Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.C([Li])CCC.[C:21](=[O:23])=[O:22]>C1COCC1.O>[CH3:15][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)[CH:5]([C:21]([OH:23])=[O:22])[C:6]=2[CH:7]=1
Reactant: O=C=O
Reactant: Cc1ccc2c(c1)Cc1cc(C)ccc1-2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C(=O)O)c1cc(C)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
A solution of 2,7-dimethylfluorene (5.0 g, 25.7 mmol) in THF (100 mL) at -78° C. was charged with butyl lithium (16.8 mL, 26.0 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5g, 113.6 mmol) was introduced with cannula over a period of 15 min at -78° C. The reaction mixture Was Warmed up to room temperature and stirred overnight, diluted with water (150 mL). The layers were separated, the water layer was washed with ethyl acetate (5×20 mL), then acidified with conc. HCl. The precipitate formed was collected, washed with water and dried to give 4.4 g of 2,7-dimethyl-9-fluorenecarboxylic acid (72.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:12][N:8]1[CH2:7][CH2:6][C:5]2[N:4]=[CH:3][C:2]([NH:1][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:10]=2[CH2:9]1
Reactant: CN1CCc2ncc(N)cc2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCc2ncc(NC(=O)c3ccccc3)cc2C1
Temperature: 25 °C
Yield: 53 %

Procedure:
3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine (314 mg, 1.9 mmol) was dissolved in dichloromethane (10 ml) and treated sequentially with triethylamine (214 mg; 2.1 mmol) and benzoyl chloride (297 mg; 2.1 mmol). The mixture was stirred at ambient temperature until tlc showed no starting material remaining. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate, water, saturated brine, dried (anhydrous magnesium sulphate) and evaporated to dryness under reduced pressure. Chromatography through silica gel, eluting with methanol in dichloromethane (0 to 50% methanol gradient), gave the title compound as an off-white foam (269 mg; 52%)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH:10]=2)[O:3]1
Reactant: NC(=O)CCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCC(N)=O)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 3-bromopropanamide (47 mg, 0.31 mmol, TCI-EP, Cat. No. B1410), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 2 hours. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 45 mg of the product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=266.2
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH2:15]([C@@H:18]1[C:23](=[O:24])[CH:22]=[CH:21][N:20]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C@H:19]1[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)[CH:16]=[CH2:17]>C1COCC1>[CH2:15]([C@@H:18]1[C:23](=[O:24])[CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C@H:19]1[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=1)[CH:16]=[CH2:17]
Reactant: C=CC[C@@H]1C(=O)C=CN(c2ccc(C(C)C)cc2)[C@H]1c1ccc(C(F)(F)F)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1C(=O)CCN(c2ccc(C(C)C)cc2)[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Yield: 84.5 %

