Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[H-].[Na+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: COc1ccc(CNc2nc(C)nc(Cl)n2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of 4-chloro-N-(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (160 g, 604 mmol) in DMF (800 mL) at 0° C., was added sodium hydride (18.86 g, 786 mmol) slowly over 5 min. 1-(Chloromethyl)-4-methoxybenzene (91 mL, 665 mmol) was slowly added over 15 min. The reaction mixture was stirred at 0-5° C. for 30 min and allowed to warm to room temp 25° C. After 1 h, cold water (2.5 L) was added and the mixture was stirred overnight. The resulting slurry was filtered, washed with water (150 mL, ×2) and dried to afford 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine as a solid (215.3 g, 559 mmol, 93% yield). LCMS (ES, pos.): Cacld for C20H21ClN4O2: 384.1; found: 385.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=8.12 Hz, 4H); 6.81-6.95 (m, 4H); 4.74 (s, 2H); 4.69 (s, 2H); 3.81 (s, 6H); 2.45 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:17](=[O:19])=[O:18].O>C1COCC1.CCCCCC>[Cl:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=C=O
Reactant: Clc1cc(Br)c2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1cc(Cl)cc2cc[nH]c12
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
1.15 g (5 mmol) of 7-bromo-5-chloro-1H-indole were dissolved in 30 ml THF. At −75° C. under argon 9.4 ml (15 mmol) of a 1.6 M n-butyllithium solution in hexane were added dropwise. After complete addition the reaction mixture was stirred at 5° C. for 30 min, cooled to −75° C. and 10 g dry ice was added. The reaction mixture was warmed to RT and stirred for 15 min. It was poured onto 100 ml of water and extracted twice with ethyl acetate. The aqueous layer was acidified with 1N aqueous HCl solution and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated. The residue was treated with hexane and stirred for 10 min. The precipitate was filtered, washed with hexane and dried to yield 700 mg (72%) of 5-chloro-1H-indole-7-carboxylic acid as a white solid. MS (ISP) 194.0 (M−H)−.
Reaction SMILES: [SH2:1].[CH2:2]([O:4][C:5]([NH:7][CH2:8][C:9]#[N:10])=[O:6])[CH3:3].N1C=CC=CC=1.C(N(CC)CC)C>>[CH2:2]([O:4][C:5]([NH:7][CH2:8][C:9]([NH2:10])=[S:1])=[O:6])[CH3:3]
Reactant: S
Reactant: CCOC(=O)NCC#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(N)=S
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stream of H2S is passed into a mixture of 27.5 g of ethoxycarbonylaminoacetonitrile (210 mmol), pyridine (21ml, 210 mmol) and triethylamine (14.5 ml, 105 mmol) according to the procedure of Example 23. After stirring for 4 hours at room temperature and washing with water, a beige precipitate is obtained which is filtered off to give 6.6 g of ethoxycarbonylaminothioacetamide, which is a beige powder melting at 116° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([OH:16])=O)[N:7]=3.[C:19]([O:23][C:24]([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][N:27]([C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:16])[CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)NNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)OC(C)(C)C)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a mixture of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (1.92 g, 6.2 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (1.30 g, 7.5 mmol) in DMF (20 mL) at 0° C. was added DIPEA (2.70 mL, 15.5 mmol) and HATU (3.54 g, 9.3 mmol). The reaction mixture was stirred for 7 h at RT before the addition of DMF (40 mL) and stirring overnight. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between DCM and water. The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution then brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-90% ethyl acetate in cyclohexane) to give N′-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester as a white solid (3.02 g, quantitative yield). LCMS RT=4.76 min, [M+H]+=465/467. 1H NMR 400 MHz (DMSO-d6) δ: 8.62 (1 H, s), 8.40 (1 H, d, J=8.59 Hz), 7.69 (1 H, s), 7.23-7.22 (2 H, m), 4.81 (1 H, s), 4.44 (4 H, s), 1.32 (9 H, s), 1.13 (6 H, d, J=6.64 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][C:5]([C:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1Br.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:4][C:5]([C:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(c2cc(OCC3CC3)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Yield: 73.4 %

Procedure:
A mixture of ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd (PPh3)4 (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (4.6 g) as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6]2.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6]2
