Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:30]O.Cl>CO.CO.O.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@H:7]2[CH2:12][C@H:11]([C:13]3[O:20][NH:30][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(Cc2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
A solution of methyl 2-(4-chlorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (780 mg, 2.04 mmol) (from example 115, step 2) in MeOH (5 mL) was added to a solution of sodium hydroxide (1.705 mL, 2.05 mmol) in MeOH/H2O (1.608 mL/0.097 mL) at −30° C. After 10 min a solution of hydroxylamine hydrochloride (284 mg, 4.09 mmol) and sodium hydroxide (163 mg, 4.09 mmol) in MeOH (5 mL) and H2O (5 mL) was added. Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (3.40 mL, 20.43 mmol) at 80° C. and heated at 80° C. for 30 min. Concentration of the organic solvent and extraction with diethyl ether (×3), drying over Na2SO4 and evaporation gave a yellow foam. Purification using prepLC (pH=3, large column 20-80% MeCN over 30 min) yielded trans-methyl 2-(4-chlorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (272.5 mg, 38%). 1H NMR (400 MHz, cdcl3) δ 1.44-2.18 (m, 4H), 2.70-3.01 (m, 2H), 3.02-3.14 (m, 2H), 3.42-3.76 (m, 3H), 4.04-4.37 (m, 1H), 4.39-4.79 (m, 1H), 5.64 (s, 1H), 7.05-7.31 (m, 4H). MS m/z 351, 353 (M+H)+
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[C:15]([NH2:17])=[O:16])C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:15]1(=[O:16])[C:7]2=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[N:6]2[CH:5]=[CH:4][NH:17]1
Reactant: CCOC(Cn1c(C(N)=O)cc2c1CCCC2)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]ccn2c3c(cc12)CCCC3
Temperature: 110 °C
Yield: 88.5 %

Procedure:
A mixture of 121d (2.7 g, 9.6 mmol) and acetic acid (10 mL) was heated at 110° C. for 2 h. The mixture was cooled to room temperature and neutralized with aqueous sodium carbonate solution and extracted with ethyl acetate (3×30 mL). The combined organic phase was concentrated under reduced pressure to afford 121e as a yellow solid (1.6 g, 88%). MS-ESI: [M+H]+ 189.3. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.02 (d, J=5.5 Hz, 1H), 6.63 (s, 1H), 6.52 (pt, J=5.5 Hz, 1H), 2.66 (t, J=6.0 Hz, 2H), 2.57 (t, J=6.0 Hz, 2H), 1.83-1.82 (m, 2H), 1.73-1.72 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27]([Cu])#[N:28]>CN(C=O)C.[Cl-].[NH4+]>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:27]#[N:28])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C#N)cc1OCC2)c1ccccc1Cl
Temperature: 250 °C

Procedure:
To a solution of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (50 mg, 0.11 mmol) in 1 mL of DMF in a 10 mL microwave vial was added CuCN (30 mg). The reaction vessel was sealed and heated to 250° C. in a microwave for 20 min. The whole was cooled to room temperature, diluted with saturated aqueous ammonium chloride and extracted with ethylacetate. The combined organic extracts were concentrated and the crude residue purified by reverse phase HPLC to give 143. 1H NMR (500 MHz, DMSO-d6) δ 7.65 (m, 2H), 7.58-7.46 (m, 5H), 6.64 (s, 1H), 4.22 (m, 2H), 3.28 (s, 3H), 3.00 (m, 2H). MS: (ESI+) 395.1
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].N1C=CC=CC=1.[CH:16]([O:19][CH:20]([O:34][CH:35]([CH3:37])[CH3:36])[C:21]([CH3:33])([CH3:32])[C:22](=[O:31])[CH2:23][C@@H:24]([OH:30])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:18])[CH3:17].[Na+].[Cl-]>C(Cl)Cl>[CH:35]([O:34][CH:20]([O:19][CH:16]([CH3:18])[CH3:17])[C:21]([CH3:32])([CH3:33])[C:22](=[O:31])[CH2:23][C@@H:24]([O:30][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:37])[CH3:36]
Reactant: C=CC[C@H](C)[C@H](O)CC(=O)C(C)(C)C(OC(C)C)OC(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)C(OC(C)C)OC(C)C)OC(=O)OCC(Cl)(Cl)Cl
Reaction time: 5 h

