Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:23])[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]2[CH:30](O)[CH2:31][CH2:32][C:25]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([O:23][CH:30]2[C:26]3[C:25](=[N:24][CH:29]=[CH:28][CH:27]=3)[CH2:32][CH2:31]2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1
Reactant: OC1CCc2ncccc21
Reactant: CC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3O)n2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3OC3CCc4ncccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
1-(4-(5-(5-Bromo-3-hydroxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (0.083 g, 0.21 mmol), 6,7-dihydro-5H-cyclopenta[b]pyridin-5-ol (0.028 g, 0.21 mmol) and triphenylphosphine (0.057 g, 0.22 mmol) were combined in THF (1 mL) under nitrogen. Diisopropyl azodicarboxylate (0.043 ml, 0.22 mmol) was added in one portion. The reaction stirred at ambient temperature overnight. The solution was diluted with water, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated. Flash chromatography gave 1-(4-(5-(5-bromo-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-5-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (0.022 g, 21%); Mass spectrum (apci) m/z=515.0, 517.0 (M+H).
Reaction SMILES: [Cl:1][C:2]([CH3:16])([CH2:13][CH2:14][CH3:15])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([Cl:11])=[C:7](Cl)[CH:6]=[N:5]1.[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1)[CH3:18].[OH-].[K+]>CN(C)C=O>[Cl:11][C:8]1[C:9](=[O:10])[N:4]([CH2:3][C:2]([Cl:1])([CH3:16])[CH2:13][CH2:14][CH3:15])[N:5]=[CH:6][C:7]=1[O:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=1
Reactant: CCCC(C)(Cl)Cn1ncc(Cl)c(Cl)c1=O
Reactant: CCc1ccc(CO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCC(C)(Cl)Cn1ncc(OCc2ccc(CC)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
In 20 ml of N,N-dimethylformamide were added 1.2 g of 2-(2-chloro-2-methylpentyl)-4,5-dichloro-3(2H)-pyridazinone and 0.64 g of 4-ethylbenzyl alcohol, and thereto was added 0.31 g of powdery potassium hydroxide under ice-cooling and stirred for one day at room temperature. Then, the procedures in Preparation Example 2 were repeated to give 600 mg of the intended compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([S:27][CH2:28][CH2:29]O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:29][CH2:28][S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: OCCSc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCSc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-phenylthioethanol (1.16 g). The mixture was heated at 60° C. for five hours and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl etherhexane to provide 0.5 g of alpha-oxo-4-[[2-(phenylthio)ethyl]oxy]benzeneacetic acid methyl ester, mp 49°-51° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 99.7 %

Procedure:
A mixture of 0.5 g of 4-bromopyrazole and 1.43 g of tritylchloride in 30 ml of pyridine was stirred at reflux for 18 hours. The pyridine was removed in vacuo and the resulting residue was purified by silica column chromatography (ethylacetate/hexane=1:1) to yield 1.32 g of 4-bromo-1-N-tritylpyrazole.
Reaction SMILES: [CH2:1]([N:8](C)[C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH2:10]1)C1C=CC=CC=1.CO>C1COCC1.[Pd]>[CH3:1][NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH2:10]1
Reactant: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(C)Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN[C@H]1CCc2c(cccc2-c2c(C)nn(C)c2C)C1
Reaction time: 16 h
Yield: 91.6 %

Procedure:
A solution of (2S)-benzyl-methyl-[5-(1,3,5-trimethyl-1 H-pyrazol-4-yl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amine (3.70 g, 10.291 mmol) in THF (20 mL) was added to Pd/C (1.20 g, 10% weight of Pd on activated carbon), and MeOH (120 mL) was added to the suspension. The reaction mixture was stirred under H2 overnight (ca. 16 h). It was filtered through Celite washing with AcOEt (2×100 mL) and the solvent was concentrated off to give 2.54 g of the methylamine as pale brown oil. The crude was purified by flash chromatography on silica gel (10-20-60% MeOH/CH2Cl2), to yield 2.05 g of the title product (Rf=0.3 (AcOEt/MeOH/Et3N 20:3:2), pale yellow coloured oil, 74% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][NH:18][C:19]2[N:27]=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:34])[CH:33]=3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:35]([CH3:40])[C:36](OC)=[O:37])=[CH:8]1.O>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][NH:18][C:19]2[N:27]=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:34])[CH:33]=3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:35]([CH3:40])[CH2:36][OH:37])=[CH:8]1
Reactant: COC(=O)C(C)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(-c3cncc(F)c3)nc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(-c3cncc(F)c3)nc21
Temperature: 25 °C

