Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[N:12]#[C:13][NH2:14].[Na].S(OC)(O[CH3:20])(=O)=O>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[N:12][C:13]#[N:14])[S:11][CH3:20])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: COS(=O)(=O)OC
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: CSC(=NC#N)Nc1ccc(C#N)cc1
Yield: 151.7 %

Procedure:
A mixture of 32 g (0.1 mol) of 4-cyanophenyl isothiocyanate and of 12.8 g (0.2 mol) of monosodium cyanamide in 100 cm3 of absolute ethanol is maintained for 2 hours at boiling point. After cooling, the precipitate obtained is filtered and washed with 200 cm3 of absolute ethanol. The solid is then placed in suspension in a solution of dimethyl sulfate (25 g, 0.2 mol) in 500 cm3 of ethanol; the mixture is heated for two hours at boiling point. The final precipitate is filtered, washed with 2×100 cm3 of water and with 2×100 cm3 of ethanol, then is dried in vacuo. 32.8 g (yield 70%) of N-(4-cyanophenyl)-N'-cyano-S-methylisothiourea are obtained: ##STR9## which is a white solid, whose melting point is 225°-230° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[Si:31]([O:38][CH2:39][CH2:40][CH2:41]Br)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:41][CH2:40][CH2:39][O:38][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cccc(OCCCO[Si](C)(C)C(C)(C)C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 72.2 %

Procedure:
In the same manner as described in Example 38, 0.35 g (0.820 mmol) of the product of Example 37 and 0.290 g (1.147 mmol) of 1-t-butyldimethylsilyloxy-3-bromopropane provided 0.355 g (72%) of the desired product as a colorless oil. Electrospray Mass Spec: 600 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:9][C:10]([NH:12][C:13]1[N:14]=[C:15]([CH2:18][NH:19][CH:20]=O)[S:16][CH:17]=1)=[O:11])[CH:7]=[CH2:8]>C1(C)C=CC=CC=1>[CH2:6]([O:9][C:10]([NH:12][C:13]1[N:14]2[CH:20]=[N:19][CH:18]=[C:15]2[S:16][CH:17]=1)=[O:11])[CH:7]=[CH2:8]
Reactant: C=CCOC(=O)Nc1csc(CNC=O)n1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCOC(=O)Nc1csc2cncn12
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 75.8 %

Procedure:
A 6.4 ml portion of phosphorus oxychloride was added to a suspension obtained by adding 17 ml of dry toluene to 3.408 g of 4-allyloxycarbonylamino-2-(formylamino)methylthiazole, and the mixture was then stirred at an oil temperature of 100° C. for 45 minutes. The solvent was evaporated under reduced pressure, and to the resulting residue, 200 ml of dichloromethane and 100 ml of 0.1N sodium hydroxide were added. The solution was adjusted to pH 8.0 with a 2N aqueous sodium hydroxide solution under stirring. After the removal of insolubles by filtration, the organic layer was separated from the filtrate, and it was combined with a liquid extracted from the aqueous layer with 100 ml of dichloromethane, dried (magnesium sulfate), and then filtered. Further, the solvent was evaporated under reduced pressure to obtain an ocherous powder, and this powder was then purified by a silica gel column chromatograph to obtain 2.390 g of the title compound as a light orange powder.
Reaction SMILES: CO.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18](=[O:36])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:8]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:50](=S)=[S:51]>O>[N:3]([CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18](=[O:36])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:8]=1)=[C:50]=[S:51]
Reactant: S=C=S
Reactant: CCCCCCCCCCCCCCCCNC(=O)c1cc(OCCN)c2ccccc2c1O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCNC(=O)c1cc(OCCN=C=S)c2ccccc2c1O
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Into 300 ml of methanol were dissolved 64 g of 4-(2-aminoethyloxy)-2-hexadecylcarbamoyl-1-naphthol and 35 g of triethylamine. To this mixture was added dropwise 19 g of carbon disulfide at a temperature not exceeding 10° C., and the resulting mixture was stirred for 1 hour. Thereafter, 11.9 g of ethyl chloroformate was added dropwise and stirred for additional 30 minutes. The resulting reaction mixture was poured into 1.5 l of water, and precipitated crystals were collected by filtration and recrystallization from acetonitrile to give 47 g of 4-(2-isothiocyanatoethyloxy)-2-hexadecylcarbamoyl-1-naphthol. Yield: 92%. M.P.: 90°-91° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:12][C:11](=[O:13])[C:10]4[C:2](=[C:3]([CH3:14])[CH:4]=[C:5]5[CH:6]=[N:7][NH:8][C:9]5=4)[N:1]=3)=[CH:25][C:24]([O:30][CH2:31][C:32]([F:35])([F:33])[F:34])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Reactant: O=C(O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 500 mg (2.61 mmol) of 6-amino-5-methyl-1H-indazole-7-carboxylic acid in 20 mL of anhydrous tetrahydrofuran is added 790 mg (2.61 mmol) of 2-(3-chloro-pyridin-2-yl)-5-(2,2,2-trifluoro-ethoxy)-2H-pyrazole-3-carboxylic acid followed by 945 μL (11.7 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 708 μL (9.1 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at 50° C. for 16 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated and washed with cold water. The pale yellowish product obtained (1.0 g) is engaged in the next step: LC/MS:477/479 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1[C:33]2[NH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:30]1[C:31]2[N:32]([C:2]3[CH:3]=[C:4]([C:8]4[O:9][C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=5)=[N:11][N:12]=4)[CH:5]=[CH:6][CH:7]=3)[C:33]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(-c2nnc(-c3cccc(I)c3)o2)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nnc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Reaction time: 5 h