Reactant: CCOC(=O)C1Cc2ccc(OC)c(C)c2C1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1Cc2ccc(O)c(C)c2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of ethyl 5-methoxy-4-methylindane-2-carboxylate (896 mg, 3.82 mmol, from Step B) in dichloromethane (10 mL) cooled to 0° C., BBr3 (1.0 M in CH2Cl2, 19.1 mL, 19.1 mmol) was added dropwise. The reaction mixture was stirred for 30 min at 0° C. and warmed to ambient temperature. After 2 hr, the reaction mixture was slowly transferred to an ice-old solution of methanol (10 mL). The resulting solution was warmed to ambient temperature, concentrated in vacuo, and azeotroped with methanol (2×5 mL). The residue was partitioned between EtOAc (15 mL) and sat. NaH2PO4 (5 mL). The layers were separated, and the EtOAc layer was washed with H2O (1×5 mL), brine (1×5 mL) and dried (MgSO4). The mixture was filtered, concentrated in vacuo and purified by flash chromatography (10, 20% EtOAc/hexanes) on SiO2 to afford 560 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 2.15 (s, 3H), 3.13-3.22 (m, 4H), 3.35 (quintet, 1H, J=8.6 Hz), 3.73, (s, 3H), 4.66 (s, 1H), 6.61 (d, 1H, J=8.1 Hz), 6.89 (d, 1H, J=8.1 Hz).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[C:18]1([N:24]2[CH2:29][CH2:28][CH:27]([C:30](=O)[CH2:31][C:32]#[N:33])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:31]([C:32]#[N:33])=[C:30]([CH:27]4[CH2:26][CH2:25][N:24]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:29][CH2:28]4)[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CCC(=O)C1CCN(c2ccccc2)CC1
Reactant: O=Cc1cccc2nonc12
Reactant: Nc1cc[nH]n1
Solvent: CC#N
Product: N#CC1=C(C2CCN(c3ccccc3)CC2)Nc2n[nH]cc2C1c1cccc2nonc12
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of ethyl isonipecotate (8.9 g) in CH2Cl2 (500 mL) was added triphenyl bismus (25 g) and Copper(II)acetate (10.3 g) at room temperature, the mixture was stirred overnight. After filteration, the mixture was extracted with CH2Cl2. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) as colorless crystals. To a solution of acetonitrile (1.9 g) in THF (200 mL) was added n-BuLi (41 mmol) at −78° C. Further, ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-phenylpiperidin-4-yl)-2-cyanoethan-1-one (2.0 g) as colorless crystals. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.2 g) and 1-(1-phenylpiperidin-4-yl)-2-cyanoethan-1-one (0.5 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([P:15](Cl)Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[OH-].[NH4+]>CCOCC.O>[CH:1]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: ClP(Cl)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: c1ccc(P(c2ccccc2)C2CCCCC2)cc1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
154 ml of a 1.72 Molar titrated solution of 0.266 mole of cyclohexylmagnesium chloride in ether was added dropwise to a stirred solution of 47.54 g (0.2656 mole) of phenyldichlorophosphine in 400 ml of anhydrous ether, maintained at +10° C. under an inert atmosphere. After the addition was complete the mixture was stirred for 15 minutes at +10° C. A 2.0 Molar solution of 0.319 mole of phenylmagnesium bromide in 159 ml of ether was then added dropwise at a temperature of between +10° and +22° C. The mixture was warmed to reflux for one-half hour, then cooled to +6° C. and treated dropwise with 160 ml of water then 14 ml of concentrated hydrochloric acid. The mixture was made basic with 10 ml of concentrated ammonium hydroxide (to pH=9) and the ether phase was separated, dried with magnesium sulfate and concentrated to yield a yellow waxy solid. Recrystallization from ethanol gave cyclohexyldiphenylphosphine. MP=52.5°-57.5° C., 31P-NMR δ=-1.97 ppm (relative intensity 999.93) and δ=-1.25 ppm (dicyclohexylphenylphosphine impurity-relative intensity=13.25), Yield=about 70%.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:29])=[CH:26][CH:25]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccccc2)C(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.60 g, 5.69 mmol) and 4-methoxybenzoyl chloride (1.16 g, 6.82 mmol) in chloroform (20 ml) was added triethylamine (0.87 ml, 6.26 mmol) and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. Water (30 ml) was added into the residue and the product was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and an aqueous, saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from methanol to obtain 1.70 g (72% yield) of the title compound. Melting point: 190-192° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1CCN2C(=NCCC2)CC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=CCC1
Yield: 91.7 %

Procedure:
Heat a solution of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.69 mol, 193 g) in DBU (400 mL) at 80° C. for 16 h. Dilute the reaction mixture with water, extract with diethyl ether, and wash the organic layer with 1 N hydrochloric acid and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (116 g, 92%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 2.12 (br s, 2H), 3.47 (t, 2H), 3.87 (s, 2H), 5.65 (br s, 1H), 5.81 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=[C:3]1[C:14]([O:16][CH3:17])=[O:15].[H-].[Na+].[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]N)=[CH:24][CH:23]=1)#[N:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:7]2[C:2](=[O:1])[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]2=3)=[CH:24][CH:23]=1)#[N:21]
Reactant: COC(=O)c1cc2c([nH]c1=O)CCCCCC2
