Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19](Cl)(Cl)=[O:20].[CH3:23][NH:24][CH2:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:20])[N:24]([CH3:23])[CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[S:3][C:4]=2[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CNCc1ccc(C)nc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N(C)Cc3ccc(C)nc3)nc12
Yield: 25 %

Procedure:
Conversion of 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.377 mg) with phosgene (20% in toluene, 0.2 ml) and methyl-(6-methyl-pyridin-3-ylmethyl)-amine (0.064 ml, 0.47 mmol) using the general procedure D affords the product as white solid in 25% yield. MS: m/e=429 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10](=O)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(O)=O.C([BH3-])#N.[Na+]>CCO>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a solution of (RS)-4-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (commercial; 1 g, 3.9 mmol) in EtOH (15 mL) were added benzylamine (0.85 mL, 7.77 mmol) and AcOH (0.45 mL, 7.77 mmol) and the mixture was stirred 3 h at rt. Sodium cyanoborohydride (0.98 g, 15.5 mmol) was then added at rt and the mixture was heated to 75° C. for 5 h, then 15 h to 50° C. and again 1 h to 75° C. The mixture was concentrated under reduced pressure, water was added and the mixture extracted 3× with EA. The combined org. extracts were washed with brine dried over MgSO4 and concentrated under reduced pressure. The residue was purified by CC (Hep/EA from 2:1 to 1:1) to afford the title intermediate as a yellow oil (0.73 g, 54%).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:19][O:18][C@H:17]2[C@@H:12]([O:13][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:15][CH2:16]2)[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CO.C1COCC1>[C:20]1([CH:14]2[O:13][C@H:12]3[CH2:11][C@H:10]([OH:9])[CH2:19][O:18][C@@H:17]3[CH2:16][O:15]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1

Procedure:
To a stirred solution of (4aR,7S,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl benzoate (650 mg, 1.910 mmol) in methanol (10 mL) and THF (5 mL) was added 5N aqueous NaOH (4.0 mL, 20.0 mmol). After 18 hours the mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with EtOAc (2×120 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resultant white solid was chromatographed using a Biotage™ 25 g silica gel cartridge eluted with 0-100% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The product fractions were combined and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C13H16O4 236.10, observed m/e: 237.15 (M+H)+ (Rt 1.13/4 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.O=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]1[C:33](=O)[CH2:34][CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][O:37]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:18]=[C:33]([CH2:34][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][O:37]3)[C:21]3[CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:24][CH2:25][C:20]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CCC2CCCO2)C1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc(CCC3CCCO3)c3c(n2)CCN(C(=O)OC(C)(C)C)C3)ccc1-n1cnc(C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
A reaction mixture of 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (0.800 g, 2.17 mmol), tert-butyl 4-oxo-3-(3-(tetrahydrofuran-2-yl)propanoyl)piperidine-1-carboxylate (0.705 g, 2.17 mmol) and potassium carbonate (0.599 g, 4.33 mmol) in ethanol (6 mL) was stirred at 60° C. overnight. The reaction mixture was transferred to a microwave vial (20 mL) and run in the microwave at 120° C. for 45 minutes. The reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated and the residue was dissolved in dichloromethane and washed with water, dried (MgSO4) and concentrated. The crude product was purified by silica flash chromatography using a gradient of methanol in dichloromethane (0 to 4%) giving tert-butyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(2-(tetrahydrofuran-2-yl)ethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.335 g, 28.9%) as the product.
