Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17](=[CH:21][N:22](C)[CH3:23])[C:18](=O)[CH3:19])=[CH:11][N:10]=3)[N:7]=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(=O)C.C(N)=[NH:35].CC[O-].[Na+]>C(O)C>[CH:1]1([C:4]2[N:8]([C:9]3[N:10]=[CH:11][C:12]([NH:15][C:16]([C:17]4[C:18]([CH3:19])=[N:35][CH:23]=[N:22][CH:21]=4)=[O:25])=[CH:13][N:14]=3)[N:7]=[C:6]([C:26]([F:27])([F:28])[F:29])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)C(=CN(C)C)C(=O)Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ncncc1C(=O)Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Yield: 4 %

Procedure:
N-{2-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-5-yl}-2-[(dimethylamino)methylene]-3-oxobutanamide (0.3 g, 0.78 mmol) and formamidine acetate (98 mg, 0.94 mmol) were dissolved in ethanol and added NaOEt (60 mg, 0.94 mmol). The above mixture was refluxed for 3 h. Ethanol was removed on rotavapour and worked up (H2O/AcOEt) to obtain the crude. Crude was purified by column on 60-120 mesh silica gel using AcOEt and Petether (1:1) as eluent to obtain the title compound (12 mg) as a brown solid. M.P.: 201-203° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.29 (s, 1H), 9.26 (s, 2H), 9.19 (s, 1H), 8.99 (s, 1H), 6.68 (s, 1H), 2.64 (s, 3H), 2.55-2.49 (m, 1H), 1.02-0.94 (m, 2H), 0.83-0.75 (m, 2H). MS (m/z): 389.93 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=1)=O.[Sn](Cl)(Cl)(Cl)Cl.O.O>Cl.C(O)C>[S:6]1[C:5]2[C:3](=[O:2])[NH:17][C:16]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7]1
Reactant: COC(=O)c1sccc1Nc1ncccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: O=C1Nc2cccnc2Nc2ccsc21
Temperature: 25 °C
Yield: 56.4 %

Procedure:
3-(3-Nitropyridin-2-yl)aminothiophene-2-carboxylic acid methylester (14.6 g) is added to a suspension of dihydrate tin chloride (64 g) in conc. HCl (210 ml) and ethanol (235 ml). The reaction mixture is refluxed for 2 hours obtaining the gradual dissolution of the reagents and subsequent precipitation of a solid. After cooling at the room temperature, the solid is filtered and triturated with a saturated solution of NaHCO3, filtered, washed with H2O and dried to give 6.4 g (56%) of the title product, melting at 273°-279° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[C:2](=[C:4](\[CH:6]=O)/[Br:5])/Br.S(O)(O)(=O)=O.[CH3:15][S:16][C:17](=[NH:19])[NH2:18].C(N(CC)CC)C.C>O>[Br:5][C:4]1[C:2]([C:1]([OH:9])=[O:8])=[N:18][C:17]([S:16][CH3:15])=[N:19][CH:6]=1
Reactant: CSC(=N)N
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1ncc(Br)c(C(=O)O)n1
Reaction time: 24 h
Yield: 59.1 %

Procedure:
Mucobromic acid (58.05 g, 0.225 mol) was added to a stirred solution of 2-methyl-2-thio-pseudourea sulfate (62.66 g, 0.225 mol) in water (500 mL) at r.t. The suspension was cooled to 10° C. (ice bath) and triethylamine (94.1 mL, 0.675 mol) was added dropwise over 4 h. The reaction mixture was then left to stand at r.t. for 24 h. Activated carbon (Darco G-60) was added to the now dark red/brown solution and after stirring for 10 min the charcoal was filtered off. The filtrate was acidified with concentrated hydrochloric acid (50 mL) and the yellow precipitate was filtered off, washed with water (2×80 mL) and diethyl ether (2×100 mL), and then placed in a vacuum oven at 50° C. for 2 days to yield 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (33.13 g, 59%) as a yellow amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 2.75 (s, 3H), 9.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:5][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:13])[CH3:12]
Reactant: Cc1cccc(C)c1CO
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1c(C)cccc1C
Temperature: 70 °C
Yield: 100.5 %

