Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][O:4][C@@H:3]2[CH2:7][NH:8][CH2:9][CH2:10][C@@H:2]12.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C(N(CC)CC)C>C(Cl)Cl>[N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][O:4][C@@H:3]2[CH2:7][N:8]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:9][CH2:10][C@@H:2]12
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2CNCC[C@H]21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl (4aR,8aR)-octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (250 mg, 1.03 mmol) dissolved in DCM (2 mL) was added benzyl chloroformate (0.21 mL, 1.44 mmol). Triethylamine (0.4 mL, 2.89 mmol) was added slowly and stirred for 3 hours at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with DCM, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford (4aR,8aR)-6-benzyl 1-tert-butyl hexahydro-1H-pyrido[3,4-b][1,4]oxazine-1,6(7H)-dicarboxylate. 1H NMR (500 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 5.12 (s, 2H), 4.40-4.15 (m, 1H), 3.93-3.87 (m, 1H), 3.86-3.79 (m, 1H), 3.77-3.71 (m, 1H), 3.42-3.29 (m, 2H), 3.19-3.13 (m, 1H), 2.81-2.48 (m, 2H), 1.76-1.66 (m, 1H), 1.58 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(OCC)(=O)C>CO.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]4[N:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of 1-(4-Fluoro-phenyl)-5-(5-nitro-pyridin-2-yloxy)-1H-indazole (0.28 g, 0.79 mmol) in 10 mL of methanol was added 10 mL of ethyl acetate and 30 mg of platinum (IV) oxide. After shaking under 50 psi of H2 for 3 h, the mixture was filtered through a pad of Celite and concentrated in vacuo, affording 0.25 g of 6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-ylamine as a colorless solid. 1H NMR (CD3OD, 400 MHz): δ 8.96 (d, 1H, J=2.8 Hz), 8.58 (dd, 1H, J=2.8, 9.2 Hz), 8.25 (s, 1H), 7.6-7.8 (m, 3H), 7.66 (1H, d, 2.4 Hz), 7.3-7.2 (m, 3H), 7.19 (d, 1H, J=9.2 Hz) ppm.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[C@H:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[C:30]([CH3:38])[CH:29]=3)=[CH:22][CH:21]=2)=[O:18])[C@@H:15]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10]1>C(Cl)Cl>[CH3:8][N:9]1[C@H:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[C:30]([CH3:38])[CH:29]=3)=[CH:24][CH:25]=2)=[O:18])[C@@H:15]([C:39]([OH:41])=[O:40])[CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10]1
Reactant: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)OC(C)(C)C)CC4(CC4)CN3C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)O)CC4(CC4)CN3C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 149.6 %

Procedure:
TFA (1.0 mL) was added to a solution of tert-butyl (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (105.0 mg) in CH2Cl2 (1.0 mL) and the mixture was stirred at room temperature for 5 h. The solvent was removed to provide (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylic acid (140 mg) as an TFA salt. ESI (M+H)+ 460.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C:8]2[N:9]=[C:10]([NH:24][C:25]3[C:30](C(O)=O)=[CH:29][N:28]=[CH:27][CH:26]=3)[C:11]3[CH:17]=[CH:16][C:15](NCCN(C)C)=N[C:12]=3[N:13]=2)[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN.[CH3:49][N:50]([CH:52]=[O:53])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C:8]2[N:9]=[C:10]([NH:24][C:25]3[C:30]([C:52]([NH:50][CH3:49])=[O:53])=[CH:29][N:28]=[CH:27][CH:26]=3)[C:11]3[CH2:17][CH2:16][CH2:15][C:12]=3[N:13]=2)[CH:7]=1
Reactant: CN(C)CCNc1ccc2c(Nc3ccncc3C(=O)O)nc(-c3cc(Cl)ccc3F)nc2n1
Reactant: CN(C)C=O
Agent: CN
Agent: O=C(n1ccnc1)n1ccnc1
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a suspension of substituted nicotinic acid, 4-[2-(5-Chloro-2-fluoro-phenyl)-7-(2-dimethylamino-ethylamino)-pyrido[2,3-d]pyrimidin-4-ylamino]-nicotinic acid (0.030 g) in dry DMF (1 ml) was added Carbonyldiimidazole (0.020 g) followed by methylamine (156 uL, 2 M solution if THF). The reaction mixture was stirred at room temperature for 16 h. The crude residue was purified by preparative HPLC (Acetonitrile/water 5% to 95% gradient) to give 4-[2-(5-Chloro-2-fluoro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-N-methyl-nicotinamide (280 mg, 68%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][CH2:31]O)=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:58]([O:62][C:63]([NH:65][C:66]([NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])=[NH:67])=[O:64])([CH3:61])([CH3:60])[CH3:59].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:72]([O:71][C:69](=[O:70])[N:68]=[C:66]([NH:65][C:63]([O:62][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:64])[NH:67][CH2:31][CH2:30][O:29][C:28]1[CH:33]=[C:34]([F:35])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:26]([F:36])[CH:27]=1)([CH3:75])([CH3:74])[CH3:73]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 8 h
Yield: 128.5 %