Procedure:
Lithium aluminum hydride (230 mg, 6.1 mmol) was added in portions to a 0° C. solution of methyl 2-(6-(2-(1H-indol-3-yl)ethylamino)-2-(5-fluoropyridin-3-yl)-9H-purin-9-yl)propanoate (282 mg, 0.61 mmol) in anhydrous THF (15 mL). The stirred reaction mixture was allowed to warm to rt over 2 h, then water was added carefully. The mixture was extracted with EtOAc (50 ml×3). The organic fractions were combined, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (0 to 5% solvent B in dichloromethane; solvent B=2M ammonia in methanol) to afford the partially purified title product. This was further purified by preparative TLC (5% solvent B in dichloromethane) to provide the title compound as a white solid.
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:28])[C:6]2[C:11]([C:12](=[O:27])[C:13]=1[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:16][CH2:15]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.O>[NH2:1][C:4]1[C:5](=[O:28])[C:6]2[C:11]([C:12](=[O:27])[C:13]=1[C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: [N-]=[N+]=NC1=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC1=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The impure product of stage (a) (0.9 g) was dissolved in dry tetrahydrofuran (THF) and added dropwise to a suspension of lithium aluminium hydride (2.0 g) in THF. The mixture was stirred at room temperature for 1 hour and then 2.0 ml of water was added dropwise with caution. A current of air was passed through the mixture for 1 hour and then 0.7 g of sodium hydroxide in 6 ml of water was added. The mixture was filtered and washed with THF. The filtrate was evaporated to dryness leaving an amorphous orange material which was triturated with SVM whereupon orange crystals formed. These were filtered off, washed well with SVM and dried to yield a first crop of product (200 mg) mp210°-215°. The reaction was repeated to give a further crop of product (300 mg) mp200°-210°. The two crops were combined and chromatographed, eluting with chloroform, to give the title compound (350 mg) mp212°-215°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)O1.C([O-])(=O)C.[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12
Reactant: Cn1ncc2c(Cl)cc(Cl)nc21
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1ncc2c(Cl)cc(-c3ccc4[nH]ncc4c3)nc21

Procedure:
4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5 (0.180 g, 0.89 mmol) was dissolved in 2 mL dioxane and 2 mL acetonitriile in a microwave tube, and nitrogen was bubbled through the solution. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.217 g, 0.89 mmol) and a 1M solution of potassium acetate (2 mL, 2 mmol) were added. Nitrogen gas was bubbled through the mixture followed by the addition of 5 mole % of tetrakis(triphenylphosphine) palladium (0). The resultant mixture was microwaved at 125° C. for 30 minutes. Purification via Biotage reverse phase system (4:1 ethyl acetate/hexanes) gave 12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.O[NH:22][C:23](=[NH:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](=[O:33])(=[O:32])[NH2:31])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]4[O:19][N:34]=[C:23]([C:24]5[CH:25]=[C:26]([S:30]([NH2:31])(=[O:32])=[O:33])[CH:27]=[CH:28][CH:29]=5)[N:22]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(C(=O)O)cnc12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.33) (143 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (MeOH/diethyl ether) as an off-white solid (152 mg, 65%). MS (EI) 465.1 [(M)+]; mp 301° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.[Na].O>C(O)C>[CH:5]1([NH:4][CH2:3][CH2:1][OH:2])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: O=C1CCCC1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: OCCNC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35181.5 %