Procedure:
To a solution of 2-(3-iodophenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (3.0 g, 7.93 mmol), carbazole (1.5 g, 8.97 mmol), Cu (2.0 g, 31.47 mmol) in DMF (20.0 ml) was added potassium carbonate (4.0 g, 28.94 mmol) under nitrogen and stirring. Heating was started. The reaction was carried out at 150° C. for 5 h. After cooling, the reaction mixture was filtrated. The solid residues were carefully washed with THF. THF was evaporated from the combined filtration solution. Water (150.0 ml) was added, the brown solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.5:0.5) as eluent. After evaporating solvent, the white solid was recrystallized from acetone/methanol and finally dried under vacuum. Pure product was obtained as white solid in 3.15 g (95.4%) yield. 1H NMR (400 MHz, CDCl3, δ): 8.34 (m, 1H), 8.27 (m, 1 Hz), 8.18 (m, 2H), 7.78 (m, 2H), 7.71-7.65 (m, 2H), 7.46-7.41 (m, 5H), 7.36-7.31 (m, 2H), 7.09 (m, 1H), 3.89 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 164.85, 163.84, 159.96, 140.60, 138.70, 130.85, 130.32, 130.25, 126.19, 125.84, 125.40, 124.72, 123.55, 120.45, 120.37, 119.39, 118.44, 111.52, 109.55, 55.55. [M]+ calcd for C39H26N4O2, 417.2. found 417.1.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O-:7])=[CH:3][CH:2]=1.[Na+].C1C=CC=CC=1.CN(C)C=O.[Cl:20][CH2:21][C:22]1[N:26]=[C:25](Cl)[S:24][N:23]=1>O>[Cl:20][CH2:21][C:22]1[N:26]=[C:25]([O:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[S:24][N:23]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: ClCc1nsc(Oc2ccccc2)n1
Reaction time: 24 h
Yield: 63.6 %

Procedure:
5.8 g of sodium phenate were added to a mixture of 50 ml of benzene, 10 ml of dimethylformamide and 8.5 g of 3-chloromethyl-5-chloro-[1,2,4]-thiadiazole and the mixture was stirred at20° C. for 24 hours. 50 ml of water were added to the mixture and the decanted aqueous phase was extracted with benzene. The combined organic phase was dried and evaporated to dryness. The oil residue was distilled under reduced pressure to obtain 7.2 g of 3-chloromethyl-5-phenoxy-[1,2,4]-thiadiazole boiling at 114°-116° C. at 0.5 mm Hg.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14](Br)=[C:13]([CH3:19])[N:12]=1.C([O-])([O-])=O.[K+].[K+].Cl>C(O)CO.O>[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([S:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)=[C:13]([CH3:19])[N:12]=1
Reactant: OCc1ccc(S)cc1
Reactant: Cc1nc(N)nc(O)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: Cc1nc(N)nc(O)c1Sc1ccc(CO)cc1
Temperature: 155 °C