Reactant: N#Cc1ccc(CN)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(n(Cc3ccc(C#N)cc3)c1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under the nitrogen gas atmosphere, methyl 2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylate (300 mg, 1.27 mmol) was dissolved in DMF (5 mL), sodium hydride (61 mg, 1.53 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After that, 4-cyanobenzylamine (274.9 mg, 1.40 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. Subsequently, water and 5% citric acid were added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was refined with silica gel (10 g) column chromatography (ethyl acetate-hexane of 1:1 in mixing ratio), and colorless solid of methyl 1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylate (AA04, 100 mg, 22%, mp: 72-75° C.) and colorless solid of methyl 2-(4-cyanophenoxy)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridine-3-carboxylate (123 mg, 28%, mp: 122-123° C.) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[N:20][C:19]([C:22]([O:24]C)=O)=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[NH3:26]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[N:20][C:19]([C:22]([NH2:26])=[O:24])=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncn(Cc2cnc(OC)c(-c3cccc(Cl)c3)c2)n1
Reactant: N
Solvent: CO
Product: COc1ncc(Cn2cnc(C(N)=O)n2)cc1-c1cccc(Cl)c1
Yield: 77 %

Procedure:
To a solution of methyl 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (Example 141, 103 mg, 0.28 mmol) in methanol (2 mL) was added ammonia in methanol (2 mL of 7N solution, 14 mmol). The mixture was heated using microwave irradiation at 130° C. for 20 min. The LC/MS showed incomplete conversion. To the reaction mixture was added more ammonia in methanol (2 mL, 14 mmol) and irradiated in a microwave at 120° C. for an additional 20 min. The solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-5% MeOH/DCM) afforded the title compound (77 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.78-7.70 (m, 1H), 7.62-7.40 (m, 5H), 5.45 (s, 2H), 3.87 (s, 3H). [M+H]=354.18.
Reaction SMILES: [CH2:1]([C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:11][O:12][CH3:13])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.C(N(CC)CC)C.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C)C=O.O>[CH2:14]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:9][O:10][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:11][O:12][CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCC(CO)(Cc1ccccc1)Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCC(CO[Si](C)(C)C(C)(C)C)(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4.16 Mmol of 2,2-dibenzyl-3-methoxy-1-propanol was dissolved in 10 ml of N,N-dimethyl formamide, and 0.14 g (2.08 mmol) of imidazole was added thereto. The solution was cooled in ice-water bath to below 5° C., and 0.87 ml (6.24 mmol) of triethyl amine was added thereto. After stirring for 5 minutes, 0.88 g (5.82 mmol) of tert-butyldimethylsilyl chloride in 10 ml of N,N-dimethyl formamide was slowly added to the reaction mixture, and the mixture was stirred in ice-water bath for further 2 hours, and at room temperature for further 1 hour. The reaction mixture was diluted with 10 ml of water, and extracted using 30 ml of dichloromethane. The organic layer was separated, wished twice with 20 ml of water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 2,2-dibenzyl-1-methoxy-3-[(tert-butyldimethylsilyl)oxy]propane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]#[N:26])=[CH:7]2.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccc(Cl)c23)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3cccc(Cl)c23)C1

Procedure:
To (S)-tert-butyl 3-((8-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (120 mg, 0.32 mmol) in MeOH (50 mL) was added NH2NH2—H2O (5 mL). The resulting mixture was heated to reflux for 2 hours and then cooled and concentrated in vacuo to give the title compound as a yellow solid, which was used without further purification (130.3 mg, 100%). ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:32])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CC(CN1CC=CC1)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(CN1CC=CC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarbonitrile, L series (12.57 g) and triethylamine (5.5 cc) in pyridine (115 cc) is treated with hydrogen sulphide by bubbling in for 2 hours. After 16 hours' stirring at a temperature in the region of 25° C., the light brown solution obtained is purged with nitrogen for 2 hours, diluted with ethyl acetate (300 cc), washed with distilled water (10×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The yellow product (13.3 g) of meringue-like consistency is purified by chromatography on a column (height: 47 cm; diameter: 3.8 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with ethyl acetate (2 liters) and collecting 125-cc fractions. Fractions 4 to 10 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (10.6 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1>>[CH2:13]([C:7]1([CH2:15][CH3:16])[C:6]2[CH:17]=[C:2]([NH:1][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=3)[CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9](=[O:12])[O:8]1)[CH3:14]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: N#Cc1ccc(Br)cc1F
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(C#N)c(F)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromo-2-fluorobenzonitrile according to the coupling procedure described in example 2. 1H NMR (DMSO-d6): δ 9.15 (s, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.24 (dd, J=8.6, 2.3 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.76 (m, 2H), 3.29 (s, 3H), 1.99 (m, 4H), 0.81 (t, J=7.3 Hz, 6H); MS (ESI) m/z 354 ([M+H]+); MS (ESI) m/z 352 ([M−H]−); Anal. calcd for C20H20FN3O2: C, 67.97; H, 5.70; N, 11.89. Found: C, 67.09; H, 5.64; N, 11.53.