Procedure:
A mixture of ethanolamine (4 ml, 0.066 mmol) and cyclopentanone (6.85 ml, 0.08 mmol) in ethanol (60 ml) was stirred at ambient temperature for 30 minutes. The mixture was cooled in ice and then sodium borohydide (3.04 g, 0.08 mmol) was added slowly over 20 minutes. The mixture was stirred for 15 minutes before water (10 ml) was added. The mixture was evaporated under reduced pressure and the residue dissolved in dichloromethane and dried over magnesium sulphate and then evaporated under reduced pressure. The crude product was purified by vacuum distillation to give 2-(cyclopentylamino)ethanol (3 g, 35% yield) as a clear oil:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH2:14]([NH2:16])[CH3:15].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C1COCC1.C(N(CC)CC)C>[CH2:14]([NH:16][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1)[CH3:15]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzoic acid (9.16 g) in DMF (100 ml) were successively added 2M ethylamine in THF solution (30 ml), triethylamine (8.3 ml), HOBt (9.19 g) and WSC (11.5 g), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, ethyl acetate and 1N hydrochloric acid were added to the residue and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (10.6 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][NH:30]2.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.N#N>O1CCOCC1>[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][N:30]2[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1
Reactant: C1NC2CNC1C2
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: N#N
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(N4CC5CC4CN5)ccc2OCC3)c(F)c1
Temperature: 120 °C
Reaction time: 0.1 h
Yield: 13 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol) Pd(OAc)2 (22.4 mg, 0.1 mmol), 2,5-Diaza-bicyclo[2.2.1]heptane (120 mg, 1.2 mmol), X-phos (47 mg, 0.10 mmol), tert-butoxide (200 mg, 20 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 6 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 310. (61.4 mg, yield=13%). 1H NMR (CDCl3, 400 MHz): δ 8.27 (s, 1H), 7.89-7.88 (m, 1H), 7.72-7.99 (m, 1H), 7.41-7.39 (m, 1H), 7.28-7.16 (m, 2H), 6.39 (d, J=8.8 Hz, 1H), 4.41 (s, 1H), 4.16 (s, 2H), 3.46-3.41 (m, 6H), 2.74 (s, 2H), 1.06 (t, J=6.8 Hz, 2H). LC-MS (ESI): m/z=479 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([CH3:12])=[C:5]([N+:13]([O-])=O)[CH:4]=1)#[N:2].[Sn].[OH-].[NH4+]>Cl.C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH2:13])[C:6]([CH3:12])=[C:7]([NH2:9])[CH:8]=1)#[N:2]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(N)cc(C#N)cc1N
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A solution of 4-cyano-2,6-dinitrotoluene (8.55 g) in concentrated hydrochloric acid (70 mL) and glacial acetic acid (10 mL) is treated with tin metal (granules, 14.66 g), which is added slowly so that the temperature does not exceed 50° C. The reaction is stirred at 50° C. for 2.5 hours, then poured into ice and basified to pH=11 with concentrated ammonium hydroxide. The products are extracted with ethyl acetate (5×300 mL). The combined extracts are dried over sodium sulfate and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 50% ethyl acetate/hexane to afford 4-cyano-2,6-diaminotoluene as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:25]=[N:26][C:27]([NH:39][C:40]([NH:42][CH2:43][CH3:44])=[O:41])=[CH:28][C:29]=4[C:30]4[S:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=4)=[CH:21][N:22]=3)[C:17](=[O:45])[C:16]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:15]2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:43]([NH:42][C:40](=[O:41])[NH:39][C:27]1[N:26]=[CH:25][C:24]([C:20]2[CH:19]=[C:18]3[C:23](=[N:22][CH:21]=2)[N:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:15]=[C:16]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:17]3=[O:45])=[C:29]([C:30]2[S:31][CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[N:34]=2)[CH:28]=1)[CH3:44]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCNC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-ethyl 1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (300 mg) in dioxane (3 mL) was added 4 N HCl in dioxane (2 eq). The reaction mixture was stirred at room temperature overnight and the solid that formed was collected by filtration to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][C:14]([CH2:18][CH2:19][OH:20])([OH:17])[CH2:13][CH2:12]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([S:27]([O:20][CH2:19][CH2:18][C:14]2([OH:17])[CH2:15][CH2:16][N:11]([C:3]3[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:12][CH2:13]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc(N2CCC(O)(CCO)CC2)c(Cl)cc1Cl
Solvent: c1ccncc1
Product: COc1cc(N2CCC(O)(CCOS(=O)(=O)c3ccccc3)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 1-(2,4-dichloro-5-methoxyphenyl)-4-(2-hydroxyethyl)piperidin-4-ol (500 mg, 1.561 mmol) in pyridine (2 mL) was cooled to 0° C. and then treated with benzenesulfonyl chloride (331 mg, 1.874 mmol). The reaction was stirred at RT for 1 h before being quenched with water. The resultant mixture was extracted with EtOAc. The organic phase was concentrated in vacuo, and the resultant residue was purified by flash chromatography using 0-30% EtOAc in hexanes as the eluent to give 2-(1-(2,4-dichloro-5-methoxyphenyl)-4-hydroxypiperidin-4-yl)ethyl benzenesulfonate (340 mg, 0.739 mmol, 47% yield) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21]C)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)C1C=CC2OCOC=2C=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:18]=[CH:19][C:20]2[O:21][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1OC
Product: COc1ccc(C(=O)c2ccc3c(c2)OCO3)cc1OC