Procedure:
A stirred mixture of (4-mercaptophenyl)methanol (6.72 g), 2-amino-5-bromo-6-methylpyrimidin-4-ol (10.76 g) and K2CO3 (7.29 g) in ethylene glycol (120 ml) was heated at 155° C. for 9 h. After cooling the mixture was poured into water (500 ml) and neutralised with conc. HCl. The precipitate was filtered, washed with water then 50% EtOH/ether and dried to give the subtitle compound as a solid, 6.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:17](=[O:18])[CH2:16][NH:15][C:14](=O)[CH:13]=[C:8]12.O=P(Cl)(Cl)Cl.[CH:25]([C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>ClCCCl>[CH:25]([C:28]1[N:29]=[CH:30][N:31]([C:14]2[CH:13]=[C:8]3[C:9]4[C:4]([CH2:5][CH2:6][N:7]3[C:17](=[O:18])[CH2:16][N:15]=2)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH:32]=1)([CH3:27])[CH3:26]
Reactant: COc1cccc2c1CCN1C(=O)CNC(=O)C=C21
Reactant: CC(C)c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c1CCN1C(=O)CN=C(n3cnc(C(C)C)c3)C=C21
Temperature: 100 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To a stirred solution of 9-methoxy-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (80 mg, 0.31 mmol) in 1,2-dichloroethane (8 mL) was added POCl3 (0.058 mL, 0.62 mmol) and the resulting yellow suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to RT and concentrated under reduced pressure to dryness. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (8 mL), 4-isopropyl-1H-imidazole (102 mg, 0.93 mmol) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to RT. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (eluent: gradient 0% to 100% ethyl acetate/cyclohexane in 30 min) to yield 15 mg of a brown solid. Further purification by SFC (column: Diol 5 μm, 250×30 mm, 60 A, Princeton; eluent: 13% MeOH/CO2 for 0.5 min, then from 13% MeOH/CO2 to 18% MeOH/CO2 in 6 min; then from 18% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) yielded the title compound (9 mg). UPLC-MS: MS 351.3 (M+H+); UPLC rt 0.90 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.35 (d, J=6.8 Hz, 6 H), 2.95 (t, J=6.2 Hz, 2 H), 3.03-3.19 (m, 1 H), 3.88 (s, 3 H), 3.92-4.05 (m, 2 H), 4.40 (s, 2 H), 6.87-7.05 (m, 2 H), 7.19-7.58 (m, 4 H).
Reaction SMILES: [C:1]([C@@:5]1([OH:29])[C@@H:9]([CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[O:8][C@@:7]([SiH:26]([CH3:28])[CH3:27])([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C[OH:31]>CCO.O.C(Cl)Cl>[C:1]([C@@:5]1([OH:29])[C@@H:9]([CH2:10][O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[O:8][C@@:7]([SiH:26]([CH3:27])[CH3:28])([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21]=[O:31])[C:19]=3[N:18]=[CH:17]2)[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[SiH](C)[C@]1(n2cnc3c(N)ncnc32)C[C@@](O)(C(C)(C)C)[C@@H](COC(C)(C)C)O1
Reactant: CO
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: C[SiH](C)[C@]1(n2cnc3c([NH2+][O-])ncnc32)C[C@@](O)(C(C)(C)C)[C@@H](COC(C)(C)C)O1
Reaction time: 48 h
Yield: 39 %

Procedure:
To a solution of 3′,5′-O-bis-tert.-butyldimethylsilyl-2′-deoxyadenosine (Ogilvie, K. K. (1973) Can. J. Chem. 51, 3799-3807.) (6.0 g, 12.5 mmol) in a mixture of EtOH and H2O (2.5:1) was added at RT monopermaleic acid (24 mmol). After 2 days, another 6 equiv. of monopermaleic acid were added, and the reaction continued for two weeks. Continuous monitoring (TLC on SiO2, 10% MeOH in CH2Cl2) showed that the reaction did not proceed to completion even though peracid was still detectable (KI test). After two weeks, CH2Cl2 was added, the organic phase extracted with saturated NaHCO3, and 3′,5′-O-bis-tert.-butyldimethylsilyl-2′-deoxyadenosine N-oxide (3.41 g, 55%) isolated by chromatography (SiO2, EtOAc:hexane 4:1) together with starting material (2.33 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:36][C@H:37]1[CH2:39][O:38]1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:26]=[N:25][N:24]([CH2:36][C@@H:37]([OH:38])[CH3:39])[CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: C[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(C[C@H](C)O)c4)cc3n2)cc(OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (from Example 35, Step 1, 30.0 mg, 0.0613 mmol) and (S)-(−)-methyloxirane (8.56 μL, 0.122 mmol) in isopropyl alcohol (2 mL)/N,N-dimethylformamide (0.5 mL), triethylamine (17.1 μL, 0.122 mmol) was added at ambient temperature. The reaction mixture was then warmed up to 90° C. After 2 hours, the volatiles were removed and the residue was dissolved in methanol (2 mL). Potassium carbonate (16.9 mg, 0.122 mmol) was added and the reaction mixture was warmed up to 60° C. After 30 minutes, the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.8 mg) as its TFA salt. LCMS calculated for C22H26N5O3 (M+H)+: m/z=408.2. Found: 408.2.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[O:35][N:34]=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:51][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.[Cl-].[NH4+]>C1COCC1.O>[C:1]1([C:7](=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[O:35][N:34]=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 52.5 %