Procedure:
A mixture of 2,6-dimethylbenzyl alcohol (8.17 g) and acetic anhydride (8.1 g) was heated at 70° C. for 3 hours and evaporated in vacuo. To the residue was added aqueous sodium bicarbonate and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo to give an oil of 2,6-dimethylbenzyl acetate (10.75 g).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH:8]([OH:18])[CH:9]([OH:17])[CH2:10][S:11]([CH2:14][CH2:15]Cl)(=[O:13])=[O:12])(=[O:6])=[O:5].C(N(CC)CC)C>CC(C)=O>[CH:14]([S:11]([CH2:10][CH:9]([OH:17])[CH:8]([OH:18])[CH2:7][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])(=[O:13])=[O:12])=[CH2:15]
Reactant: O=S(=O)(CCCl)CC(O)C(O)CS(=O)(=O)CCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)CC(O)C(O)CS(=O)(=O)C=C
Yield: 84.7 %

Procedure:
11.4 g of 1,4-bis(chloroethylsulfonyl)-2,3-butanediol was dissolved in 300 ml of acetone and the same procedures as described in Synthesis Example 3 were followed using 6.8 g of triethylamine to obtain 7.6 g of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCc3ncc(Br)cc3C)[nH]c2=O)cn1
Yield: 63.3 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine (2.12 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (3.18 g) were refluxed in pyridine (12 ml) for 9.5 hrs. The pyridine was removed in vacuo and the residue was re-evaporated with n-propanol (2×50 ml), triturated with chloroform, filtered and the solution was chromatographed on silica in chloroform-methanol (10:1). The product was crystallised from ethanol-ether to give 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-yl-methyl)-4-pyrimidone (2.44 g) m.p. 151°-152° C.
Reaction SMILES: Br[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:19]12[O:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][NH:21][CH2:20]2>C(#N)C>[CH:23]12[O:26][CH:19]([CH2:25][CH2:24]1)[CH2:20][N:21]([CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:22]2
Reactant: C1CC2CNCC1O2
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)N1CC2CCC(C1)O2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4.72 g (19.8 mmol) of diethyl 2-bromomalonate are introduced into 30 ml of acetonitrile. Then 3.82 g (27.7 mmol) of potassium carbonate and 2.46 g (21.7 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane from step 4 are added. The suspension is stirred at 50° C. overnight. This is followed by filtration with suction and evaporation of the filtrate to dryness in a rotary evaporator. The residue is employed without further purification in the next stage.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:28][C:29]1[CH:45]=[CH:44][C:32]([C:33]2[CH:38]=[C:37]([CH2:39][CH3:40])[C:36]([Pb+3])=[C:35]([CH2:42][CH3:43])[CH:34]=2)=[CH:31][CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]2[CH:34]=[C:35]([CH2:42][CH3:43])[C:36]([CH:4]3[C:5](=[O:10])[C@H:6]4[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]4)[C:3]3=[O:11])=[C:37]([CH2:39][CH3:40])[CH:38]=2)=[CH:44][CH:45]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 12.4 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.20 g, 1.30 mmol) and 4-dimethylamino-pyridine (0.792 g, 6.49 mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4′-Chloro-3,5-diethylbiphen-4-yllead triacetate (0.896 g, 1.43 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×5 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4′-chloro-3,5-diethyl-biphenyl-4-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.064 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:14].[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: BrCCNCCBr
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(N3CCNCC3)ccc2N1
Yield: 50.5 %

