Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:7][C:8]1[CH:13]=[C:12]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[Cl:1])[N:11]=[CH:10][N:9]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Clc1ncc[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(-n2ccnc2Cl)ncn1
Temperature: 120 °C
Yield: 60.5 %

Procedure:
2-Chloro-1H-imidazole (2.0 g, 20 mmol), 4,6-dichloropyrimidine (6 g, 40 mmol) and DIEA (10.4 ml, 60 mmol) were mixed in 40 mL butanol and refluxed at 120° C. for 24 hours. The solvent was removed by rotary evaporation. The crude product was purified by flash chromatography on silica gel (0% EtOAc/hexanes to 20% EtOAc/hexanes gradient), afforded the title compound (2.6 g, 62% yield) as yellow solid. Rf=0.25 (20% EtOAc/hexanes); 1H NMR 400 MHz (DMSO-d6) δ 9.13 (s, 1H), 8.17 (s, 1H), 7.94 (d, 1H), 7.17 (d, 1 H); MS m/z 215.4 (M+1).
Reaction SMILES: C=O.[F:3][C:4]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=3)=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7].[CH2:36](Cl)Cl.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O>[F:3][C:4]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH2:19][CH2:20][N:21]([CH3:36])[CH2:22][CH:23]=3)=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7]
Reactant: ClCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4=CCNCC4)c3c2)c1F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4=CCN(C)CC4)c3c2)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
37% Aqueous formaldehyde (100 μL) was added to a solution of 2,6-difluoro-3-(propylsulfonamido)-N-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (22 mg, 0.046 mmol) in 5:1 CH2Cl2/MeOH (6 mL), followed by a drop of AcOH. After 5 minutes, sodium triacetoxyborohydride (49 mg, 5 equiv) was added, and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was quenched with MeOH, concentrated, and purified by silica gel chromatography (10:90:1 MeOH/CHCl3/NH4OH) to afford 2,6-difluoro-N-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide as a white solid (14 mg, 62%). 1H NMR (400 MHz, CD3OD) δ 8.90-8.88 (m, 1H), 8.62-8.60 (m, 1H), 7.70-7.63 (m, 1H), 7.17-7.11 (m, 1H), 6.57-6.53 (m, 1H), 3.35-3.31 (m, 2H), 3.14-3.09 (m, 2H), 2.90-2.83 (m, 4H), 2.49 (s, 3H), 1.92-1.82 (m, 2H), 1.08-1.04 (m, 3H); m/z (APCI-pos) M+1=491.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH:15]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([C:22]([F:32])([F:21])[F:31])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH:15]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: OC1CCC(N2CCc3[nH]c4ccc(Cl)cc4c3C2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: OC1CCC(N2CCc3c(c4cc(Cl)ccc4n3CCc3ccc(C(F)(F)F)nc3)C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(8-chloro-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)cyclopentanol (300 mg, 1.03 mmol), 2-trifluoromethyl-5-vinylpyridine (140 mg, 0.809 mmol) and potassium hydroxide (310 mg, 5.5 mmol) in 0.6 ml of NMP was heated to 60 deg C. for 2 h. The reaction mass was cooled at RT and diluted with 20 ml of ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate and concentrated under vacuum. It was purified on 230-400 silica gel (flash) deactivated with triethylamine using ethyl acetate/methanol (5-10%) as eluant, followed by isolation of 3-(8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)cyclopentanol by PREP HPLC. Yield: 70 mg as TFA salt.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1.CC[C@@H]([C@H](NCN[C:36]([O:38][CH2:39]C)=O)C(O)=O)C.C=O.C(OCC)(=O)C>CO>[Cl:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][C:12]1[S:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([NH:1][CH2:36][O:38][CH3:39])=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(=O)NCc2ccc(Cc3cccc(Cl)c3)s2)cn1
Reactant: CCOC(=O)NCN[C@H](C(=O)O)[C@@H](C)CC
Agent: C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COCNc1ccc(C(=O)NCc2ccc(Cc3cccc(Cl)c3)s2)cn1
Yield: 54 %