Procedure:
To a solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (153 mg, 0.27 mmol) in THF (0.39 mL) were added PPh3 (107 mg, 0.41 mmol), 1,3-bis(tert-butoxycarbonyl)guanidine (144 mg, 0.55 mmol) and DIAD (85 μL, 0.41 mmol). After stirring overnight, the reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (80% EtOAc/hexanes) to afford tert-butyl(tert-butoxycarbonylamino)(2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethylamino)methylenecarbamate (279 mg), which was taken to the final step without further purification. MS (EI) m/z 804.5 (MH+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2COC2C(C(OCC)=O)=NC=CC=2)=[O:10])[CH2:5][CH2:4]1.CO[C:33]1[CH:34]=[C:35]([O:44][CH2:45][C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)[C:36]([C:39]([O:41]CC)=[O:40])=[N:37][CH:38]=1>>[F:30][C:2]([F:1])([F:29])[C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([N:11]2[CH2:12][CH2:13][CH:14]([CH2:45][O:44][C:35]3[C:36]([C:39]([OH:41])=[O:40])=[N:37][CH:38]=[CH:33][CH:34]=3)[CH2:15]2)=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)c1ncccc1OCC1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: O=C(O)c1ncccc1OCC1CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 31 using ethyl 3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinate (EXAMPLE 92 Step 3) in stead of ethyl 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([N:13]([C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[C:39]([F:42])([F:41])[F:40])[N:26]=[CH:25]4)[C:18](=[O:20])[N:19]=2)[CH3:14])[CH2:10][CH:9]1[C:43](O)=[O:44])=O)(C)(C)C.Cl.[CH3:47][O:48][NH2:49].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:47][O:48][NH:49][C:43]([CH:9]1[CH2:10][CH:11]([N:13]([C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[C:39]([F:41])([F:40])[F:42])[N:26]=[CH:25]4)[C:18](=[O:20])[N:19]=2)[CH3:14])[CH2:12][NH:8]1)=[O:44]
Reactant: CON
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)C1CC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.066 g, 0.1 mmol) and methoxyamine hydrochloride (0.014 g, 0.15 mmol) in DMF (2 mL) was added EDC hydrochloride (0.03 g, 0.15 mmol) followed by DIPEA (0.3 mL, 1.72 mml). The reaction mixture was stirred at room temperature for 16 hours and partitioned between water and dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (100% ethyl acetate) to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][C:22]1N(C)N=NN=1.Cl[C:29]1C(=O)C2C(=CC=CC=2)C(=O)C=1NC1C=CC(S(NC2C=CC(OC)=CC=2)(=O)=O)=C(OC)C=1>>[CH2:22]([S:21][C:3]1[CH:4]=[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:29]
Reactant: COc1ccc(NS(=O)(=O)c2ccc(NC3=C(Cl)C(=O)c4ccccc4C3=O)cc2OC)cc1
Reactant: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: CCSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O