Procedure:
Trichloroethyl chloroformate (2.5 mL) and pyridine (2.95 mL) are added to a solution of (5R,6S)-1,1-diisopropoxy-5-hydroxy-2,2,6-trimethyl-8-nonen-3-one (2.9 g) in 40 mL of CH2Cl2 at 0° C., and the mixture is stirred for 5 hours before pouring into sat. aq. NaCl and extracting with CH2Cl2. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1O
Temperature: 120 °C
Yield: 104.5 %

Procedure:
The mixture of 3-hydroxy-4-methoxy-benzaldehyde (30 g) and malonic acid (42 g) in pyridine (80 ml) and piperidine (4 ml) was heated at 120° C. for 6 hours. The solution was cooled to room temperature and concentrated to 20 ml. The residue was dissolved in 500 ml of water and the solution was acidified with concentrated HCl until PH=3. The solid was collected to give 3-(3-Hydroxy-4-methoxy-phenyl)-acrylic acid (40 g). LC-MS: m/e 195 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:11])=[N:5][C:6](Cl)=[N:7][C:8]=1[Cl:9].C[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1C=CC=CC=1>[O:16]1[CH2:17][CH2:18][N:13]([C:6]2[N:5]=[C:4]([Cl:11])[C:3]([O:2][CH3:1])=[C:8]([Cl:9])[N:7]=2)[CH2:14][CH2:15]1
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Reactant: CN1CCOCC1
Solvent: c1ccccc1
Product: COc1c(Cl)nc(N2CCOCC2)nc1Cl

Procedure:
150 parts by volume of benzene, 34 parts of 5-methoxy-2,4,6-trichloro-pyrimidine and 17.7 parts of N-methyl-morpholine are introduced into a reactor. The mixture is heated under reflux for 3 hours, then filtered and the solution is evaporated. The residue obtained is recrystallised from ethanol. 30 parts of 2-morpholino-5-methoxy-4,6-dichloro-pyrimidine of melting point 116°C are thus obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:20]([N+:17]([O-:19])=[O:18])[CH3:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1C
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1C

Procedure:
The starting material is prepared as follows: The mixture of 100 g of 3-methyl-4-methoxybenzaldehyde, 300 ml of nitroethane and 52 g of ammonium acetate is refluxed for 4 hours and evaporated, to yield the 1-(3-methyl-4-methoxyphenyl)-2-nitropropene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[CH3:29][C:30]1([CH3:38])[O:34][C@@H:33]([CH2:35][O:36][NH2:37])[CH2:32][O:31]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:37][O:36][CH2:35][C@H:33]1[CH2:32][O:31][C:30]([CH3:38])([CH3:29])[O:34]1)=[O:21]
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)NOC[C@H]2COC(C)(C)O2)c(=O)n(C)c1=O
Yield: 42.2 %