Procedure:
To a clear solution of ethyl 2-(diphenylmethyleneamino)-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 91A, 560 mg, 0.829 mmol) in anhydrous THF (20 mL) was added 1 M THF solution of lithium bis(trimethylsilyl)amide (4 mL, 4.00 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at the same temperature for 60 min. before half the amount of the required iodomethane (0.25 mL, 4.00 mmol) was added. The mixture was stirred at 0° C. for 20 min. before the rest of the iodomethane was added. The mixture was stirred at 0° C. for an additional 50 min. and saturated aqueous ammonium chloride solution (5 mL) and water (2 mL) were added. The mixture was extracted with ethyl acetate (10 mL and then 2×5 mL). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (24 g silica gel column, 5→50% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (300 mg, 0.435 mmol, 52.5% yield) as a glassy solid. The compound had an LC/MS M+1=690.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.[Cl:11][C:12]1[CH:32]=[CH:31][C:15]2[C:16](=[O:30])[C:17]3[C:24]([C:25](OCC)=[O:26])=[N:23][NH:22][C:18]=3[C:19](=[O:21])[NH:20][C:14]=2[CH:13]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:32]=[CH:31][C:15]2[C:16](=[O:30])[C:17]3[C:24]([C:25]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:26])=[N:23][NH:22][C:18]=3[C:19](=[O:21])[NH:20][C:14]=2[CH:13]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12)N1CCOCC1
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
Morpholine (268 μL, 3.06 mmol) was added to a solution of trimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution was stirred for 20 minutes. A portion (365 μL) of the resulting solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100 mg, 0.313 mmol) in toluene (0.760 mL). The resulting solution was stirred for 4 hours at room temperature and then quenched with aqueous hydrochloric acid (1.88 mL, 1N) and water (50 mL). The aqueous layer was extracted with chloroform (7×50 mL) and ethyl acetate (3×50 mL). The combined organic layers were concentrated on a rotary evaporator. The crude product was purified by flash chromatography eluting with chloroform:2-propanol (99:1-80:20) to give the title compound (89.9 mg, 80% yield, m.p. 347° C.).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C@H:30]([NH:40][CH3:41])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C@H:30]([N:40]([CH3:41])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:18])[CH3:17])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2002079134) (0.88 g, 2.76 mmol) in CH2Cl2 (5 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.72 g, 2.53 mmol) and ethyl-diisopropyl-amine (0.64 ml, 3.78 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 1 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 1.06 g (74%) of the title product as colorless foam. ES-MS m/e: 567.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]=[O:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br>O1CCCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:23])[CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C=O)nc3N21
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.00 g (4R,9aR)-6-Formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 100 ml tetrahydrofuran was added drop wise at 0° C. 20 ml of a ca 3M solution of methyl magnesium bromide solution in ether. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with 105 aqueous citric acid, 10% aqueous sodium bicarbonate and brine, dried over sodium sulfate, evaporated and dried to constant weight under high vacuum to yield 10.0 g of the title compound as colorless oil (MS: 334.5 (M+H+)).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].CO.ClC(Cl)C(O)=O>O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: O=C(O)C(Cl)Cl
Solvent: O
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 136 %

Procedure:
15.4 g. of Acetonine was dissolved in a mixed solvent comprising 169.8 g. of acetone and 56.6 g. of methanol. The solution was ice-cooled, added with 12.9 g. of dichloroacetic acid and 1.8 g. of water under stirring. The mixture was stirred at room temperature for 24 hours to effect the reaction. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, added with 40% aqueous potassium carbonate solution and extracted with ether. The extract was dried over anhydrous potassium carbonate, then ether was distilled off and the resulting residue was purified by distillation under reduced pressure to obtain triacetonamine in a yield of 136%.