Procedure:
5.2.52 N-(3-(ethylthio)-4-hydroxynaphthalen-1-yl)thiophene-2-sulfonamide (14j) was prepared according to the procedure for 14d except using (E)-N-(3-ethylthio-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13j), which afforded the title compound 14 mg (100%) as a grey solid, m.p.: ° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1([OH:25])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1)#[CH:16].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:17]3([OH:25])[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1ccc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
A mixture of 4-bromo-4'-hydroxybiphenyl (747 mg), 3-ethynyl-3-hydroxyquinuclidine (453 mg), bis(triphenylphosphine)-palladium (II) chloride (105 mg), copper (I) iodide (55 mg) and dry triethylamine (5.0 ml) in dry dimethylformamide (10 ml) was stirred at 70° C. under an atmosphere of argon for 4 hours. The reaction mixture was cooled and the dimethylformamide and triethylamine were removed by evaporation. The residue was purified by flash column chromatography on alumina (ICN--Alumina N32-63) using a gradient of 10% methanol in ethyl acetate to 20% methanol in ethyl acetate as eluent to give 3-[(4'-hydroxybiphenyl-4-yl)ethynyl]quinuclidin-3-ol (220 mg) as a solid, m.p. 230°-233° C.; microanalysis, found C, 76.7; H, 6.6, N, 4.4%; C21H21NO2.0.5H2O requires C, 76.8; H, 6.7; N, 4.26%; NMR (DMSO-d6): 1.2-1.42(1H, m), 1.5-1.72(1H, m), 1.8-2.0(3H, m), 2.65-2.8(4H, t), 2.8-3.2(2H, d of d), 5.6-5.7(1H, br), 6.8-6.9(2H, d) and 7.48-7.63(6H, m); m/z 320 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(O[C:24](SC(OCC)=S)=[S:25])C.[K]>N1C=CC=CC=1.C(OCC)(=O)C>[S:25]=[C:24]1[NH:1][C:2]2[C:19](=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)[O:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Reactant: CCOC(=S)SC(=S)OCC
Agent: [K]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cc3[nH]c(=S)oc3cc2CC1
Temperature: 70 °C
Yield: 69.4 %

Procedure:
1,1-Dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (3.6 mmol) and potassium [(ethyloxy)carbonothioyl]sulfide (3.96 mmol) were suspended in pyridine (6 ml) and the reaction mixture was heated at 70° C. for 3 h. The solvent was removed under reduced pressure providing a crude product that after dissolution in ethyl acetate, washing with water and evaporation of the organic phase under reduced pressure gave the title compound as a yellow solid (2.5 mmol, 69% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][C@@H:44]1[CH2:49][CH2:50][OH:51])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.C(N(CC)CC)C>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH2:45][C@@H:44]1[CH2:49][CH2:50][OH:51])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CCO
Reactant: O=C(O)c1cccc2cccnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3cccnc23)C[C@@H]1CCO
Reaction time: 8 h

Procedure:
8-Quinoline carboxylic acid (1.00 g, 5.78 mmol), EDC.HCl (1.22 g, 6.38 mmol), HOBT (1.77 g, 13.1 mmol) in DMF at pH 7 (adjusted with triethylamine) was stirred at 20° C. for 15 min. 1-tert-Butoxycarbonyl-2(S)-(2-hydroxyethyl)piperazine (1.33 g, 6.71 mmol) was added and the reaction stirred overnight. DMF was removed in vacuo, and the residue taken up in 1:1:1 THF, methanol, and 5% aqueous sodium hydroxide. This was stirred at 20° C. for 72 h. The volatiles were removed in vacuo, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated sodium chloride solution, then dried over magnesium sulfate. The title compound was obtained as a foam (1.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)#[N:2].[OH-:27].[Na+]>CO.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)(=[O:27])[NH2:2]
Reactant: [OH-]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)cn3)cc(C)c21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(C(N)=O)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(5-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified to pH 3 with 1 N HCl and then concentrated. HPLC purification gave product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=2 Hz, 1H), 8.20 (dd, J=8.4, 2.4 Hz, 1H), 7.96 (s, 1H), 7.41 (s, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 5.46 (dd, J=9.6, 2.4 Hz, 1H), 3.02 (dd, J=15.6, 2.4 Hz, 1H), 2.24 (s, 3H), 2.09 (dd, J=15.2, 9.6 Hz, 1H). 3 protons assumed to be exchanged with solvents. MS (ESI) m/z=341 [M−H]+.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:14]([OH:16])=O)[CH3:2].[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH:29][C:14]([C:4]3[N:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[O:7][C:3]=3[CH2:1][CH3:2])=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CCc1oc(-c2ccccc2)nc1C(=O)O
Product: CCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 16 above, 5-ethyl-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-ethyl-2-phenyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C21H22N4O3 (m/e) 378, obsd 379 (M+H).
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[O:18]1[CH2:20][CH:19]1[CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>CC(O)C.O>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([O:22][CH2:21][CH:19]([OH:18])[CH2:20][N:7]2[CH2:8][CH:1]3[CH2:9][CH:5]([CH2:4][N:3]([C:10]([O:12][C:13]([CH2:16][CH3:17])([CH3:14])[CH3:15])=[O:11])[CH2:2]3)[CH2:6]2)=[CH:24][CH:25]=1)#[N:28]
Reactant: CCC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: N#Cc1ccc(OCC2CO2)cc1
Solvent: O
Solvent: CC(C)O
Product: CCC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
tert-Pentyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.0 g; 4.16 mmol; from step (b) above) was dissolved in IPA:H2O (9:1; 4 mL) and 4-(2-oxiranylmethoxy)benzonitrile (1.46 g; 8.32 mmol; see Example A above) was added to the resultant solution. The reaction mixture was stirred at 60° C. for 3 h, concentrated and the residue subjected to column chromatography (DCM:MeOH; gradient 1:0 to 68:32) giving the title compound (1.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 2-chloro-6-methylbenzoic acid (4.0 g, 23.4 mmol) in methanol (50 mL) and a few drops of concentrated sulfuric acid were stirred at reflux for 5 hours. After cooling to room temperature, methanol was evaporated, and the residue was dissolved in ethyl acetate (50 mL) The solution was extracted with saturated NaHCO3 (3×50 mL). The organic layer was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording methyl 2-chloro-6-methylbenzoate (3.07 g, 71% yield). The product was used without further purification.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([O:11][B:12](OC(C)C)[O:13][CH:14]([CH3:16])[CH3:15])([CH3:10])[CH3:9].C(Cl)(=O)C>>[C:1]1([B:12]([O:13][CH:14]([CH3:16])[CH3:15])[O:11][CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: CC(=O)Cl
Product: CC(C)OB(OC(C)C)c1ccccc1