Reaction SMILES: [C:1]([CH:4]([S:6][C:7](=[N:9][OH:10])[CH3:8])[CH3:5])(=[O:3])[NH2:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.CC(C)=O>[CH3:11][NH:12][C:13]([O:10][N:9]=[C:7]([S:6][CH:4]([C:1](=[O:3])[NH2:2])[CH3:5])[CH3:8])=[O:14]
Reactant: CC(=NO)SC(C)C(N)=O
Reactant: CN=C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C)SC(C)C(N)=O
Reaction time: 48 h
Yield: 74 %

Procedure:
A mixture of 4.0 g (0.0247 m) of 1-(1-carbamoylethylthio)acetaldoxime, 75 ml of dry acetone, 4.0 g (0.07 m) of methyl isocyanate, and 2 drops of triethylamine was allowed to stand at room temperature, with occasional shaking, for two days. The acetone and excess methyl isocyanate were removed from the product under reduced pressure. The white solid residue was recrystallized from ethanol and then dried at room temperature to give 4.0 g (74% yield) of 1-(1-carbamoylethylthio]acetaldehyde O-(methylcarbamoyl)oxime; melting point=161°-163° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[N:14]1([S:20](Cl)(=[O:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C.CC(=O)OCC>[CH3:1][C:2]1[N:3]([S:20]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:22])=[O:21])[CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: O=S(=O)(Cl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(S(=O)(=O)N2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (3.06 g, 20 mmol) in dry DMF (40 mL) was added NaH (0.96 mg, 24 mmol) in portions and the mixture was stirred at rt for 30 min. Then a solution of piperidine-1-sulfonyl chloride (4.4 g, 24 mmol) in dry DMF (10 mL) was added and the resulting mixture was stirred overnight, diluted with EA, washed with water and brine, dried over Na2SO4, concentrated and purified by CC (PE/EA=1/0 to 10/1) to give compound 4a (4.77 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[C:21]=1[O:22][CH3:23].[CH2:24]=O>C(O)C.[H][H].[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[CH2:11][CH2:10][N:9]([CH3:24])[CH2:8][C:7]=2[C:21]=1[O:22][CH3:23]
Reactant: COc1ccc2c(c1OC)CNCCc1cc(O)ccc1CC2
Reactant: [H][H]
Reactant: C=O
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc2c(c1OC)CN(C)CCc1cc(O)ccc1CC2

Procedure:
Platinum oxide (50 mg) is hydrogenated in 50 ml of ethanol by shaking in hydrogen atmosphere. To this catalyst is added a solution of 51mg of 3,4-dimethoxy-10-hydroxy-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine and 1 ml of 37% formaldehyde in 5 ml of ethanol, and the mixture is shaken in hydrogen atmosphere for 6 hours. After removal of the catalyst by filtration, the mixture is evaporated to dryness under reduced pressure, and the residue (46 mg) is chromatographed on thin layer plates of silica gel containing 0.2N-sodium hydroxide [developed by chloroform - methanol (20 : 1)]. The product is recrystallized from benzene to yield 35 mg of 3,4-dimethoxy-10-hydroxy-6-methyl-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine as colorless crystals having mp. 138° - 140°C. IR: νmaxNujol 3461 cm-1.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.Cl.[C:15]1([CH:21](Cl)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]/[C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[C:15]1([CH:21]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=3)[CH:5]=[CH:4]2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]/[C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH:23]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)c1cccc(/C=C/c2ccc3ccccc3n2)c1
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=Cc1ccc2ccn(C(c3ccccc3)c3cccc(/C=C/c4ccc5ccccc5n4)c3)c2c1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Powdered potassium hydroxide (0.50 g, 8.93 mmol) was added to a stirred solution of indole-6-carboxaldehyde (Example 29a) (0.54 g, 3.70 mmol) in dimethyl-sulphoxide (10 ml). The solution was stirred under nitrogen for 10 minutes then solid a-phenyl-3-[2(E)-(quinolin-2-yl)ethenyl]benzyl chloride hydrochloride (Example 16a) (1.75 g, 4.46 mmol) was added and then stirred mixture was heated at 60° C. for 4 hours. The mixture was poured onto ammonium chloride solution and extracted with dichloromethane and the extract was dried and evaporated. The residue was chromatographed on silica in ethyl acetatehexane (1:3) to give a gummy solid which was recrystallised from ether-hexane, m.p. 75° C.
