Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]2[NH:22][CH:23]=[C:24]([NH2:25])[C:13]=12>N1C=CC=CC=1>[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:15]=[C:14]2[NH:22][CH:23]=[C:24]([NH:25][C:8](=[O:9])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[C:13]=12
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
Picolinoyl chloride hydrochloride (270 mg, 1.53 mmol) was added to 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (240 mg, 1.02 mmol, Example 11, step G) in pyridine (5 mL). The reaction was stirred at 0° C. for 10 minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3 mL) were added and stirred for 20 minutes. The THF was removed, and water (20 mL) was added. The solid formed was collected by filtration and dried to give N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (280 mg, 79% yield) as a solid.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[Br:17][C:18]1[CH:19]=[C:20](O)C=[CH:22][CH:23]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Br:17][C:18]1[CH:19]=[CH:20][C:25]([O:28][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:22][CH:23]=1
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(Br)c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c2ncccc2c2cc(Oc3ccc(Br)cc3)ccc12
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 2.9 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), 3-bromophenol (97 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in dimethylacetamide (2 mL), and stirred for 30 minutes at 200° C. in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to provide 93 (2 mg, 3% yield) as a solid. LC-MS (M+H=367, obsd.=367). 1H NMR (400 MHz, d6-DMSO): δ 12.01 (s, 1H), 8.78 (d, 1H), 8.52 (d, 1H), 8.35 (d, 1H), 8.22 (d, 1H), 7.43 (m, 3H), 7.29 (m, 2H), 7.18 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N+:27]([O-])=O)[CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pt]=O>[NH2:27][C:26]1[CH:25]=[CH:24][C:11]([CH2:12][N:13]([CH3:23])[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)S(=O)(=O)c1ccccc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(N)c(OCc2ccccc2)c1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a suspension of N-(3-Benzyloxy-4-nitrobenzyl)-N-methylbenzenesulfonamide (1.09 g, 2.643 mmol) in EtOAc is added platinum oxide (60 mg). The reaction is placed under an atmosphere of H2 and stirred at RT for 50 min. Additional platinum oxide is added (60 mg) and the reaction is stirred under an atmosphere of H2 at RT for an additional 50 min. During this time, the reaction changes from a greenish brown slurry to a black slurry. The slurry is filtered through Celite to remove the catalyst and the filter cake is washed with several portions of EtOAc. The filtrate and washings are combined, and concentrated under vacuum to afford an orange oil. LC/MS shows a 1:1 mixture of starting material and product. The orange oil is re-dissolved in. EtOAc, slurried with platinum oxide (150 mg) and stirred under an atmosphere of H2 at room temperature for 1.5 h. The reaction mixture is filtered through Celite and the filter cake is washed with EtOAc. The filtrate is concentrated to afford the title compound: (M+1)+=383.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])(C)C)=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:26]1COC[CH2:27]1>[Pt]>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][CH2:21][CH2:24][CH2:26][CH3:27])=[CH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cnc(-c2cccc(CO)c2)nc1
Reactant: C1CCOC1
Agent: [Pt]
Product: CCCCOC(=O)NCCCc1cnc(-c2cccc(CO)c2)nc1

Procedure:
280 mg (0.82 mmol) of tert-butyl {(E)-3-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]allyl}carbamate are dissolved in 10 ml of THF, shaken at room temperature for 17 h with 300 mg of platinum on active carbon (5%, comprises 56% of water) under a hydrogen atmosphere. The catalyst is filtered off with suction, and the filtrate is evaporated to dryness.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17].[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1[NH:28][C:29]1[N:30]=[CH:31][C:32]2[CH2:38][NH:37][CH2:36][CH2:35][C:33]=2[N:34]=1.N1C=CC(N)=CC=1.C(N(CC)CC)C>ClCCl>[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1[NH:28][C:29]1[N:30]=[CH:31][C:32]2[CH2:38][N:37]([C:1]([O:18][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])=[O:2])[CH2:36][CH2:35][C:33]=2[N:34]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: C#CCCCO
