Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][O:19]C4CCCCO4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CO.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][OH:19])[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:40])[F:41])[CH:33]=2)=[CH:43][CH:44]=1
Reactant: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)n(CCO)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione (70 mg, 0.107 mmol) in methanol (3 mL) was added concentrated HCl (4 drops). The mixture was stirred for 1 h at room temperature. The mixture was neutralized with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated to give a crude product which was recrystallized from ethanol to give 7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione (16 mg, 25.6% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.45-7.41(t, 1H), 7.32-7.27(m, 4H), 7.03-6.95(m, 3H), 5.19(s, 2H), 4.81(s, 2H), 4.49-4.46(t, 1H), 4.41-4.40(d, 2H), 3.91-3.88(t, 2H), 3.44-3.40(m, 5H), 1.69-1.65(t, 2H). LCMS retention time 3.142 min; LCMS MH+ 569.
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]([NH:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[C:16]([NH:28][C:29](=O)[CH2:30][C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.Cl>>[CH:22]([CH:21]([N:20]1[C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:12][C@@H:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:5])=[O:38])=[O:37])=[CH:15][C:16]=2[N:28]=[C:29]1[CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[CH:25]([CH3:26])[CH3:27])([CH3:24])[CH3:23]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(NC(C(C)C)C(C)C)c(NC(=O)Cc2cccs2)c1)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1ccc2c(c1)nc(Cc1cccs1)n2C(C(C)C)C(C)C)C(=O)O
Yield: 4.3 %

Procedure:
80 mg of (S)-2-[4-(1-Isopropyl-2-methyl-propylamino)-3-(2-thiophen-2-yl-acetyl-amino)-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester and 2 ml of hydrochloric acid (4M in dioxin) were heated in a microwave reactor for 2 min to 100° C. and for 15 min to 130° C. The reaction was then concentrated in vacuo and the resulting residue purified by HPLC to obtain 3 mg (4%) of (S)-2-{[1-(1-Isopropyl-2-methyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:10]=2[N:11]=[C:12]([NH:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31])[N:13]=1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3F)nc(S(C)(=O)=O)nc21
Reactant: NC(CO)CO
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3F)nc(NC(CO)CO)nc21

Procedure:
4-(2-Fluorophenyl)-8-(1-ethylpropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(2-fluoro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.82 (m, 6H), 1.32 (m, 4H), 1.90 (m, 2 H), 2.32 (m, 2H), 3.71 (m, 2H), 4.24 (m, 1H), 5.38 (m, 0.5H), 5.69 (m, 0.5H), 5.71 (br s, 1H), 6.30 (br d, 1H, J=9.6), 7.13 (d, 1H, J=9.6 Hz), 7.30-7.55 (m, 4H). LC MS (m/e)=401 (MH+)
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][C:11]([O:13][CH3:18])=[O:12]
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1CC(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c(C)[nH]c(=O)[nH]c1=O
Yield: 97 %