Procedure:
Following the procedure of Example 9, phenyllithium (17 mL, 30.6 mmol) and triisopropoxyborane (5.6 g, 30 mmol) were reacted, and the reaction quenched with acetyl chloride (2.1 mL, 30 mmol) to yield after distillation 5.2 g (25.2 mmol, 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]1[CH:11]=[CH:12][C:13](C2C=CC=C(C3N4C=CC(C(O)(C)C)=NC4=NC=3)N=2)=[C:14]([CH:17]=1)[C:15]#[N:16]>>[Br:8][C:4]1[N:3]=[C:2]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:17][C:14]=2[C:15]#[N:16])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(O)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)n3)cnc2n1
Product: N#Cc1cc(F)ccc1-c1cccc(Br)n1
Yield: 49.8 %

Procedure:
2,6-Dibromopyridine (1.17 g, 5.0 mmol) was coupled to 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (synthesised as in Example 22) (1.48 g, 6.0 mmol) as described in Example 27 to afford 2-(6-bromopyridin-2-yl)-5-fluorobenzonitrile (0.69 g, 50%) as a white solid: δH (400 MHz, CDCl3) 1.42 (9H, s), 6.96 (1H, d, J 7), 7.45 (1H, d, J 1), 7.72 (1H, d, J 1), 8.33 (1H, d, J 7).
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[CH2:10](Cl)[CH:11]=[CH2:12]>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:12][CH:11]=[CH2:10]
Reactant: C=CCCl
Reactant: COCCOCCO
Agent: [K]
Solvent: O
Product: C=CCOCCOCCOC
Temperature: 10 °C
Reaction time: 8 h

Procedure:
1,700 mls of dried peroxide free tetrahydrofuran, available from Fisher Scientific Company, 15 Jet View Drive, P.O. Box 8740, Rochester, NY 14624 and 158.7 g potassium metal, available from Fisher Scientific, are charged under dry nitrogen into a 5,000 ml three-neck round bottom flask equipped with mechanical stirrer. The solution is chilled to 10° C., using an icewater bath and 494 ml of diethylene glycol monomethyl ether, available from Chemical Samples Company, 4692 Kenny Road, Columbus, OH 43221, is added dropwise. The potassium metal reacts within 24 hours at which time 350 mls of allyl chloride available from Aldrich, 159 Forest Street, Metuchen, NJ 08840, is added dropwise at such a rate to maintain a gentle reflux. After the reaction is allowed to continue overnight, one liter of distilled water is added to the reaction vessel to dissolve the precipitated salts. The tetrahydrofuran layer is washed three times with a salt water solution (270 g NaCl to 1 liter H2O) to remove excess alcohol. The tetrahydrofuran is removed with a water aspirator and the product is distilled at reduced pressure. 410 g of diethylene glycol allyl methyl ether is obtained (b.p. 109° C./30 mm). The analytical data is consistent with a product of the general formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[NH:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:26]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: OC1CCNC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)N1CCC(O)C1
Yield: 40 %

Procedure:
The compound (40 mg, 0.11 mmol) prepared in Example 27 and 3-pyrrolidinol instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (19 mg, Yield 40%).