Procedure:
Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23, 300 mg, 0.588 mmol, 1 eq) and (R)-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (260 mg, 1.826 mmol, 3 eq) were mixed in anhydrous THF (1.5 ml). The mixture was subjected to microwave irradiation at 100° C. for 50 minutes. The intended product was isolated by HPLC purification to give 140 mg of white solid (42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 3 H) 1.46 (s, 3 H) 3.04 (s, 3H) 3.38 (s, 3H) 3.85-3.8758 (m, J=8 Hz, 1 H) 4.03-4.05 (d, J=8 Hz, 2 H) 4.10-4.11 (t, J=4 Hz, 1 H) 6.70-6.72 (d, J=8 Hz, 1H) 7.56-7.58 (d, J=8 Hz,1 H) 7.82 (s, 1 H) 12.07 (s, 1 H) 12.79 (s, 1 H) [M+H] calc'd for C19H22ClIN4O6, 565; found, 565.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) (300 mg, 0.49 mmol) in tetrahydrofuran (10 mL) was added 1N HCl (2.4 mL) and stirring was continued for 1 h at room temperature. After completion of the reaction, the tetrahydrofuran was removed and the reaction mixture was basified with solid NaHCO3 (to pH 8), extracted with ethyl acetate (3×20 mL) and the organic part was dried and concentrated to yield a crude product which was purified by prep TLC (mobile phase ethyl acetate) to get 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (406) (210 mg, 86%) as a light yellow sticky solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[O:8]=[C:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=2)[NH:10]1>C1COCC1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[S:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:8])[CH2:17]2)(=[O:19])=[O:20]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: CNCCN(C)C
Solvent: C1CCOC1
Product: CN(C)CCN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reaction time: 3 h

Procedure:
To a solution of N1,N1,N2-trimethylethane-1,2-diamine (26 uL, 0.20 mmol) in THF (2 mL) was added 2-oxoindoline-5-sulfonyl chloride (30 mg, 0.130 mmol) and the reaction stirred for 3 hours. The solvent was removed and the crude material used for the next step. MS ESI 298.0 [M+H]+, calcd for [C13H19N3O3S+H]+ 298.12.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])(=O)C.[Na+].[Br:17]Br.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]2[C:10]([Br:17])=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(F)c(Br)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of 2-amino-6-fluorobenzothiazole (245 mg, 1.46 mmol) and sodium acetate (244 mg, 2.97 mmol) in acetic acid (1.60 mL) was added bromine (1.0 M in AcOH, 1.60 mL, 1.60 mmol) at RT. The mixture was stirred at RT for 1 h. The mixture was then treated with aqueous Na2CO3 until pH=7 and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with water (2×20 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated. Purification by ISCO chromatography (0 to 30% EtOAc:heptane) afforded 357 mg of the impure title compound as a dark brown solid (357 mg). MS (ESI): 246.92, 248.93 [M+H]+; HPLC tR=1.25 min (TOF: polar—3 min).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[C:18]([CH2:20][C:21]1([C:26]#[N:27])[CH2:24][C:23](=O)[CH2:22]1)#[N:19]>O1CCCC1>[C:18]([CH2:20][C:21]1([C:26]#[N:27])[CH2:24][C:23](=[CH:9][C:7]#[N:8])[CH2:22]1)#[N:19]
Reactant: N#CCC1(C#N)CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC(C#N)(CC#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (2.15 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (0.364 mL, 0.00225 mol) in tetrahydrofuran (4 mL, 0.04 mol). The reaction was warmed to rt and then cooled to 0° C. again. To the reaction mixture was added a solution of 1-(cyanomethyl)-3-oxocyclobutanecarbonitrile (0.274 g, 0.00204 mol) in tetrahydrofuran (2 mL, 0.02 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water and brine, then dried and evaporated to dryness. The crude mixture was used directly in next step.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH:19]([NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:18][CH2:17]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][C@H:19]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17][C:16]=3[CH:15]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)NC1CCc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2C1
Agent: Cl
Solvent: C1CCOC1
Product: CCCN[C@@H]1CCc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2C1
Yield: 55 %