Procedure:
2-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetic acid (5.17 g; 28,1 mmol) was suspended in methanol (70.2 mL) and to the stirred mixture was added thionyl chloride (40.7 ml; 562 mmol) dropwise at 0° C. The mixture was stirred under reflux for 12 h. After cooling, the white precipitate was filtered off, washed with methanol and dried under reduced pressure with phosphorus pentoxide to give 5.4 g (97%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][S:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[OH:19][CH:18]([C:17]1[CH:20]=[CH:21][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: CSc1ccc(C=O)cc1
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(SC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 8.4 ml (0.1 mol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 69 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 13 ml (0.1 mol) of 4-(methylthio)benzaldehyde in 100 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained methyl 4-hydroxy-4-[4-(methylthio)phenyl]-2-butynoate as a red oil.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>>[OH:32][CH2:31][C:30]([NH:29][C:15]([C:14]1[CH:18]=[CH:19][N:20]=[CH:21][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:28]=[N:27][CH:26]=[N:25][CH:24]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:11])=[O:17])([CH3:34])[CH3:33]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Product: CC(C)(CO)NC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 2-amino-2-methylpropan-1-ol, providing the title compound was obtained as yellow solid (33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:17][C:18]1([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)(=O)C.C([BH3-])#N>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH2:15][NH:17][C:18]3([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1cccc(-c2ccc(F)c(Cl)c2)n1
Reactant: NC1(CO)CCCC1
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: OCC1(NCc2cccc(-c3ccc(F)c(Cl)c3)n2)CCCC1
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a solution of Example 266A (0.500 g, 2.12 mmol) in methanol (20 mL) and CH2Cl2 (20 mL) at ambient temperature was added cycloleucinol (0.244 g, 2.12 mmol), acetic acid (0.50 mL, 8.5 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated and the residue partitioned between ether and 1N NaOH. The organic extract was concentrated and purified by chromatography to provide 418 mg (59%) of the title compound. MS (DCI+) m/z 335 (M+H); 1H NMR (500 MHz, CDCl3) δ 8.03 (dd, J=7.1, 2.2 Hz, 1H), 7.86 (ddd, J=8.6, 4.6, 2.3 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.30-7.19 (m, 2H), 3.95 (s, 2H), 3.48 (s, 2H), 1.87-1.52 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:17][C:18]1[C:19]([Sn](CCCC)(CCCC)CCCC)=[N:20][CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[C:19]([C:11]2[N:12]=[N:13][CH:14]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:21]4[C:22]([F:24])=[CH:23][C:18]([F:17])=[CH:19][N:20]=4)[CH:3]=3)[N:10]=2)=[N:20][CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: CSc1nncc(-c2ccc(F)c(Br)c2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(F)cc1F
Product: Fc1cnc(-c2nncc(-c3ccc(F)c(-c4ncc(F)cc4F)c3)n2)c(F)c1

Procedure:
A solution of 5-(3-bromo-4-fluorophenyl)-3-methylsulfanyl-[1,2,4]triazine and 3,5-difluoro-2-tributylstannylpyridine were coupled together by the method of Example 36 to give 3-(3,5-difluoropyridin-2-yl)-5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-[1,2,4]triazine: δH (500 MHz, CDCl3) 7.38-7.46 (3H, m), 8.44-8.48 (1H, m), 8.50 (1H, dd, J 2.3, 6.7 Hz), 8.52 (1H, d, J 2.3 Hz), 8.63 (1H, s), 9.77 (1H, s); m/z (ES+) 402.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[N:3]=1
Reactant: NCc1ccc2ccccc2n1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc3ccccc3n2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-aminomethyl-quinoline dihydrochloride and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=CCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=CCCCCc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
t-butyl diethylphosphonoacetate (18 g; 70 mmol) is dissolved in dry THF (250 mL) and cooled to -40° C. NaH (60% in oil; 2.8 g; 70 mmol) is added and the reaction is warmed to 0° C. Gas evolution is controlled with cooling and then stirred at 20° C. for 30 minutes. 5-Phenylpentanal (11.3 g; 70 mmol) is added and the reaction stirred 20 minutes. The reaction is concentrated to half volume and petroleum ether (500 mL) is added. The reaction is washed with 100 mL water, 100 mL 0.5 N HCl, NaHCO3, brine and dried (MgSO4). The solution is concentrated in vacuo to obtain t-butyl 7-phenylhept-2-enoate which is used directly in Step C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])=[S:4].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[OH:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]1([N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:3](=[S:4])[NH:2][CH3:1]
Reactant: CNC(=S)C1(n2cnc(C)c2)CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNC(=S)C1(n2cnc(C)c2)CCCCC1O
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
19.09 g of the N-methyl-1-(4-methylimidazol-1-yl) 2-oxocyclohexanecarbothioamide prepared in the Preparative Example 2 was suspended in 290 ml of methanol. The obtained suspension was stirred under cooling with ice, followed by the addition of 1.44 g of sodium borohydride. The reaction mixture was analyzed by silica gel thin-layer chromatography (developer: a 10:1 mixture of chloroform and methanol). The product was a mixture comprising a lower-polarity diastereomer (L-form) as the main product and a higher-polarity one (M-form). After 30 minutes, the reaction mixture was concentrated to about 70 ml, followed by the addition of about 200 ml of water. The precipitate formed was recovered by filtration and washed with water to give 11.85 g of the title compound as a white solid (yield: 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:9][O:10][C:5]2=[CH:4][CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:50][C:51]1[CH:55]=[C:54]([Sn](CCCC)(CCCC)CCCC)[O:53][N:52]=1.O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO.C(Cl)Cl>[CH3:50][C:51]1[CH:55]=[C:54]([C:2]2[N:7]=[C:6]3[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:9][O:10][C:5]3=[CH:4][CH:3]=2)[O:53][N:52]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Reactant: COC(=O)Cc1coc2ccc(Cl)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)Cc1coc2ccc(-c3cc(C)no3)nc12
Temperature: 100 °C
Yield: 96.3 %