Procedure:
L-Selectride® (1.0 M in THF, 1.4 ml, 1.4 mmol) was added slowly to a stirred solution of the enone (Step 1, 538 mg, 1.35 mmol) in dry THF (10 ml) under N2, such that the internal temperature was kept below −70° C. The reaction was maintained at −78° C. for 1 hour, then quenched with saturated aqueous NH4Cl solution. After warming to room temperature the mixture was partitioned between EtOAc/H2O. The layers were separated and the aqueous layer was further extracted with EtOAc (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 5-10% EtOAc/isohexane to give the ketone (458 mg, 85%) as an oil. 1H NMR (500 MHz, CDCl3) δ: 1.21 (6H, d, J 6.9), 2.48 (2H, t, J 7.0), 2.56-2.62 (1H, m), 2.67-2.73 (1H, m), 2.78-2.85 (1H, m), 2.98-3.00 (1H, m), 3.47-3.53 (1H, m), 3.65-3.71 (1H, m), 4.95 (1H, d, J 3.3), 5.03 (1H, dd, J 17.0, 1.3), 5.10 (1H, d, J 9.2), 5.75-5.83 (1H, m), 6.76 (2H, d, J 8.6), 7.09 (2H, d, J 8.5), 7.29 (2H, d, J 8.1), 7.51 (2H, d, J 8.2).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][N:26]=2)[C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:7]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([N:32]([CH2:33][CH3:34])[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][N:26]=2)[C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:7]=1)[CH3:31]
Reactant: CCNCC
Reactant: O=C(N[C@H]1CCCc2ccccc21)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-(5-fluoro-2-nitrophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide (12.77 mmol, 5 g), diethylamine (25.55 mmol, 1.87 g), and K2CO3 (31.93 mmol, 4.41 g) in DMF (30 mL) was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate, and the resulting solution was washed with water (2×), and then with brine. The solution was dried (Na2SO4) and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel to give a yellow solid. (4.73 g, 83%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:65][CH2:64][N:63]([C:66]3[C:71]([C:72]4[CH:79]=[CH:78][C:75]([CH2:76][NH2:77])=[CH:74][CH:73]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:62][CH2:61]2)[CH:55]=[N:54]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:61][CH2:62][N:63]([C:66]3[C:71]([C:72]4[CH:73]=[CH:74][C:75]([CH2:76][NH:77][C:6]([CH:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:8])=[CH:78][CH:79]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:64][CH2:65]2)[CH:55]=[N:54]1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN)cc3)CC2)cnn1C
Reactant: O=C(O)C1CCOC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CNC(=O)C4CCOC4)cc3)CC2)cnn1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.8 %

Procedure:
Dissolve racemic tetrahydro-furan-3-carboxylic acid (0.067 g, 0.58 mmol) in methylene chloride (5 mL). Add benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.453 g, 0.87 mmol). Add 1-hydroxybenzotriazole (0.118 g, 0.87 mmol). Add 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.24 g, 0.63 mmol) dissolved in methylene chloride (5 mL). Stir at rt for 5 min. Add diisopropylethylamine (0.113 g, 0.87 mmol). Stir at rt for 4 hr. Purify by normal phase chromatography (4% 7 N ammonia-methonal/ethyl acetate) to give racemic tetrahydro-furan-3-carboxylic acid 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamide (0.107 g, 39%). MS (ES): m/z=476.3[M+H]. Dissolve this racemate (0.107 g, 0.23 mmol) in acetonitrile (1 mL) and water (4 mL). Add aq. 1 N HCl (1 eq., 0.23 mmol, 0.23 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilizer for 48 hr. to give the title compound (0.110 g, 94%). MS (ES): m/z=476.3 [M+H].
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I/[C:10](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[C:17]1(/[C:10](/[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C=C(\I)c1ccccc1
Reactant: C#Cc1ccccc1
Product: CCOC(=O)/C=C(\C#Cc1ccccc1)c1ccccc1

Procedure:
The general procedure was used to convert phenylacetylene and (Z)-ethyl 3-iodo-3-phenylacrylate to the title product. Purification by flash chromatography (5% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a light yellow oil (530 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ 7.78 (m, 2H), 7.63 (m, 2H), 7.38 (m, 6H), 6.59 (s, 1H), 2.06 (q, 2H), 1.35 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 165.12, 136.92, 136.08, 131.85, 129.66, 128.99, 128.42, 128.18, 126.96, 122.54, 122.48, 101.88, 86.68, 60.16, 14.17. Anal. Calc'd. for C19H16O2: C, 82.58; H, 5.84; Found C,
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].C([O-])([O-])=O.[Na+].[Na+].[CH3:16][C:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O.ClCCl>[CH3:16][C:17]1([C:23]([NH:2][C@H:3]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]2=[O:9])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N[C@H]1CCCNC1=O
Reactant: CC1(C(=O)Cl)CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C(=O)N[C@H]2CCCNC2=O)CCCCC1
Reaction time: 18 h
Yield: 41.7 %