Agent: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCOC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Add 1,1′-carbonyldiimidazole (0.936 g; 5.66 mmoles) slowly dropwise to a −78° C. solution of 4-pentyn-1-ol (0.50 mL; 5.39 mmoles) in dichloromethane (18 mL). Allow the reaction to warm to ambient temperature for 30 minutes, then add half of this solution to a solution of N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.581 g; 1.05 equiv; 2.18 mmoles), 4-pyridinamine, N,N-dimethyl-(0.258 g; 1.0 equiv; 2.08 mmoles), and triethylamine (0.58 mL; 2.0 equiv; 4.15 mmoles). Warm the resulting pale yellow solution to ambient temperature and stir for 16 hours, then warm to 40° C. for an additional 24 hours. Cool the reaction mixture to ambient temperature and load directly onto a silica gel column. Purify by column chromatography (20 to 100% ethyl acetate in dichloromethane) to afford pent-4-yn-1-yl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.76 g; 88%): MS (m/z): 377(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:30])[C:18]([C:21]1[O:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=1)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@H:17]([CH3:30])[C:18]([C:21]3[O:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=3)([CH3:20])[CH3:19])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: COC(=O)c1coc(C(C)(C)[C@@H](C)N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1coc(C(C)(C)[C@@H](C)Nc2c(C(N)=O)cnn3cc(Br)cc23)n1
Temperature: 50 °C
Reaction time: 52 h
Yield: 25.9 %

Procedure:
To a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (200 mg, 0.729 mmol) in DMF (15 mL) was added (R)-methyl 2-(3-amino-2-methylbutan-2-yl)oxazole-4-carboxylate hydrochloride (217 mg, 0.874 mmol) and potassium carbonate (302 mg, 2.186 mmol) at RT and the reaction mixture was allowed to stir at 50° C. for 52 h. It was then quenched with water (150 ml) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. Crude product was purified by combiflash (12 g silica column, 60% EtOAc: Pet-Ether) to get desired product as yellow solid (85 mg, 25.9%). 1H NMR (400 MHz, DMSO) δ ppm: 1.23-1.25 (d, J=8.0 Hz, 3H), 1.42-1.44 (d, J=8.0 Hz, 6H), 3.79 (s, 3H), 4.61-4.62 (d, J=4.0 Hz, 1H), 7.09-7.10 (d, J=4.0 Hz, 1H), 7.892-7.896 (d, J=1.6 Hz, 1H), 8.22 (s, 1H), 8.75 (s, 1H), 10.91-10.95 (t, J=16.0 Hz, 1H). LC retention time: 1.680 min (analytical HPLC Method P).
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>C(O)CO.O>[CH3:26][C:21]1[CH:20]=[C:19]([O:18][CH3:17])[CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1ccc(N)c(C)c1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Solvent: O
Solvent: OCCO
Product: COc1ccc(N2CCc3c2c2cccc(OC)c2[nH]c3=O)c(C)c1
Temperature: 210 °C
Yield: 80.3 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of ethylene glycol and 4-methoxy-2-methylaniline (322 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 210° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 270 mg of desired compound as solid in 81% of yield.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+].CCOCC>CC#N>[CH2:18]([O:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=1)/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCC/C=C\COCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCCCCCCCCC/C=C\COCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.4 %

Procedure:
To a solution of silyl ether (41) (341 mg, 0.84 mmol) in CH3CN (10 mL) was added 50% aqueous HF (1 mL) the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into saturated aqueous NaHCO3 (50 mL) and ether (75 mL). The organic layer was separated and washed with two 50-mL portions of water, dried (MgSO4), and concentrated to yield (42) (290 mg, 98%) as a colorless oil: Rf 0.24 (9:1 petroleum ether/EtOAc); 1H NMR (CDCl3) δ 7.30 (s, 4 H), 5.60 (m, 2 H), 4.63 (s, 2 H), 4.49 (s, 2 H), 4.07 (d, J=5.1 Hz, 2 H), 239 (s, 2 H), 2.04 (q, J=6.6 Hz, 2 H), 1.27 (m, 16 H), 0.89 (t, J 6.6 Hz, 2 H); 13C NMR (CDCl3) δ 140.49, 137.82, 134.24, 128.10, 127.12, 125.94, 71.88, 65.85, 65.03, 32.03, 29.76, 29.66, 29.48, 29.37, 27.73, 22.82, 14.24. ##STR9##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: Cc1ccccc1CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccccc1CCNc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 160 °C