Procedure:
A sealable flask was charged with methyl 2-(5-chlorofuro[3,2-b]pyridin-3-yl)acetate, palladium (II) acetate (49.8 mg, 222 μmol), X-Phos (211 mg, 443 μmol), and 3-methyl-5-(tributylstannyl)isoxazole (1319 mg, 3546 μmol). The flask was sealed and dioxane (20 mL) was added. The mixture was sparged with N2 for 10 min, then heated at 100° C. for 48 h. The mixture was cooled to rt and concentrated for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 25 g loading cartridge and passed through a Redi-Sep®, pre-packed silica gel column (40 g) using 98:2 CH2Cl2:MeOH to 90:10 CH2Cl2: MeOH to afford methyl 2-(5-(3-methylisoxazol-5-yl)furo[3,2-b]pyridin-3-yl)acetate (581 mg, 96.3% yield). LRMS (ESI) m/z calcd for C4H113N2O4 (M+H) 273.1. found 273.3.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]([NH2:26])=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3[CH:25]=[CH:24][C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:17]=3[NH:26][C:2](=[O:3])[C:1]2=[O:5])=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Nc2ccc3ccccc3c2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of oxalyl chloride (0.12 mL) was added dropwise an anhydrous tetrahydrofuran (10 mL) solution of N2-(4-methoxyphenyl)naphthalene-1,2-diamine (322 mg, 1.22 mmol) under cooling in an ice-bat. The mixture was stirred under cooling in ice-bath for 30 minutes and at room temperature for one hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The obtained solid was filtered. The crude crystal was washed with ethyl acetate and hexane to obtain the titled compound as a slightly off-white crystal (220 mg, yield 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[C:27]([F:32])[CH:28]=[CH:29][CH:30]=3)[O:25][CH2:24][CH2:23]2)[C:18]([N+:33]([O-])=O)=[CH:17][N:16]=1>O.C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[C:27]([F:32])[CH:28]=[CH:29][CH:30]=3)[O:25][CH2:24][CH2:23]2)[C:18]([NH2:33])=[CH:17][N:16]=1
Reactant: COc1ccc(CNc2cc(F)ccc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4c(F)cccc43)n2)c(OC)c1
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(F)ccc2Nc2ncc(N)c(N[C@@H]3CCOc4c(F)cccc43)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an Ar atmosphere, a catalytic amount of a Raney Ni solution in water was added to a solution of (R)—N2-(2-(2,4-dimethoxybenzylamino)-4-fluorophenyl)-N4-(8-fluorochroman-4-yl)-5-nitropyrimidine-2,4-diamine (21 mg) in THF. The flask was closed with a septum, evacuated under house vacuum and hydrogen added via balloon. The resulting suspension was stirred at RT for 2 hr, when the H2 balloon was removed, the mixture evacuated and filtered through a plug of celite, that was thoroughly rinsed with THF and MeOH, to yield (R)—N2-(2-(2,4-dimethoxybenzylamino)-4-fluorophenyl)-N4-(8-fluorochroman-4-yl)pyrimidine-2,4,5-triamine that was used directly.
Reaction SMILES: [F:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.CC1C2C=C3[C:33]4([C:41]5[C:36](=CC=[CH:39][CH:40]=5)[NH:35][C:34]4=O)COC3=CC=2ON=1.Br.BrCC1C=NC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:33][C:41]4[CH:36]=[N:35][CH:34]=[CH:39][CH:40]=4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Br
Agent: BrCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccnc2)c2ccccc2C12COc1cc(F)c(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5,6-difluoro-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (57%) as a colorless solid: mp 175-177° C.; 1H NMR (300 MHz, CD3OD) δ 8.98 (s, 1H), 8.84 (d, J=5.4 Hz, 1H), 8.67 (d, J=8.4 Hz, 1H), 8.12 (dd, J=8.1, 6.0 Hz, 1H), 7.37 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.26 (d, J=6.9 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.93 (dd, J=10.5, 6.3 Hz, 1H), 6.76 (dd, J=9.6, 7.8 Hz, 1H), 5.27 (s, 1H), 5.26 (s, 1H), 5.00 (d, J=9.6 Hz, 1H), 4.83 (d, J=9.6 Hz, 1H); MS (ES+) m/z 365.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: COc1cccc(S)c1
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Product: COc1cccc(Sc2nc(C(=O)NCC(=O)O)c(O)c3ccccc23)c1