Procedure:
(S)-3-Amino-tetrahydropyridin-2-one hydrochloride (2 mmol) and Na2CO3 (6 mmol) in water (25 ml) were added to a solution of 1-methylcyclohexanecarbonyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction was stirred for 18 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane. The combined organic layers were dried over Na2SO4 and reduced in vacuo. The residue was purified by silica column chromatography (EtOAc:hexanes 1:3 to MeOH:EtOAc 1:19) to give as an amorphous solid (199 mg, 42%); νmax/cm−1 3335, 3269 (NH), 1650, 1621 (CO), 1529 (NH); δH (500 MHz, CDCl3) 6.65 (1H, br d, J5, NH), 6.59 (1H, br s, NH), 4.18 (1H, dt, J 11.5, 5.5, CHNH), 3.30 (2H, td, J6.5, 2.5, CH2NH), 2.52 (1H, ddt, J 13, 5.5, 4.5, lactam CH2), 1.92-1.83 (4H, m, 2× lactam CH and 2× cyclohexane CH2), 1.55-1.23 (9H, m, lactam CH and 8× cyclohexane CH2) and 1.11 (3H, s, CH3); δC (125 MHz, CDCl3) 178.0, 172.3 (CO), 50.4 (NHCHCO), 42.6 (CH3C quat), 41.5, 35.6, 35.5, 27.0 (CH2), 26.3 (CH3), 25.7, 22.8 (×2), 20.9 (CH2); m/z (MNa+C13H22N2O2Na requires 261.1579) 261.1570.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: OB(O)c1ccccc1
Product: CC1(C)CC(Nc2nccc(-c3ccccc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and phenylboronic acid according to Method C (Example 178). Yield: 190 mg (82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].ClCCCl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: C1COCCN1
Reactant: COc1c([N+](=O)[O-])ccc2c1CCC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a stirred solution of 1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (236 mg, 0.00100 mol) in 1,2-dichloroethane (8 mL, 0.1 mol) at room temperature was added morpholine (0.23 mL, 0.0026 mol) followed by acetic acid (0.15 mL, 0.0026 mol) dropwise. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride was added in one portion. The reaction mixture was stirred at 0° C. for 2 h then warmed to room temperature overnight. Workup involved addition of 1N NaOH to bring pH to ˜10. The reaction mixture was extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to a orange oil. Purification was accomplished using ISCO chromatography on silica gel using hexane-ethyl acetate and methylene chloride-methanol to give 4-(1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine as a yellow solid (0.24 g, 78%). 1H NMR (400 MHz, CDl3). δ 6.70 (s, 1H, J=7.92 Hz), 6.51 (d, 1H, J=7.88), 3.70 (m, 9H), 3.29 (q, 1H, J=14.41, 8 Hz), 2.74 (q, 1H, J=14.28, 7.48 Hz), 2.55 (m, 6H), 2.31 (m, 1H), 2.10 (m, 2H), 1.35 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[O:58][C:59]([F:62])([F:61])[F:60].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[O:58][C:59]([F:62])([F:60])[F:61]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: FC(F)(F)Oc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 mg, 0.226 mmol), HBTU (125 mg, 0.33 mmol), 1-(4-Chloro-3-trifluoromethoxy-phenyl)-piperazine dihydrochloride (177 mg, 0.50 mmol), anhydrous DMF (2.0 mL), and DIPEA (0.4 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-trifluoromethoxy-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone. MS (ES) [M+H]+ found: 506.4
Reaction SMILES: [CH3:1][N:2]([CH:30]([CH3:32])[CH3:31])[C:3]1[C:4]([C:17]2[C:21]3[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:20]=3[O:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:30]([CH3:32])[CH3:31])[C:3]1[C:4]([C:17]2[C:21]3[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:20]=3[O:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3coc4ccc(C(F)(F)F)cc34)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1coc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-[5-(trifluoromethyl)-1-benzofuran-3-yl]quinoxaline-6-carboxylate (135 mg, 0.30 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (48.8 mg, 1.22 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-[5-(trifluoromethyl)-1-benzofuran-3-yl]quinoxaline-6-carboxylic acid as a light yellow solid (42.6 mg, 33%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[N:15]=3)[S:10][C:3]=12.[CH:20]1([CH2:23][NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=3)[N:29]([CH3:37])[C:28]=2[CH3:38])=[O:26])[CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:20]1([CH2:23][NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][C:32]([O:36][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]6[S:12][CH:13]=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[N:15]=6)[S:10][C:3]=45)=[CH:33][CH:34]=3)[N:29]([CH3:37])[C:28]=2[CH3:38])=[O:26])[CH2:22][CH2:21]1
Reactant: CC(C)(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Reactant: Cc1c(C(=O)NCC2CC2)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCC2CC2)c2ccc(Oc3ccnc4cc(-c5nc(C(C)(C)O)cs5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of 2-[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]propan-2-ol 40a (0.102 g, 0.33 mmole) with N-(cyclopropylmethyl)-6-hydroxy-1,2-dimethyl-1H-indole-3-carboxamide 55b (0.085 g, 0.33 mmole) and Cs2CO3 (0.1089, 0.33 mmole) in a manner as previously described for example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (1H, d, J=5.5 Hz), 8.12 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.73 (1H, t, J=5.8 Hz), 7.58 (1H, s), 7.54 (1H, d, J=2.1 Hz), 7.05 (1H, dd, J=2.1, 8.6 Hz), 6.59 (1H, d, J=5.5 Hz), 3.68 (3H, s), 3.17 (2H, t, J=6.1 Hz), 2.61 (3H, s), 1.50 (6H, s), 1.08 (2H, m), 0.43 (2H, m), 0.25 (2H, m); ESIMS (MH+): 533.15.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccccc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccccc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and phenylboronic acid. The title compound was obtained in 48% yield as white foam. MS (m/e): 482.3 (MH+, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][N:29]=1)[C:6]([NH:8][C:9]1[O:10][C:11]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]([O:25][CH3:26])[C:12]=2[N:13]=1)=[O:7].[H-].[Na+].[CH2:32]([OH:34])C>O1CCOCC1.CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:11]3[O:10][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:27]=[CH:28][N:29]=[C:3]([CH2:2][O:34][CH3:32])[CH:4]=4)=[N:13][C:12]=3[C:14]([O:25][CH3:26])=[CH:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(-c4ccc(F)cc4)c3o2)ccn1