Yield: 42.2 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(2-methylphenyl)ethanamine (300 mg, 2.22 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (150 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.33 (s, 3H), 2.82-2.86 (m, 2H), 3.50-3.45 (m, 2H), 5.36 (s, 2H), 5.98 (s, 2H), 6.29 (s, 1H), 6.97 (s, 1H), 7.09-7.22 (m, 4H), 7.43 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[O:29]C>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][N:23]=[C:22]4[OH:29])[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: COc1ncnc2ccc(Br)cc12
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ncnc(O)c3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg, 0.6 mmol; Example 2B) and 6-bromo-4-methoxyquinazoline (215 mg, 0.9 mmol; ChemBridge) was performed as described in Example 68 to afford the title compound as the major product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.21 (m, 4H) 2.42 (s, 3H) 2.90-2.97 (m, 1H) 3.09-3.41 (m, 4H) 4.33 (s, 2H) 6.91-6.96 (m, 1H) 6.98-7.03 (m, 1H) 7.21 (s, 1H) 7.74-7.81 (m, 1H) 7.86-7.93 (m, 1H) 8.11 (d, J=3 Hz, 1H) 8.17 (s, 1H); MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:23][O:22][C:18](=[O:21])[C:19]([CH:8]([OH:9])[C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1)=[CH2:20]
Reactant: C=CC(=O)OC
Reactant: Cc1ncc(C=O)cn1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C(=O)OC)C(O)c1cnc(C)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
A mixture of 2-methylpyrimidine-5-carbaldehyde (1 g, 8.18 mmol, 1 eq), DABCO (1 eq, 935 mg) and methyl acrylate (5 eq, 3 68 ml) dissolved in a 1,4-dioxane (40 ml/H2O (40 ml) mixture was stirred at room temperature for 2 hours. The mixture was then poured into 300 ml of brine and the organic substances were extracted with DCM (3 times, 300 ml was used in total). The gathered DCM layers were dried, the solvent was evaporated and the obtained crude oil was triturated with diethyl ether to afford 2-[hydroxy-(2-methyl-pyrimidin-5-yl)-methyl]-acrylic acid methyl ester (1.58 g, yield=83.40%, purity=90%) in form of white powder. MS: [M+H]+=209.18 1H NMR (300 MHz; CDCl3) δ/ppm 2.72 (s, 3H), 3.61 (br.s., 1H), 3.75 (s, 3H), 5.58 (s, 1H), 5.97 (s, 1H), 6.43 (s, 1H) 8.64 (s, 2H)
Reaction SMILES: COC(C1N=[C:12]2[C:8]([N:9]=CN2[C@@H]2C[C@H](N3C=C(CO)C=N3)C(O)C2O)=[C:7](NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O.NC1CC[CH:47]([NH:50][C:51]([C:53]2[N:61]=[C:60]3[C:56]([N:57]=[CH:58][N:59]3[C@@H:62]3[CH2:66][C@H:65]([N:67]4[CH:71]=[C:70]([CH2:72][OH:73])[CH:69]=[N:68]4)[C@@H:64]([OH:74])[C@H:63]3[OH:75])=[C:55]([NH:76][CH2:77][CH:78]([C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)[C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)[N:54]=2)=[O:52])CC1.NCC(N)(C)C>>[NH2:9][C:8]([CH3:12])([CH3:7])[CH2:47][NH:50][C:51]([C:53]1[N:61]=[C:60]2[C:56]([N:57]=[CH:58][N:59]2[C@@H:62]2[CH2:66][C@H:65]([N:67]3[CH:71]=[C:70]([CH2:72][OH:73])[CH:69]=[N:68]3)[C@@H:64]([OH:74])[C@H:63]2[OH:75])=[C:55]([NH:76][CH2:77][CH:78]([C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)[N:54]=1)=[O:52]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)C(O)C3O)c2n1
Reactant: NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)CC1
Agent: CC(C)(N)CN
Product: CC(C)(N)CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1

Procedure:
This compound is prepared from 9-[(1R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Example 62) using a procedure analogous to that of 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (4-amino-cyclohexyl)-amide (Example 83, first step a) replacing trans-1,4-diaminocyclohexane with 1,2-diamino-2-methylpropane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[NH2:18])[CH2:8][CH2:7]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[NH:18][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:33])[CH2:10][CH2:11]1
Reactant: COc1cccc(N=C=O)c1
Reactant: NC1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Product: COc1cccc(NC(=O)NC2CCCCC2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)c1
Reaction time: 17 h
Yield: 44.9 %

