Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][N:24]2[C:28]3[CH:29]=[N:30][C:31]([CH:33]([NH2:35])[CH3:34])=[CH:32][C:27]=3[N:26]=[CH:25]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>CC(C(O)C(C)C)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH:33]([C:31]4[N:30]=[CH:29][C:28]5[N:24]([CH2:23][C:22]6[CH:36]=[CH:37][C:19]([O:18][CH3:17])=[CH:20][CH:21]=6)[CH:25]=[N:26][C:27]=5[CH:32]=4)[CH3:34])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(Cn2cnc3cc(C(C)N)ncc32)cc1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2cnc3cc(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)ncc32)cc1
Temperature: 120 °C
Yield: 39.5 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (167 mg, 0.71 mmol), 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanamine (200 mg, 0.71 mmol), DIPEA (275 mg, 2.31 mmol) in 2,4-dimethylpentan-3-ol (3.0 mL) in a sealed tube was heated at 120° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue purified by SiO2 chromatography eluting with DCM/MeOH (15:1) to 135 mg (61%) to afford 135 mg (56%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethyl)pyrimidine-2,4-diamine as white solid. MS (ESI): m/z=482.2[M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[CH:15][N:16]=2)[N:13]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>CS(C)=O>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:25])([F:27])[F:26])[CH:18]=3)=[CH:15][N:16]=2)[N:13]=1
Reactant: CC(C)(O)CN
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(O)CNc1ccc2ncc(-c3cccc(OC(F)(F)F)c3)n2n1
Temperature: 120 °C
Reaction time: 5 h
Yield: 14.2 %

Procedure:
To the solution of compound 1-amino-2-methylpropan-2-ol (55 mg, 0.57 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (150 mg, 0.48 mmol) in 3 mL DMSO was added DIEA (0.21 mL, 0.96 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120° C., Then the mixture was purified by HPLC to afford the compound 2-methyl-1-((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)propan-2-ol (25 mg, 12%) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[CH2:29](N)CC.CC1C=C(NCC2(C(F)(F)F)CO2)C2C=NN(C3C=CC=CC=3)C=2C=1>>[F:7][C:6]([F:9])([F:8])[C:5]([CH2:4][NH:3][CH2:1][CH2:2][CH3:29])([OH:10])[CH2:11][NH:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: CCCN
Agent: Cc1cc(NCC2(C(F)(F)F)CO2)c2cnn(-c3ccccc3)c2c1
Product: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 18 from n-propylamine and 6-methyl-1-phenyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:26])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[OH:26][CH2:3][CH:2]1[CH2:1][C:4]2=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[C:13]2[O:14]1
Reactant: C=CCc1c(C(=O)OC)ccc([N+](=O)[O-])c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(CO)O2
Reaction time: 24 h
Yield: 86.9 %

Procedure:
Methyl 2-allyl-3-hydroxy-4-nitro-benzoate 1d (0.47 g, 2 mmol) was dissolved in 80 mL of dichloromethane followed by the addition of m-chloroperbenzoic acid (0.99 g, 4 mmol). The reaction solution was stirred for 24 hours. The resulting solution was added with 20 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate solution successively, stirred for 5 minutes and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 2-(hydroxymethyl)-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 40a (440 mg, yield: 87.0%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
4-Chlorobenzenesulfonyl chloride (300 mg, 1.38 mmol) was added to a stirred solution of 8-aminoquinoline (200 mg, 1.38 mmol) in pyridine (2 ml). DMAP (cat.) was added and the reaction was stirred at room temperature for 4 h. After no further progress of the reaction was observed (monitored by TLC and LCMS), water was added and the mixture was extracted with DCM. The organic phase was washed with a sat. KHSO4 solution, dried (Na2SO4) and concentrated in vacuo. The crude residue was triturated with n-hexane to give the title compound (270 mg, 61%).