Procedure:
1-(3,4-Dimethoxybenzoyl)-3,4-methylenedioxybenzene was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.5 g, 11 mmol) and piperonyloyl chloride (1.9 g, 10 mmol) with a reaction time of 2.5 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) to afford 1.99 g (69%) of the product as a white solid: mp 164–165° C.; 1H NMR (CDCl3) δ 7.46–7.26 (m, 4H), 6.95–6.82 (m, 2H), 6.06 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H); 13C NMR (CDCl3) δ193.9, 152.7, 151.0, 148.9, 147.8, 132.4, 130.6, 126.1, 124.8, 112.2, 109.9, 109.7, 107.6, 101.7, 56.0, 56.0; Anal. Calcd for C16H14O5. Theoretical: C, 67.13; H, 4.93. Found: C, 66.86; H, 5.11.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH2:32][C@@H:31]2[CH2:33][C@H:28]1[CH2:29][N:30]2[C:34]([C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][C@@H:31]2[CH2:33][C@H:28]1[CH2:29][N:30]2[C:34]([C:36]1[CH:37]=[N:38][C:39]([NH:42][C:10]2[N:11]=[CH:12][C:7]3[CH:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[N:14]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[C:8]=3[N:9]=2)=[CH:40][CH:41]=1)=[O:35])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CNC(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(N)nc1
Product: CNC(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide, see WO 2010020675, (0.120 g, 0.431 mmol) was combined with (1S,4S)-5-(6-amino-pyridine-3-carbonyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.144 g, 0.452 g, 1.05 eq), which gave (1S,4S)-5-[6-(7-Cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a yellow solid. This material was used directly in the following step 3. MS m/z 561.5 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C:10]2[C:5](=[N:6][C:7](S(C)(=O)=O)=[N:8][CH:9]=2)[N:4]([CH3:16])[C:3]1=[O:17].[CH2:18]([N:20]([CH2:31][CH3:32])[CH2:21][CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:19]>ClCCl.CO.C(O)(=O)C.O>[CH2:31]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:7]2[N:6]=[C:5]3[N:4]([CH3:16])[C:3](=[O:17])[N:2]([CH3:1])[CH2:11][C:10]3=[CH:9][N:8]=2)=[CH:29][CH:30]=1)[CH3:32]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1Cc2cnc(S(C)(=O)=O)nc2N(C)C1=O
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(C)C3)cc1
Temperature: 180 °C
Yield: 6.1 %

Procedure:
A mixture of 250 mg (0.98 mmol) of 3-methyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 560 mg (2.7 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered off and dried to give 23 mg (7%) of 7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1,3-dimethylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 186° C.