaction was allowed to warm to 0° C. After stirring for 1 hour, the reaction mixture was diluted with ether (100 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography, eluting with a gradient of 3% to 25% ethyl acetate in hexanes, gave the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+].[F:16][C:17](Br)([F:19])[F:18]>CN(C)C=O>[F:16][C:17]([F:19])([F:18])[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)Br
Reactant: Sc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Sc1ccccc1-c1ccccc1
Temperature: 0 °C
Yield: 87.9 %

Procedure:
A reaction tube in a photoreaction apparatus was charged with 50 ml of dimethylformamide (DMF) and 5.59 g (30 mmol) of 2-mercaptobiphenyl, and with ice cooling and stirring, 1.2 g (30 mmol) of sodium hydride (60% in oil) was added. When foaming ceased, trifluoromethyl bromide was introduced into the reaction solution. The atmosphere within the reaction system was replaced by gaseous trifluoromethyl bromide, and while irradiating light from a high-pressure mercury lamp, about 2 equivalents of trifluoromethyl bromide was passed into the reaction system over about 2 hours. Ice water (150 ml) was added to the resulting brown reaction solution, and it was extracted with pentane. The organic layer was washed with water and then with saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 6.71 g (87.9%) of 2-(trifluoromethylthio)biphenyl as an oil. It was purified by silica gel column chromatography. The properties of the product were as shown below.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:9](C3C=CC(O)=CC=3)[CH:10]=2)[CH:5]=[CH:6][N:7]=1.[C:22](=[O:25])([O-])[O-].[K+].[K+].CN(C=O)C.[C:33](#[N:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:19][CH2:20][CH2:21]3)=[N:9][C:10]=2[C:19]2[CH:20]=[CH:21][C:22]([O:25][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]#[N:40])=[CH:8][CH:18]=2)[CH:5]=[CH:6][N:7]=1
Reactant: NC1=NC=CN2C1=CN(c1ccc(O)cc1)C2C1CCC1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(-c2nc(C3CCC3)n3ccnc(N)c23)cc1
Temperature: 120 °C

Procedure:
Into a 10 mL round bottom flask was added 4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-2-yl)phenol (20 mg, 0.00007 mol), benzonitrile, 2-fluoro-(0.017 g, 0.00014 mol), potassium carbonate (0.015 g, 0.00011 mol), DMF (0.6 mL, 0.007 mol) and the reaction was heated at 120° C. for 4 h. Purification by Gilson HPLC afforded 5.0 mg of the title compound as a white solid. The compound was passed through an SPE cartridge washing with NH3 in MeOH to elute 4.8 my of the desired compound free of the TFA salt. MS(ES+): m/z 381.93 (100)[MH+]. HPLC: tR=2.39 min (Open Lynx polar—5 min).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:9]1[N:10]=[C:11]([NH2:13])[S:12][C:8]=1[CH2:7][CH2:6]2.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl>ClC(Cl)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:9]1[N:10]=[C:11]([NH:13][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:12][C:8]=1[CH2:7][CH2:6]2
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nc2c(s1)CCc1cc(O)ccc1-2)c1ccccc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
To 7-methoxy-4,5-dihydronaphtho[1,2-d]thiazol-2-amine (17 mg, 0.073 mmol) in dichloroethane (2 mL) and pyridine (17.37 mg, 0.220 mmol) was added benzoyl chloride (0.015 mL, 0.132 mmol) at room temperature. The reaction mixture was heated to 45° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, 3 ml of dichloromethane was added, and the contents were washed with sat. NaHCO3. The organic layer was dried over Na2SO4 and concentrated and dried under vacuum overnight. The residue was dissolved into 2 ml dichloromethane, cooled to 0° C. using an ice bath. Borontribromide (0.293 mL, 0.293 mmol) was added slowly at 0° C. The reaction mixture was allowed to warm to room temperature slowly and stirred at room temperature for 4 hours. The reaction mixture was quenched with a few drops of MeOH and purified on prep. HPLC (Luna 5 u C18 21.2*100 mm column; 0%-100% 10mins gradient; Solvent A: 10% MeOH-90% H2O-0.1% TFA; Solvent B: 90% MeOH-90% H2O-0.1% TFA). The desired fractions were collected, concentrated and dried overnight to provide 3.5 mg of product. (two-step yield: 11%). LC/MS M+1=323.1. The product had an HPLC retention time=3.31 min. (condition A). 1H NMR (400 MHz, CD3OD) δ ppm 7.99-8.07 (2H, m), 7.63 (2H, d, J=7.48 Hz), 7.57 (2H, d, J=7.70 Hz), 6.70 (2H, s), 2.98 (4H, d, J=4.84 Hz).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:11]1[C:16]([CH:17]([CH:20]=O)[CH:18]=O)=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=1>N1C=CC=CC=1>[Cl:22][C:13]1[CH:14]=[CH:15][C:16]([C:17]2[CH:18]=[N:9][C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:10][CH:20]=2)=[CH:11][CH:12]=1
Reactant: O=CC(C=O)c1ccc(Cl)cc1
Reactant: N=C(N)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Clc1ccc(-c2cnc(-c3ccncc3)nc2)cc1
Yield: 55.9 %

Procedure:
Isonicotinamidine, hydrochloride (0.488 g) and 2-(4-chlorophenyl)malon-dialdehyde (0.566 g) were combined in anhydrous pyridine (10 ml) and heated to reflux under nitrogen, for 18 h. The resultant dark solution was cooled and poured onto ice-water (150 ml) and the mixture extracted with ethyl acetate (150 ml, then 50 nml). The combined organic extracts were washed with water (3×10 ml), saturated brine (20 ml), dried (Na2SO4), evaporated to dryness under reduced pressure and the residue purified by silica gel column chromatography with 3.5% methanol/dichloromethane as eluent, to give the title compound as a white solid (0.463 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: Cc1c(F)cc(C(=O)O)cc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(C)c(I)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
3-Fluoro-5-iodo-4-methylbenzoic acid (1.3 g, 4.6 mmol, 1 eq) was dissolved in Methanol and treated with conc. Sulphuric acid (0.49 ml, 9.2 mmol, 2 eq). The above solution was stirred at 50° C. for 15 h. Later on solvent was removed and to the resulting residue diethylether was added and the organic layer was washed with 10% sodium bicarbonate solution and water. Finally, the organic layer was concentrated and purified by flash silica gel column chromatography using 240-400 silica gel and using 10% EtOAc in hexane as the eluent. Yield: 1 g (77%). 1H NMR (400 MHz CDCl3). δ 2.39 (s, 3H), 3.90 (s, 3H), 7.64 (d, 1H, J=8 Hz), 8.25 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(#N)C>C([O-])(=O)C>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Ethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate 0.4 ml of a solution containing 6.25 mg/ml in acetate buffer (0.1 M, pH 5 with acetonitrile 12.5 vol. % added to the buffer) was added followed by a sample of Protease 2 (or Aspergillopepsin I) from Aspergillus aculeatus expressed in Aspergillus oryzae also containing secreted enzymes from Aspergillus oryzae (WO95/02044; Handbook of Proteolytic Enzymes, Barrett, Rawlings, and Woessner Eds., 1998, Academic Press ref.1 chap. 294) (0.1 ml of a solution containing 5 mg/ml) in an acetate buffer (0.1 M; pH=5). The reaction mixture was shaken at room temperature and analysed at different times (maximum 24 h). The reaction mixture was analysed by the gradient HPLC method 1 and by the chiral HPLC method 1.