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 3-methoxybenzenethiol under conditions analogous to Example D-110. The final product was precipitated from a solution of ethyl acetate using hexanes; MS (−) m/z 385.12 (M−1)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:28]1[CH2:29][CH2:30][C:25]([F:31])([F:24])[CH2:26][CH2:27]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Reactant: FC1(F)CCNCC1
Product: Cc1cc(Cl)cc2c(-c3ccccc3)c(C(=O)O)c(N3CCC(F)(F)CC3)nc12

Procedure:
The title compound was prepared in analogy to example 40 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 40 step C) and 4,4-difluoro-piperidine. Light yellow foam. MS (ESI): 417.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][OH:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:45])[CH:10]=1)#[N:2].[CH3:46][C:47]1[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1.Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][O:43][S:53]([C:50]4[CH:51]=[CH:52][C:47]([CH3:46])=[CH:48][CH:49]=4)(=[O:55])=[O:54])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:45])[CH:10]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CCO)C(=O)OCC)CC2)c2ncnn12
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CCOS(=O)(=O)c3ccc(C)cc3)C(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-hydroxybutanoate (0.47 g), 4-methylbenzenesulfonyl chloride (0.59 g) and pyridine (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.42 g, 70%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[CH3:14][C:15]([NH2:26])([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][NH:26][C:15]([CH3:25])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCCCCCCCC1CO1
Product: CCCCCCCCCCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 18.7 %

Procedure:
Using the method of Example 5, supra, 1,2-epoxydodecane (240 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine (197 mg, 1.1 mmol) were used to prepare 68 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 363 (M+1, 0.2), 348 (2), 242 (100), 224 (8), 163 (7), 121 (20); 1H-NMR (CDCl3) δ 7.08 (2H, d, J=8.4), 6.83 (2H, d, J=8.4), 3.79 (3H, s), 3.50 (1H, m), 2.78 (1H, dd, J=11.8 and 3.1), 2.66 (2H, s), 2.41 (1H, dd, J=11.5 and 9.3), 1.26 (18 H, m), 1.07 (6H, s), 0.88 (3H, t, J=6.5); 13C-NMR (CDCl3) 5 158.2, 131.4, 129.9, 113.4, 76.9, 70.0, 55.2, 53.6, 47.8, 46.6, 35.1, 31.9, 29.7, 29.6, 29.3, 26.7, 26.5, 25.7, 22.7, 14.1; FT-IR (film) cm−1 3386, 1612, 1512, 1246, 1039, 824.