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-4-(2-aminocyclohexyl)piperazine (100 mg, 0.29 mmol) and 3-methoxyphenyl isocyanate (38 μl, 0.29 mmol) in methylene chloride (5 ml) was stirred at room temperature. After 17 h, the product was extracted into ethyl acetate, washed with a bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. Column chromatography with methylene chloride/methanol (97:3) as the eluant gave 1-{2-[4-(3,4-dichlorobenzyl)piperazin-1-yl]cyclohexyl}-3-(3-methoxyphenyl)urea (64 mg) as an oil consisting of the trans diastereomer.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccccc2)cc1N
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a solution of 4-benzyloxy-2-nitroaniline (2.31 g, 9.46 mmol) in acetic acid (50 ml) was added conc. hydrochloric acid (1 ml), and gradually added zinc powder (2.16 g, 0.330 mmol) with ice-cooling and the mixture was stirred for 15 minutes, and further added gradually zinc powder (2.16 g, 0.33 mmol) and stirred for 20 minutes. The reaction solution was filtered with celite, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in chloroform and neutralized with a saturated sodium bicarbonate solution. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo to provide 2.01 g (yield 99%) of crude 4-benzyloxy-1,2-phenylenediamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](/[C:17]([OH:19])=[O:18])=[CH:15]\[CH3:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](/[C:17]([OH:19])=[O:18])=[CH:15]/[CH3:16])[N:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C=C(/C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C(\C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.25 h

Procedure:
8.3 g (29 mMol) of E-1-(5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)propene-1-carboxylic acid were dissolved in 40 ml of DMF and the solution was added to a solution of 10 g of potassium t-butylate in 30 ml of DMF at 0° C., whereupon the internal temperature rose to 30° C. The mixture was stirred for 15 minutes, 300 ml of water were poured in and the pH was adjusted to 2 with 1N HCl. The mixture was extracted 2×ethyl acetate and the combined organic phases were washed with water, dried over MgSO4 and evaporated in vacuo. 8.0 g (96%) of E/Z mixture~1:2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].CC1C=C(C)N=C(C)C=1.CC1C([IH+:40])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([I:40])[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: COC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)c1nc(I)c2ccn(Cc3ccccc3)c(=O)c2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (130 mg, 0.42 mmol) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.08 g, 2.10 mmol) in 5 mL of CH2Cl2 was stirred at r.t. for 16 h. The mixture was diluted with CH2Cl2 (50 mL) and washed with dilute sodium bisulfite and 1 M HCl. The organic layer was dried over MgSO4 and concentrated to give 180 mg of the title compound as a pale yellow solid. 1H NMR (CDCl3, 200 MHz): δ=13.56 (s, 1H), 7.20-7.50 (m, 6H), 6.77 (d, 1H, J=7.4 Hz), 5.30 (s, 2H), 3.99 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH2:7][CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])(=[O:6])=[O:5].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18]([CH2:17][N:9]([CH2:8][CH2:7][S:4]([CH3:3])(=[O:5])=[O:6])[C:10](=[O:15])[C:11]([F:12])([F:14])[F:13])=[O:19])[CH3:22]
Reactant: CS(=O)(=O)CCNC(=O)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCS(C)(=O)=O)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.190 g, 4.75 mmol) was added to a solution of N-(2-methylsulphonylethyl)trifluoroacetamide (0.986 g, 4.50 mmol) in dry DMF (10 ml) and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Ethyl bromoacetate (0.55 ml, 0.828 g, 4.96 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into ice-water, and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), and concentrated in vacuo to give the title compound as a white solid (1.239 g, 4.03 mmol, 90%); δH CDCl3 4.17 (4H,m), 3.91 (2H,t), 3.46 (2H,t), 2.98 (3H,s), 1.30 (3H,t).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate (150 mg, 0.28 mmol) from Example 76 in methanol (3 mL) was added 5N sodium hydroxide (0.170 mL, 0.84 mmol). The reaction was stirred at rt for 20 h and then at 40° C. for 2 h. The reaction was diluted with water, acidified with 2N hydrochloric acid, and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield crude 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid. HPLC/MS: 520 (M+1), 522 (M+3); Rt=4.61 min.