Procedure:
To a solution of 6-amino-N-(5-(3-chloro-benzyl)-thiophen-2-ylmethyl)-nicotinamide described in Example A-145 (110 mg, 0.3 mmol) in methanol (10 mL) were added 5,5-dimethylimidazo phospho-2,4-dione (43 mg, 0.33 mmol) and an aqueous solution of 37% formaldehyde (0.5 mL), and the solution was stirred under reflux for 2 hours. NH silica gel was added to the reaction solution, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate), and the title compound (65 mg, 0.16 mmol, 54%) was obtained as a slightly yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21](Cl)[N:20]=[C:19]([C:34]#[N:35])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]1[C:39]2([CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]2)[CH2:38]1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([NH:46][CH2:45][CH:42]3[CH2:43][CH2:44][C:39]4([CH2:37][CH2:38]4)[CH2:40][CH2:41]3)[N:20]=[C:19]([C:34]#[N:35])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC1CCC2(CC1)CC2
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(Cl)c2C(=O)NCc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CC3)CC4)c2C(=O)NCc2ccccc2)CC1
Temperature: 70 °C

Procedure:
To a solution of 4-[2-(5-benzylcarbamoyl-6-chloro-2-cyanopyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (0.23 mmol) in CH3CN (5 mL), C-spiro[2.5]oct-6-yl-methylamine hydrochloride (0.25 mmol) and K2CO3 (0.7 mmol) are added at room temperature. After warmed up to 70° C., the reaction mixture is stirred over night. The mixture is diluted with H2O and AcOEt, and extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated to give 4-(2-{5-benzylcarbamoyl-2-cyano-6-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester as a white solid; 1H-NMR (CDCl3), δ 0.17-0.30 (4H, m), 0.89-1.06 (4H, m), 1.14-1.38 (3H, m), 1.46 (9H, s), 1.49-1.79 (9H, m), 2.51 (2H, br t), 3.42 (2H, t), 4.00 (2H, m), 4.45 (2H, t), 4.55 (2H, d), 7.30-7.39 (5H, m), 8.12 (1H, t), 10.16 (1H, t).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
A solution of N4-(tert-butyloxycarbonyl)-3,4-pyridine-diamine (500 mg, 2.40 mmol) and pyridine (0.213 mL, 2.63 mmol) in methylene chloride (12 mL) was treated with p-anisoyl chloride (408 mg, 2.40 mmol). After 0.75 hr, the mixture was poured into a mixture of ethyl acetate and 1 N aqueous sodium hydroxide. The organic layer was washed with saturated sodium chloride, dried (magnesium sulfate), and filtered. Concentration in vacuo and recrystallization of the residue, followed by flash chromatography (silica gel, hexanes/ethyl acetate) yielded 500 mg (60%) of the title compound.
Reaction SMILES: C([N:4]([CH:7](C)C)[CH2:5][CH3:6])(C)C.[CH2:10]([NH:14][C:15]1[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:18]=C(Cl)[N:16]=1)[CH2:11][CH2:12][CH3:13].[CH3:27][C:28](N(C)C)=O>>[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].[CH2:10]([NH:14][C:15]1[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:18]=[C:7]([NH:4][CH2:5][CH2:6][CH2:27][CH3:28])[N:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CC(=O)N(C)C
Reactant: CCCCNc1nc(Cl)nc(NCCCC)n1
Reactant: CCN(C(C)C)C(C)C
Product: CCCCN
Product: CCCCNc1nc(NCCCC)nc(NCCCC)n1
Temperature: 0 °C