Procedure:
A mixture of 9.36 g of 6-amino-3,4-dihydrocarbostyril, 18 g of bis(β-bromoethyl)amine monohydrobromide and 70 ml of methanol was refluxed for 15 hours while stirring. After cooling, 3.06 g of sodium carbonate was added and the resulting mixture was refluxed for 8 hours while stirring. The reaction mixture was cooled to precipitate crystals which then were collected by filtration, the crystals were washed with methanol to give 9.1 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril hydrobromide, m.p. 289°-293° C. (decomp.) (methanol-water), colorless needles.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].[F:31][C:32]([Si](C)(C)C)([F:34])[F:33].Cl>C1COCC1>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]([OH:24])[C:32]([F:34])([F:33])[F:31]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 2-trifluoromethyl-benzaldehyde (1.74 g, 10 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (1.8 ml, 12 mmol) in 10 ml THF at 0° C. The formed mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of 1N HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 2.2 g of 1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethanol, yield 90%.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:7]=2[N:8]=1>C(O)C.[Ni]>[CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:7]=2[N:8]=1
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1nc2cc([N+](=O)[O-])ccc2o1
Agent: [Ni]
Solvent: CCO
Product: CN(CCc1ccc(N)cc1)Cc1nc2cc(N)ccc2o1
Reaction time: 18 h

Procedure:
N-Methyl-N-(5-nitrobenzoxazol-2-ylmethyl)-4-nitrophenethylamine (0.78 g, 2.2 mmole) in ethanol (50 ml) containing Raney nickel (0.1 g) was stirred under a hydrogen atmosphere (50 psi=344.7 kPa) for 18 hours, by which time thin layer chromatographic analysis showed that all the starting material had been consumed [silica chromatography plates using methylene chloride/methanol (19:1) as the solvent]. The reaction mixture was then filtered and evaporated to give an oil which was azeotroped with toluene and triturated with ether. The decanted ether was evaporated to give the title compound as an oil, which was used directly without further purification, yield 0.45 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](Cl)=[S:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[S:30])=[CH:24][CH:23]=1
Reactant: CCN(CCO)CCCCOc1ccc2c(c1)CCN2
Reactant: S=C(Cl)Oc1ccc(Cl)cc1
Product: CCN(CCO)CCCCOc1ccc2c(c1)CCN2C(=S)Oc1ccc(Cl)cc1

Procedure:
In analogy to example 7.8, 2-{[4-(2,3-Dihydro-1H-indol-5-yloxy)-butyl]-ethyl-amino}-ethanol and chloro-thioformic acid (4-chloro-phenyl)ester were converted to yield 5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester as yellow viscous oil, MS: 449 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]>C(O)(C)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:16]([CH3:17])[CH2:15][C:14]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: C/C=C/C(=O)OCC
Solvent: CC(C)O
Product: CCOC(=O)CC(C)N1CCC(Cc2ccccc2)CC1
Yield: 79 %