Reaction SMILES: [CH2:1]([N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([N:8]([C@@H:9]([CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:21]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])=[O:22])[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@H](Cc1ccc2ccccc2c1)N(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of N-benzyl-N-(tert-butoxycarbonyl)-3-(2-naphthyl)-L-alanine (2.9 g), glycine methyl ester hydrochloride (0.9 g) and 1-hydroxybenzotriazole hydrate (1.06 g) in dichloromethane (50 ml) was added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.43 ml) at ice-bath temperature. The resulting mixture was stirred at room temperature for 2 days and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with dilute hydrochloric acid and brine, and dried over magnesium sulfate. Evaporation of the solvent gave (2S)-2-[N-benzyl-N-(tert-butoxycarbonyl)amino]-N-methoxycarbonylmethyl-3-(2-naphthyl)propanamide.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[C:15]([N:16]3[N:20]=[CH:19][CH:18]=[N:17]3)=[CH:14][CH:13]=[C:12]([CH3:21])[N:11]=2)=[O:9])[C@@H:3]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.[H-].[Na+].[CH3:36]I>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[C:15]([N:16]3[N:17]=[CH:18][CH:19]=[N:20]3)=[CH:14][CH:13]=[C:12]([CH3:21])[N:11]=2)=[O:9])[C@@H:3]1[CH2:22][N:23]([CH3:36])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][N:25]=1
Reactant: CI
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN(C)c2ccc(C(F)(F)F)cn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (0.0215 g, 0.047 mmol) in DMF (0.5 mL) at rt was added NaH (60%, 0.006 g, 0.141 mmol). The mixture was stirred at rt for 1 h, then MeI (0.013 g, 0.094 mmol) was added. The reaction was stirred at rt for another 1 h. The crude was purified via preparative-HPLC to obtain the title compound. ESI-MS (m/z): 474 [M+1]+.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Si:13]([O:30][CH2:31][C@@H:32]([NH2:46])[CH2:33][NH:34][CH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Si:13]([O:30][CH2:31][C@@H:32]1[CH2:33][N:34]([CH2:35][C:36]23[CH2:37][CH:38]4[CH2:39][CH:40]([CH2:41][CH:42]([CH2:44]4)[CH2:43]2)[CH2:45]3)[C:5](=[O:11])[NH:46]1)([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](OC[C@@H](N)CNCC12CC3CC(CC(C3)C1)C2)(c1ccccc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1CN(CC23CC4CC(CC(C4)C2)C3)C(=O)N1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 156.3 %

Procedure:
A solution of triphosgene (124 mg, 0.42 mmol) in anhydrous CH2Cl2 (2 mL) was added slowly to a solution of (S)-3-(tert-butyldiphenylsilyloxy)-N1-(1-adamantylmethyl)propane-1,2-diamine (600 mg, 1.26 mmol) and triethylamine (140 mg, 1.4 mmol) in anhydrous CH2Cl2 (10 mL) at 0° C. The reaction mixture was stirred for another 1 h. The mixture was diluted with water and extracted with CH2Cl2 (50 mL). The organic layer was washed with 0.1 N aq HCl (2×20 mL) and brine (10 mL), dried over MgSO4 and concentrated to give a residue, which was purified by preparative TLC to provide (S)-4-((tert-butyldiphenylsilyloxy)methyl)-1-(1-adamantylmethyl)imidazolidin-2-one (330 mg, 52%). 1H NMR: (CDCl3, 400 MHz): δ=1.05 (s, 9H), 1.54 (s, 6H), 1.62-1.73 (m, 8H), 1.98 (s, 3H), 2.77 (m, 2H), 3.21 (m, 1H), 3.55 (t, 1H), 3.65 (m, 2H), 3.82 (m, 1H), 4.57 (s, 1H), 7.4 (m, 6H), 7.62 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:42]([O:44][CH2:45][C:46]([Cl:49])([Cl:48])[Cl:47])=[O:43]>O1CCCC1>[O:24]=[C:4]1[N:3]=[C:2]([NH:1][C:42](=[O:43])[O:44][CH2:45][C:46]([Cl:49])([Cl:48])[Cl:47])[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]1=3
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: C1CCOC1
Product: O=C(Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1)OCC(Cl)(Cl)Cl

Procedure:
A 500 mg amount of 5-amino-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) was suspended and stirred in 25.0 ml of dry tetrahydrofuran, then 320 mg of [1,8-bis(dimethylamino)naphthalene,N,N, N',N'-tetramethyl-1,8-naphthalenediamine] (Proton Sponge®) was added followed by 0.207 ml of 2,2,2-trichloroethyl chloroformate. This mixture was heated at reflux for 16 hours. The reaction mixture was quenched by pouring it into 200 ml of water and the precipitate formed was collected by filtration to give 419 mg of the desired product as a white solid, m.p. 225°-226° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:15](OCC)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:25])(=O)C.[N:26]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:37]/[C:15](=[C:6]3\[C:5](=[O:25])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=4)/[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:38][CH:39]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Product: COc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][OH:27])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CNCCO