Procedure:
A solution of 150 millimoles of n-butylamine in 50 ml of dimethylacetamide was prepared and cooled to 0° C. To this solution was added at 0° C. a solution of 250 millimoles of diisopropylethylamine and 50 millimoles of N,N′-dibutyl-6-chloro-[1,3,5]triazine-2,4-diamine in 50 ml of dimethylacetamide, the resulting solution was heated under reflux for 4 hours, then cooled to room temperature, and the solvent was distilled off by an evaporator. The reaction mixture was then isolated and purified by silica gel column chromatography to give N,N′,N″-tributyl-[1,3,5]triazine-2,4,6-triamine as an oily substance. The result of 1H-NMR analysis is shown in FIG. 1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][O:9][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[N:6]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1nc(CCO)c(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(CCOc2ccc([N+](=O)[O-])cc2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
2-(2,5-Dimethyl-4-oxazolyl)ethanol (17.0 g) and 4-fluoronitrobenzene (17.0 g) were dissolved in N,N-dimethylformamide (150 ml), and 60% sodium hydride in oil (6.0 g) was added dropwise to the solution under vigorous stirring. After stirring at room temperature for 1 hour, the reaction mixture was poured into water (1 l) and the crystals which separated out were collected by filtration and recrystallized from ethyl acetate-hexane to give 4-[2-(2,5-dimethyl-4-oxazolyl)ethoxy]nitrobenzene (27.5 g. 87.0%). Colorless columns, m.p. 97°-98° C. Elemental analysis for C13H14N2O4, Calcd.: C, 59.94; H, 5.38; N, 10.68. Found: C, 59.72; H, 5.44; N, 10.63.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:27][CH:26]3[CH:22]([N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25]3)[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:42]>C(Cl)Cl.CCOCC>[ClH:42].[Br:1][C:2]1[C:3]([N:20]2[CH2:27][CH:26]3[CH:22]([NH:23][CH2:24][CH2:25]3)[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CN(c3c(Br)cnc4[nH]cc(NC(=O)c5cccnc5)c34)CC21
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(N3CC4CCNC4C3)c12)c1cccnc1
Yield: 28 %

Procedure:
A solution of tert-butyl 5-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (0.070 g, 0.13 mmol) in DCM (3 mL) was treated with TFA (1 mL) followed by 1M HCl in ether as described in Example 62, Step C, to provide N-(5-bromo-4-(hexahydropyrrolo [3,4-b]pyrrol-5(1H)-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)nicotinamide hydrochloride (20 mg, 28% yield). 1H NMR (400 MHz, D2O) δ 9.15 (s, 1H), 8.84-8.83 (m, 1H), 8.78-8.75 (m, 1H), 8.24 (s, 1H), 8.00-7.96 (m, 1H), 7.43 (s, 1H), 4.15-4.11 (m, 1H), 3.97-3.92 (m, 1H), 3.73-3.69 (m, 1H), 3.65-3.61 (m, 1H), 3.54-3.50 (m, 1H), 3.27-3.23 (m, 2H), 2.91-2.87 (m, 1H), 2.00-2.94 (m, 1H), 1.88-1.86 (m, 1H); LCMS (APCI+) m/z 427, 429 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([N:18]2[CH2:23][CH2:22][C:21]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=3)([CH2:24][CH2:25][N:26]3[C@H:31]4[CH2:32][CH2:33][C@@H:27]3[CH2:28][CH:29]([N:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[N:36]=[C:35]3[CH3:43])[CH2:30]4)[CH2:20][CH2:19]2)[C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH:7]([N:18]2[CH2:23][CH2:22][C:21]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=3)([CH2:24][CH2:25][N:26]3[C@H:27]4[CH2:33][CH2:32][C@@H:31]3[CH2:30][CH:29]([N:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[N:36]=[C:35]3[CH3:43])[CH2:28]4)[CH2:20][CH2:19]2)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(=O)OCc2ccccc2)C2CCCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(=O)O)C2CCCCC2)CC1
Yield: 85.2 %