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[C:12]3[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:26]=2)=[N:6][N:5]=1)=[N+]=[N-]>CO.C1COCC1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][C:4]1[S:8][C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[C:12]3[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[N:26]=2)=[N:6][N:5]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(N=[N+]=[N-])s3)ccc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(N)s3)ccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl 5-(5-azido-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (224 mg, 0.444 mmol) in MeOH/THF (5 mL, 3:2) was added Lindlar catalyst (59.2 mg, 0.222 mmol). The mixture was stirred at RT under hydrogen for 15 h, then filtered through a plug of celite and washed with DCM/MeOH. The filtrated was concentrated to give the crude material. MS (ESI, pos. ion) m/z: 479 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:13]=O)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].Cl>CC(O)=O.CO>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][N:27]1[CH2:26][CH2:25][N:24]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:20]2[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=2)[CH2:29][CH2:28]1)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C[C@@H](CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
(S)-(1-Formyl-3-methyl-butyl)-carbamic acid tert-butyl ester (0.39 mg, 1.8 mmol) and 1-bis(4-fluorophenyl)methyl piperazine (0.50 g, 1.7 mmol) were dissolved in 1% HOAc in methanol (8 mL) under nitrogen atmosphere at ambient temperature. After stirring at that temperature for 1 hour, a solution of sodium cyanoborohydride (250 mg, 3.6 mmol) in methanol was added. The resulting reaction mixture was stirred at ambient temperature for 24 hours at which time TLC showed no starting aldehyde. 3N aqueous HCl was added in 5 mL portions until bubbling subsided; pH was adjusted to 8 with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc (3×25 mL), the combined organic solution was washed with brine (50 mL) and dried over MgSO4. The solution was concentrated in vacuo affording an amber oil. The crude product was further purified by flash chromatography (20%-30% EtOAc in hexanes) affording 342 mg (41%) of the pure titled compound as a clear oil. APCI-MS m/z 488.3 (MH+).
Reaction SMILES: O1CCCC1.C([Sn](CCCC)(CCCC)[C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[CH:12]=1)CCC.[I:39]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[I:39][C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Ic1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
To a tetrahydrofuran solution (15 mL) of 2-(4-(5-tri-n-butylstannyl-isoxazol-3-ylmethyl)-benzyloxy)-pyridine (5.1 g) described in Manufacturing Example 1-8-1 was added iodine (2.5 g) at 0° C. This mixture was stirred at this temperature for 20 minutes. A 10% sodium thiosulfate aqueous solution and ethyl acetate were added to this mixture. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1 to 4:1) to obtain the title compound (2.4 g).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].COCCN(S(F)(F)[F:29])CCOC.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:29][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCCO)COC1(C)C
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1[C@@H](CCCF)COC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl (4S)-4-(3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (3.05 g) in chloroform (40 mL) was cooled in a dry ice-acetone bath, bis(2-methoxyethyl)aminosulfur trifluoride (2.77 mL) was added thereto, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto, and the organic layer was washed with water and brine, followed by drying with anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=10:1-2:1) to afford tert-butyl (4S)-4-(3-fluoropropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (900 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH2:20])=O)=[N:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[CH:6][CH:7]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:18]#[N:20])=[N:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1nc(SCc2cc(F)cc(F)c2)ccc1N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1nc(SCc2cc(F)cc(F)c2)ccc1N
Temperature: 140 °C
Yield: 106.5 %

Procedure:
A mixture of 3-amino-6-(3,5-difluorobenzylthio)picolinamide (2.37 mmol, 0.7 g) and P2Cl5 (9.48 mmol, 1.346 g), 20 ml of toluene and 1 ml of ionic solvent (1-butyl-3-methylimidazolium tetrafluoroborate) are placed in a microwave reactor and then heated at 140° C. for 30 minutes. The crude reaction product is then concentrated under reduced pressure and the orange crystals thus obtained are redissolved in ethyl acetate and washed using saturated aqueous NaHCO3 solution. The organic phase is dried on magnesium sulfate and then concentrated to yield 0.7 g of a brown oil. This crude reaction product is purified by silica gel chromatography (AcOEt/heptane+0.1% of NEt3) to yield, after concentration, 0.15 g (23%) of orange crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](Cl)=[O:40])=[CH:34][CH:33]=1>C1COCC1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([NH:1][C:2]2[CH:10]=[C:9]3[C:5](=[CH:4][CH:3]=2)[CH2:6][O:7][C:8]3=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[O:40])=[CH:34][CH:33]=1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Nc2ccc3c(c2)C(=C2C(=O)Nc4ccccc42)OC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added 4-methoxyphenylacetyl chloride (28.9 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was warmed briefly, stirred 10 min at room temperature, filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (48.3 mg, 62%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[Br:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:15][CH2:16][C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Br:1])=[O:18]
Reactant: O=C(Cl)CBr
Reactant: Nc1ccccc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CBr)Nc1ccccc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a solution of 2-bromoaniline (2.0 g, 11.63 mmol) in 25 mL of dichloromethane was added pyridine (1.13 mL, 13.95 mmol). The solution was cooled to 0° C. and bromoacetyl chloride (1.01 mL, 12.79 mmol) was added over a 5 min. period. The cooling bath was removed and the reaction mixture was stirred at RT for 90 min and partitioned between 1N HCl and dichloromethane. The dichloromethane layer was successively washed with saturated aqueous sodium carbonate, brine, dried over sodium sulfate and concentrated to yield 2.9 g of the title compound, which was used as such for the subsequent step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].CC1C=CC(S(O[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])(=O)=O)=CC=1>CS(C)=O>[OH:1][C:2]1[C:9]([O:10][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1cccc(O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOCCOc1cccc(C#N)c1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a solution of 2,3-dihydroxybenzonitrile (13.5 g, 1 eq.) in DMSO (200 mL) was added NaH (60%, 8 g, 2eq.) and the resulting solution was stirred for 1 h at 60° C. 2-(2-Methoxyethoxy)ethyl 4-methylbenzenesulfonate (20 g, 0.7eq.) in DMSO (100 mL) was added dropwise at 60° C. and stirring was continued for another 1 h. The reaction was quenched by NH4Cl (sat.), the mixture was extracted with EtOAc (300 mL×3) and the combined organic layers were dried over Na2SO4. The solvent was evaporated and the residue was purified by silicon column (EtOAc/PE=1/1) to give the title compound (6 g, 25%).
Reaction SMILES: [CH2:1]1[CH:8]2[NH:9][CH:3]([CH2:4][C:5]([CH2:7]2)=O)[CH2:2]1.Cl.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CC(O)C.CO>[NH:9]1[CH:8]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:17][C:5]=3[CH2:4][CH:3]1[CH2:2][CH2:1]2
Reactant: NNc1ccccc1
Reactant: O=C1CC2CCC(C1)N2
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: c1ccc2c3c([nH]c2c1)CC1CCC3N1
Reaction time: 24 h
Yield: 68.4 %

Procedure:
Method A, A solution of nortropinone hydrochloride (10.0 g, 61.9 mmol) and phenylhydrazine (7.7 g, 71.2 mmol) in 175 mL of 2-propanol was refluxed for 30 minutes, then it was allowed to cool to room temperature, saturated with hydrogen chloride, and heated under reflux for an additional 10 hours. The resulting solution was concentrated under reduced pressure to give a dark residue which was dissolved in methanol. Amberlite IRA-400 resin (pre-washed with methanol) was added until the pH exceeded 10. The mixture was filtered and the filter cake was washed with hot methanol to complete removal of the product from the resin. After the filtrate was treated with decolorizing carbon, it was filtered through a pad a diatomaceous earth and concentrated in vacuo. The residue was suspended in 50 mL of methylene chloride and the mixture was held at -5° C. for 24 hours. Filtration afforded 8.4 g (69%) of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole which was converted into a hydrogen fumarate in ethanol, mp 208°-209° C. (dec); NMR (DMSO-d6) d 1.63 (1H, m), 1.90 (1H, m), 2.15-2.19 (2H, m), 2.68 (1H, d, J=16, 4 Hz), 3.31 (1H, dd, J=16.6, 4 7.28 (1H, d, J=8 Hz), 7.46 (1H, d, J=8 Hz), 11.10 (1H, s).