Procedure:
A solution of 4-benzyl piperidine (0.50 mL, 2.8 mmol) and ethyl crotonate (0.46 mL, 3.4 mmol) in isopropanol (10 mL) was refluxed for 24 h and was concentrated in vacuo. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as solvent to afford the title compound as a pale yellow oil (0.64 g, 74%): 1H NMR (CDCl3) δ1.09 (d, J=6.6 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H), 1.20-1.40 (m, 2H), 1.45-1.61 (m, 1H), 1.68 (bd, J=12.3 Hz, 2H), 2.10-2.35 (m, 3H), 2.57 (d, J=6.9 Hz, 2H), 2.50-2.70 (m, 1H), 2.82 (bd, J=10.8 Hz, 2H), 3.15-3.30 (m, 1H), 4.18 (q, J=6.9 Hz, 2H), 7.18 (d, J=7.2 Hz, 2H), 7.24 (m, 1H), 7.32 (t, J=6.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[C:14]([O:23][CH3:24])[CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[N-:25]([C:28]#[N:29])[C:26]#[N:27].[Na+].CO>CN(C=O)C>[NH2:29][C:28](=[N:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[C:14]([O:23][CH3:24])[CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1)[NH:25][C:26]#[N:27]
Reactant: N#C[N-]C#N
Reactant: COc1cc(NC(=O)Nc2cccc(N)c2)ccc1-c1cnco1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(NC(=O)Nc2cccc(N=C(N)NC#N)c2)ccc1-c1cnco1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
To a solution of 50 mg (0.15 mmol) of 49B in 1 ml of DMF was added excess HCl—ether. A precipitate was obtained. Stirring was continued for 0.5 hr and the slurry was then evaporated to dryness. The residue was diluted with 2 ml of DMF and 40 mg (0.45 mmol) of sodium dicyanamide added. The reaction was heated at 50° C. for 3 hr during which time a lightly cloudy, pale yellow solution was obtained. After removal of the solvent, the residue was diluted with 3 ml of water and stirred for 1 hr. The insolubles were removed by filtration to give 76 mg of the crude product. This material was dissolved into methanol and absorbed onto approx. 1 g of silica gel and subjected to flash chromatography on a 30 cc column of silica gel. Elution with 5% MeOH-EtOAc afforded 9 mg (0.023 mmol, 15%) of 49C as a pale yellow solid. (M+H)+ 392+.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[N:6]=[CH:7][NH:8][C:9]=1[CH2:10][S:11][CH2:12][CH2:13][N:14]=[C:15]=[S:16]>C(O)C>[NH2:2][NH:3][C:15]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:9]1[NH:8][CH:7]=[N:6][C:5]=1[CH3:4])=[S:16]
Reactant: NN
Reactant: Cc1nc[nH]c1CSCCN=C=S
Solvent: O
Solvent: CCO
Product: Cc1nc[nH]c1CSCCNC(=S)NN
Temperature: 25 °C

Procedure:
Hydrazine hydrate (0.01 mole) is added to a solution of 2-(4-methyl-5-imidazolylmethylthio)ethyl isothiocyanate (0.01 mole) in ethanol, and stirred for an hour at room temperature to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[CH3:30][C:31]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:34])[CH2:32][OH:33]>>[CH2:27]([C:19]1[N:18]([C:7]2[N:6]=[C:5]3[C:10]([N:11]=[C:3]([CH2:2][N:38]4[CH2:39][CH2:40][CH:35]([C:31]([CH3:34])([CH3:30])[CH2:32][OH:33])[CH2:36][CH2:37]4)[N:4]3[CH3:29])=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=1)[CH3:28]
Reactant: CC(C)(CO)C1CCNCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure E for amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-methyl-2-(piperidin-4-yl)propan-1-ol were reacted to give 341. LCMS: M+H+=533.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]1[N:14]=[CH:15][NH:16][C:17](=O)[C:6]2=1.O=P(Cl)(Cl)[Cl:21]>O1CCOCC1>[Cl:21][C:17]1[CH:6]2[CH:7]([NH:8][C:9]3[C:5]2=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=3)[N:14]=[CH:15][N:16]=1
Reactant: COc1cc2[nH]c3nc[nH]c(=O)c3c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)C1C(Cl)=NC=NC1N2
Temperature: 0 °C
Reaction time: 36 h
Yield: 773.3 %

Procedure:
A suspension of 6,7-dimethoxy-3H-pyrimido[4,5-b]indol-4(9H)-one 6 (2.8 g), POCl3 (20 mL) and p-dioxane 65 mL was heated at reflux for 6 hrs, then stirred at 25 0° C. for 36 hrs. The obtained mixture was filtered and concentrated. The crude product was purified by column chromatography using 1% MeOH/DCM to give title compound 773.3% (2.2 g) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[NH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[NH:20][N:19]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[N:20]([CH2:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:19]=1
Reactant: COC(=O)c1ccc2[nH]nc(N)c2c1
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)c(N)nn2Cc1cc(Cl)cc2cnn(CC(C)C)c12