Procedure:
A solution of benzyl cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetate (23.8 mg, 0.035 mmol) in 3 mL MeOH was stirred for 3 h under an atmospheric pressure of hydrogen and in the presence of catalytic 5% Pd/C. Filtration and evaporation afforded cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetic acid (17.5 mg, 85%). ESI-MS 585 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(/C=C/c2ccc(F)cc2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(/C=C/c3ccc(F)cc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of (E)-4-[2-(4-fluoro-phenyl)-vinyl]-phenylamine with itaconic acid yields the (RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid which was directly engaged in the next step without further purification and characterisation.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:25][CH2:26][N:27]([C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[O:8])[CH2:28][CH2:29]2)[N:19]=1
Reactant: COc1ccnc(N2CCNCC2)n1
Reactant: O=C(O)c1ccsc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccnc(N2CCN(C(=O)c3ccsc3)CC2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
To a solution of 1.0 g (7.81 mmol) of 3-thienylcarboxylic acid and 1 mL (7.86 mmol) of triethylamine in 30 mL of CH2Cl2 cooled to 0° C. 0.84 g (7.81 mmol) of ethyl chloroformiate are added. The mixture is maintained at 0° C. for 20 minutes and then 1.5 g (7.81 mmol) of 4-methoxy-2-(1-piperazinyl) pyrimidine dissolved in 10 mL of CH2Cl2 are added to the solution. The temperature is allowed to rise to room temperature and the solution continually stirred for 2 hours and the organic phase is washed with H2O, dried over NaSO4 and the solvent evaporated off under reduced pressure. The resulting oil is treated with ethyl ether to yield a solid which is recrystallised from ethanol/H2O to give 0.8 g (2.63 mmol) of 4-methoxy-2-[4-(3-thienylcarbonyl)-1-piperazinyl]pyrimidine. m.p.=90-92° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:34][CH2:35][O:36]C1CCCCO1.CO>O>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:34][CH2:35][OH:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: BrCCOC1CCCCO1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: OCCN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 142, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2-(2-bromo-ethoxy)-tetrahydro-pyran, the crude product subjected to reverse phase HPLC (Gemini C18 column, gradient 10 to 90% MeOH in water+0.1% HCO2H) to give 201 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.41 (s, 1H); 8.28 (s, 1H); 8.16 (s, 1H); 7.80 (td, J=8.75, 5.92 Hz, 1H); 7.62 (ddd, J=10.34, 9.02, 2.81 Hz, 1H); 7.37-7.31 (m, 1H); 7.28 (d, J=8.17 Hz, 1H); 6.95 (d, J=1.73 Hz, 1H); 6.89 (dd, J=8.25, 1.81 Hz, 1H); 4.22 (t, J=5.03 Hz, 2H); 3.69 (t, J=7.37 Hz, 2H); 3.60 (dt, J=15.08, 7.40 Hz, 1H); 3.39 (t, J=6.62 Hz, 1H); 3.23 (t, J=7.74 Hz, 2H); 3.14 (s, 2H); 3.05 (t, J=5.14 Hz, 2H); 2.61 (t, J=5.95 Hz, 2H). LCMS: RT=7.11 min, M+H+=465
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18].C([Li])CCC.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C1COCC1.CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: C#CCCCCCCCCCOC1CCCCO1
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCCCC#CCCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
5 g (0.0198 mol) of 11-tetrahydropyranyloxyundecyne of Example 7 were placed in a mixture of 50 ml of THF and 25 ml of hexamethylphosphoric triamide under an argon atmosphere. At -60° C., 12.4 ml (0.0198 mol) of n-butyllithium in hexane were added dropwise. After 30 min at -60° C., a solution of 9.0 g (0.0248 mol) of 1-bromoeicosane in 25 ml of THF was added dropwise at -60° C. The mixture was left to warm up to room temperature. After 18 h at room temperature, it was poured into 25% aqueous NaH2PO4 solution and extracted with n-heptane (3×). The combined organic phases were dried (Na2SO4) and the solvent was removed. Flash chromatography on silica gel (n-heptane/ethyl acetate =15:1) gave 6.5 g (61.3% of theory) of 1-tetrahydropyranyloxy-hentriacont-10-yne.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:12][CH2:11][CH2:10][NH2:13])=[CH:4][N:3]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: NCCN
Solvent: CC#N
Product: NCCNCc1ccc(Br)nc1
Temperature: 25 °C
Yield: 96 %