Procedure:
From 2-chloromethyl-N-[7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl]-isonicotinamide with sodium hydride and ethanol in dioxane and DMF. ES-MS m/e (%): 408 (M+H+, 100).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:36]=[CH:35][C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:34])=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:37])[CH:3]=1.Cl.[NH2:39][OH:40].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:36]=[CH:35][C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:34])=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:39]\[OH:40])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:37])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(F)c(C(=O)O)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(F)c(C(=O)O)c2)cc1

Procedure:
In analogy to example 151, step 3, 5-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenoxy}-2-fluoro-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI−): m/z=533.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH2:28])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1>>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(Nc2nc(Nc3cc[nH]n3)cc3ccccc23)cc(OC)c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,5-dimethoxy-phenylamine to give N1-(3,5-dimethoxy-phenyl)-N3-(1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 362(MH+).
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.CO>ClCCl>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:26])([F:28])[F:27])=[O:21])[C:15]([C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[CH:37][CH:38]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(N)cc2)ncc(N)c1=O)C(=O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-nitrophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was subjected to a procedure similar to that described in Example 6 to give a brown solid; chromatography solvent: methanol:dichloromethane (gradient, 5:95, 10:90); NMR (DMSO/D2O): 7.29 (s,1), 7.01 (d,2), 6.49 (d,2), 4.52 (m,2), 4.10 (d,2), 2.25 (m,1), 0.88 (d,3), 0.80 (d,3).