Procedure:
A mixture of compound 17 (0.112 g, 0.47 mmol), methyl 3-amino-1H-indazole-5-carboxylate (0.075 g, 0.39 mmol), di-tert-butyl azocarboxylate (0.135 g, 0.59 mmol), triphenylphosphine (0.155 g, 0.59 mmol), in tetrahydrofuran (4 mL) was heated at 140° C. under microwave conditions for 20 minutes. Then, the reaction was quenched by adding water and diluted with ethyl acetate. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent was evaporated. Then, the residue was purified by chromatography column on a 20 g SPE cartridge to give the title compound as a colorless solid. (0.090 g, 56%)
Reaction SMILES: [C:1]1([CH2:6][NH:7][CH2:8][CH:9](O)[C:10]2[C:15]([F:16])=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=2)[S:5][CH:4]=[CH:3][CH:2]=1.N>>[F:16][C:15]1[C:10]([CH:9]2[CH2:8][NH:7][CH2:6][C:1]3[S:5][CH:4]=[CH:3][C:2]2=3)=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=1
Reactant: COc1cc(F)c(C(O)CNCc2cccs2)cc1OC
Agent: N
Product: COc1cc(F)c(C2CNCc3sccc32)cc1OC
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 106.1 %

Procedure:
A mixture of 0.66 g of α-[[(2-thenyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol and 10 ml of polyphosphoric acid was stirred for 3.5 hours at 60° C. The reaction solution was poured into ice water, and the mixture was basified by addition of 25 ml of conc. aqueous ammonia. The mixture was extracted with chloroform, and the chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and 0.66 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]-pyridine was obtained as a syrupy matter.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Cu])#[N:12].[NH4+].[OH-]>CN1C(=O)CCC1>[NH2:12][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(C#N)c(Br)c1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(C#N)c(N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of 2-bromo-4-methylbenzonitrile (2.0 g, 10.7 mmol) and CuCN (1.92 g, 21.4 mmol) in NMP (10 mL) was reacted in a microwave for 20 min at 200° C. Upon completion the reaction was cooled to 0° C., and 15% aqueous NH4OH (215 mL) was slowly added. The mixture was stirred at rt for 30 min, then extracted with CH2Cl2. The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (3:1 Hexane:EtOAc) to provide 2-amino-4-methylbenzonitrile (1.24 g, 88%). 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 3H), 5.70 (m, 1H), 5.84 (m, 1H), 6.41 (d, J=8.0 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[N:17]=1.O>CN(C=O)C>[Cl:23][C:18]1[CH:19]=[C:20]([Cl:22])[N:21]=[C:16]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:12])[N:17]=1
Reactant: FC(F)c1nc2ccccc2[nH]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
0.84 g (5 mmol) of 2-difluoromethylbenzimidazole dissolved in DMF (25 ml) was added and reacted with 60% sodium hydride (0.24 g, 6 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 2,4,6-trichloropyrimidine (0.92 g, 5 mmol) dissolved in DMF (25 ml) and stirred at room temperature for 1.5 hours. The reaction solution was poured into water and the resulting precipitates were recrystallized from methanol to obtain 0.98 g (yield: 62%) of 4,6-dichloro-2-(2-difluoromethylbenzimidazol-1-yl)pyrimidine. (2) 0.32 g (1.0 mmol) of 4,6-dichloro-2-(2-difluoro-methylbenzimidazol-1-yl)pyrimidine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate were added to DMF (10 ml) and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.33 g (yield: 84%) of 4-chloro-2-(2-difluoro-methylbenzimidazol-1-yl)-6-(cis-2,3-dimethylmorpholino)-pyrimidine. (3) 0.33 g (0.8 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-dimethyl-morpholino)pyrimidine dissolved in morpholine (0.70 g, 8.0 mmol) was stirred at 70° C. for 1 hour. The solvent was removed under the reduced pressure from the reaction mixture and the residue was purified by silica gel column chromatography to obtain 0.326 g (yield: 90%) of the titled compound as colorless crystals.