Reaction SMILES: C[Al](C)C.[CH3:5]CCCCC.CNCCNC.[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:28]=1)[C:22]([O:24]C)=O)#[N:18]>C1(C)C=CC=CC=1.O>[C:22]([C:21]1[CH:20]=[C:19]([CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:26]=1)[C:17]#[N:18])(=[O:24])[CH3:5]
Reactant: COCCOc1cc(C#N)cc(C(=O)OC)c1
Reactant: CCCCCC
Agent: CNCCNC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOc1cc(C#N)cc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
Solution of AlMe3 in hexane (19 mmol) was dropped to the solution of DMEDA (24 mmol) in 60 ml dry toluene slowly at 0° C. under N2. The solution was then continued to stir at room temperature for another 1 h and added methyl 3-cyano-5-(2-methoxyethoxy)benzoate (17.3 mmol) and stirred at reflux for 8 h. The mixture was poured to the water and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated to give 3-acetyl-5-(2-methoxyethoxy)benzonitrile (58.6%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([NH:22][CH3:23])[N:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:24][C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[C:27]([Cl:35])[C:26]=1[N:36]=[C:37]=[O:38].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:28]=[C:27]([Cl:35])[C:26]=1[NH:36][C:37](=[O:38])[N:22]([C:20]1[CH:21]=[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)[N:17]=[CH:18][N:19]=1)[CH3:23]
Reactant: O=C=Nc1c(Cl)ccc(C(F)(F)F)c1Cl
Reactant: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)ccc(C(F)(F)F)c4Cl)ncn3)cc2)CC1
Reaction time: 1.5 h

Procedure:
This oil is re-dissolved in 2 ml of toluene and added portion-wise to a boiling solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (156 mg, 0.50 mmol; Example 145A) in 6 ml of toluene during 10 min. After 1.5 h, another 2 eq of 2,6-dichloro-3-trifluoromethyl-phenylisocyanate are added and stirring is continued for totally 2 h. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/MeOH/NH3aq, 95:5:0.5) gives the title compound: ESI-MS: 568/570 [MH]+; tR=4.1 min (gradient J); TLC: Rf=0.3 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: O.Cl.[CH2:3]([O:5][C:6](=[O:21])[CH:7]([N+:18]([O-])=O)[CH2:8][C:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[S:12][CH:13]=1)[CH3:4]>[Fe].C(O)C>[CH2:3]([O:5][C:6](=[O:21])[CH:7]([NH2:18])[CH2:8][C:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[S:12][CH:13]=1)[CH3:4]
Reactant: CCOC(=O)C(Cc1csc2ccccc12)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(N)Cc1csc2ccccc12
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a mixed solution of 7.5 ml of water, 7.5 ml of ethanol, and 10 ml of 12N hydrochloric acid were added 3.5 g of iron powder and 2.79 g of 3-(benzo[b]thiophen-3-yl)-2-nitropropionic acid ethyl ester and then the reaction was carried out for one hour at room temperature. After filtered away excess iron powder, 200 ml of water was added to the filtrate and after adjusting the pH thereof to from 9 to 10 with sodium hydrogencarbonate, the mixture was extracted thrice with 50 ml of chloroform. The chloroform layer was washed twice with 200 ml of water and then twice with 100 ml of a saturated aqueous sodium chloride solution and after drying with magnesium sulfate, chloroform was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, 10 ml of a solution composed of 1N hydrochloric acid and ethyl acetate, and crystals thus deposited were collected by filtration to provide 1.14 g (yield of 40%) of 2-amino-3-(benzo[b]thiophen-3-yl)propionic acid ethyl ester.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].[C:13]([C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)[N:18]=[CH:17][C:16]=1C(O)=O)#[N:14].C(NC)C>CN(C=O)C>[C:13]([C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)[N:18]=[CH:17][C:16]=1[C:1]([N:8]([CH3:9])[CH2:12][CH3:11])=[O:2])#[N:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1cccc(-n2ncc(C(=O)O)c2C#N)c1
Agent: CCNC
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1cnn(-c2cccc(C#N)c2)c1C#N
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Two grams of carbonyldiimidazole was added to a solution of 2.0 g of 5-cyano-1-(3-cyanophenyl)-1H-pyrazole-4-carboxylic acid dissolved in 50 ml of DMF. The reaction mixture was stirred at room temperature for approximately 25 minutes whereupon 740 mg of N-ethyl-N-methylamine was added. The reaction mixture was allowed to stir for an additional 24 hours at which point the solution was poured into ice water. The precipitate solid was collected by filtration and dried to provide 1.2 g of 5-cyano-1-(3-cyanophenyl)-N-methyl-N-ethyl-1H-pyrazole-4-carboxamide following recrystallization from ethanol. MP=185°-187° C.