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Product: CN(CCO)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and 2-(methylamino)ethanol were converted to yield 2-({4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amino)-ethanol as colorless oil, MS: 374 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH:10]=[C:11]([S:16][CH3:17])[CH2:12][C:13](=O)[CH3:14])=[CH:5][CH:4]=1.[F:19][B-:20]([F:23])([F:22])[F:21].[H+].O.C(O)(=O)C>ClCCCl>[F:19][B-:20]([F:23])([F:22])[F:21].[CH3:14][C:13]1[CH:12]=[C:11]([S:16][CH3:17])[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O+:18]=1
Reactant: COc1ccc(C(=O)C=C(CC(C)=O)SC)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2cc(SC)cc(C)[o+]2)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of this 1-(4-methoxyphenyl)-3-methylthio-2-hexen-1,5-dione (2.0 g, 7.57 mmol) in 1,2-dichloroethane (20 ml) was added tetrafluoroboric acid (10 ml, 48%). The mixture was stirred for four hours at 50° C. during which time a dense yellow solid formed. After addition of water (25 ml) and filtration, crystallization from acetic acid gave pale yellow needles of 2-methyl-4-methylthio 6-(4-methoxyphenyl)pyrylium tetrafluoroborate: 2.2 g (87%), m.p. 207°-210° C. (decomp), IR (KBr)νCO +1625 cm-1 ; NMR(DMSO-d6)δ8.34 (s,1, aromatic), 8.29 (d,2, J=9.0 Hz, aromatic), 7.80 (br. 3, 1, aromatic), 7.18 (d, 2, J=9.0 Hz, aromatic) 3.97 (s, 3, OCH3), 2.91 (s, 3, SCH3), (s, 3, CH3); M.+ 246 (100).
Reaction SMILES: [C:1]([Si:5]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:36]([OH:41])(=[O:40])[C:37]([CH3:39])=[CH2:38]>C1(C)C=CC=CC=1>[C:36]([O:41][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])(=[O:40])[C:37]([CH3:39])=[CH2:38]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)(C)C
Reactant: C=C(C)C(=O)O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 41.4 g (0.20 mol) of tert-butyldiisopropylchlorosilane, 60 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 18.9 g (0.22 mol) of methacrylic acid was added dropwise over one hour. After the completion of dropwise addition, the reaction solution was stirred for 2 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 45.4 g of a fraction having a boiling point of 93-95° C./0.27 kPa.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][C@H:17]([CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[C@H:17]([CH3:21])[CH2:16]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: C[C@@H]1CN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1S(=O)(=O)c1cccs1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A 100 mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-1-piperazinyl)phenyl)-2-propanol (0.950 g, 2.78 mmol), 5 mL of CH2Cl2, 2-thiophenesulfonyl chloride (0.583 g, 3.19 mmol, Sigma-Aldrich, St. Louis, Mo.), and triethylamine (0.580 mL, 4.16 mmol). After 1 h at room temperature, 0.010 g of DMAP was added. After an additional 30 min, the mixture was concentrated and purified via column chromatography (80 g of silica, 0 to 40% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.425 g) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ=7.70-7.46 (m, 4H), 7.12 (dd, J=3.7, 4.9 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 4.30 (m, 1H), 3.83 (td, J=3.0, 13.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.54-3.38 (m, 2H), 3.31 (s, 1H), 3.07 (dd, J=3.5, 12.3 Hz, 1H), 2.95 (dt, J=3.6, 11.6 Hz, 1H), 1.30 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 488.7 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=2.36 μM; GK-GKRP EC50 (LC MS/MS)=2.57 μM.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[O:8][C:7]=2[CH:23]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[O:8][C:7]=2[CH:23]=1
Reactant: CCOC(=O)CC1Cc2ccc(OC)cc2Oc2ccccc21
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CC1Cc2ccc(O)cc2Oc2ccccc21
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
A solution of ethyl (±)-10,11-dihydro-3-methoxydibenzo[b,f]oxepine-10-acetate (523 mg, 1.68 mmole) in CH2Cl2 (6.8 mL) was added dropwise to a cold solution of BBr3 in CH2Cl2 (1.0 M, 6.7 mL, 6.7 mmole) at 0° C. under argon. The reaction was stirred for 20 min, then CH3OH (7 mL) was added carefully. The mixture was concentrated and the residue was flash chromatographed on silica gel (15-20% EtOAc/hexanes) to afford the title compound (407 mg, 89%) as a pale yellow oil: MS (ES) m/e 299 (M+H)+.