Procedure:
2-bromo-5-pyridylmethyl bromide (25 g) in a solution of acentonitrile was added dropwise to a solution of ethylenediamine (30 g) in acetonitrile (80 ml) at 0° C. After the reaction was stirred at room temperature for some time, the produced insoluble salts were filtrated off and then the filtrate was concentrated on a water bath at 40° C. to give N-(2-bromo-5-pyridylmethyl)ethylenediamine (22 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])=S)=[CH:5][S:4][CH:3]=1.[OH-].[Na+].C1(C)C=CC(S([Cl:30])(=O)=O)=CC=1>>[ClH:30].[CH3:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=1[NH:10][C:8]1[NH:7][C:6]2=[CH:5][S:4][CH:3]=[C:2]2[N:1]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C)c1NC(=S)Nc1cscc1N
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C)c1Nc1nc2cscc2[nH]1
Product: Cl

Procedure:
was obtained in a similar manner to the method specified in Example 6b from 380 mg of N-(3-amino-4-thienyl)-N′-(2,6-dimethylphenyl)thiourea, 135.4 mg of NaOH and 287.3 mg of p-toluenesulfonyl chloride. Crystalline substance. M.p. >310° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[Br:13].CS(C)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCC.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][C:11]([F:17])([F:16])[C:12]([Br:13])([F:15])[F:14])[CH:3]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Oc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: Fc1cc(Br)cc(OC(F)(F)C(F)(F)Br)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a flame dried, 1 L, three necked round bottom flask (1 L) equipped with a temperature controller, a mechanical stirrer, a condenser and a N2 inlet was charged 3-bromo-5-fluorophenol (57.3 g, 300 mmol), 1,2-dibromotetrafluoroethane (156.0 g, 600 mmol), dry DMSO (300 mL) and Cs2CO3 (146.6 g, 450 mmol) under N2. The reaction mixture was heated to 50° C. for 5 h. After cooling to rt, water (300 mL) and hexane (300 mL) were added. The resulting mixture was stirred at rt for 30 min. The organic phase was separated and the aqueous layer was extracted with hexane (300 mL). The combined organic extracts were washed with water (500 mL), sat. NaCl (500 mL), dried over MgSO4, filtered and concentrated in vacuo to give 1-bromo-3-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-fluorobenzene (104.2 g, 94% yield) containing 5% of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (5.2 g). 1-Bromo-3-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-fluorobenzene: 1H NMR (300 MHz, CDCl3) δ 6.91-6.94 (m, 1H), 7.18-7.23 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[Cl:17]Cl>C(O)(=O)C>[Cl:17][C:3]1[C:4]2[C:5](=[O:16])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:14]=[CH:15][C:2]=1[OH:1]
Reactant: O=c1c2ccccc2[nH]c2ccc(O)cc12
Reactant: ClCl
Solvent: CC(=O)O
Product: O=c1c2ccccc2[nH]c2ccc(O)c(Cl)c12
Temperature: 15 °C
Reaction time: 8 h

Procedure:
2-Hydroxyacridone (3.17 grams; 0.015 mole) and acetic acid were charged into a glass reaction vessel equipped with a stirrer and thermometer. The mixture was cooled to 15° C. and a solution of chlorine (0.015 mole) in acetic acid (2.5 ml) was added dropwise with stirring. After the addition was completed stirring was continued at room temperature overnight. After this time the reaction mixture was filtered to recover product. The product was then washed, dried and dissolved in tetrahydrofuran (50 ml). The solution was treated with triethylamine (2 ml). The treated solution was then filtered and the filtrate treated with activated charcoal. The filtrate was then stripped of solvent in a rotary evaporator to yield chloro-2-hydroxyacridone m.p. 184°-191° C.