Procedure:
N-[6-(4-Isopropyl-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propionamide (0.19 g, 0.47 mmol) was dissolved in 10 mL of tetrahydrofuran (THF) and 3 mL (31.3 mmol) of a borane-THF complex was introduced dropwise over 20 min. The resulting mixture was stirred at reflux for 3 h. The solution was cooled, 3 mL of 2 N HCl was added slowly, and the mixture was stirred at 40° C. for 1 h. The cooled solution was quenched with water, then NaOH (2N) and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and the filtrate was evaporated in vacuo to give the product as a colorless oil (100 mg, 55%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:28])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:28])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:22]=1)[CH3:16]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
5-Phenyl-furan-2-carboxylic acid (56) (35 mg, 0.19 mmol) was coupled to 3-(3-amino-phenyl)-acrylic acid ethyl ester (60) (39 mg, 0.20 mmol) using Method D to give the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:38])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:30]=[N:29][C:28]4[NH:27][C:26](=[O:31])[C:25]([CH3:37])([C:32]([O:34]CC)=[O:33])[O:24][C:23]=4[CH:22]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2].[Li+].[OH-]>C1COCC1>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:30]=[N:29][C:28]4[NH:27][C:26](=[O:31])[C:25]([CH3:37])([C:32]([OH:34])=[O:33])[O:24][C:23]=4[CH:22]=3)=[CH:11][C:9]=2[N:10]=1)=[O:38])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc4c(c3)OC(C)(C(=O)OCC)C(=O)N4)cc(-c3ccccn3)c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc4c(c3)OC(C)(C(=O)O)C(=O)N4)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
To an ice-cold solution of ethyl 7-(2-(3-ethylureido)-7-(pyridin-2-yl)benzothiazol-5-yl)-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-2-carboxylate (0.10 g, 0.19 mmol) in THF was added LiOH (0.023 g, 0.57 mmol dissolved in minimum amount of H2O) and the mixture stirred at rt for 3 h. After completion of reaction (by TLC), the solvent was concentrated and 10 mL of water added to the reaction. The aqueous layer was washed with EtOAc (2×50 mL) and the organic layer discarded. The pH of the aqueous layer was adjusted up to 4-5, extracted with hot EtOAc (3×50 mL) and the combined organic layer dried over Na2SO4, filtered and concentrated under reduced pressure. The residue thus obtained was triturated with ether to afford Compound 190 as an off-white solid (0.06 g, 63%). 1H NMR (DMSO-d6): δ 1.11 (t, J=7.20 Hz, 3H), 1.74 (s, 3H), 3.21 (m, 2H), 6.86 (br s, 1H), 7.44 (m, 1H), 7.97-8.06 (m, 3H), 8.28 (s, 1H), 8.50 (s, 1H), 8.56 (d, J=8.0 Hz, 1H), 8.81 (d, J=4.0 Hz, 1H), 10.63 (br s, 1H) and 11.57 (br s, 1H). MS: 505.29 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH:9]([C:14]([OH:16])=[O:15])[CH2:8][CH2:7][C:6]=2[N:5]=1)(=[O:3])[CH3:2].[CH3:17][Mg]Cl>C1COCC1>[OH:3][C:1]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH:9]([C:14]([OH:16])=[O:15])[CH2:8][CH2:7][C:6]=2[N:5]=1)([CH3:17])[CH3:2]
Reactant: CC(=O)c1ccc2c(n1)CCC(C(=O)O)C2
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(n1)CCC(C(=O)O)C2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 25 mL flask was added 2-acetyl-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (146 mg, 0.667 mmol) and tetrahydrofuran (2.7 mL). The system was purged with nitrogen and cooled to 0° C. 3M of methylmagnesium chloride in tetrahydrofuran (0.598 mL, 2.00 mmol) was added dropwise over 3 minutes. The mixture was stirred at 0° C. for 5 minutes then allowed to warm to room temperature. Additional THF (5 mL) was added and the mixture was sonicated for 1 minute to break up solids. After a total of 2 hours the reaction was carefully quenched by dropwise addition of 1M NaH2PO4 (10 mL). The mixture was diluted with DCM (10 mL) and citric acid (0.5 mL) was added to obtain a pH of 4. The layers were separated and the aqueous was extracted with 3:1 DCM/THF (10 mL) followed by with 3:1 CHCl3/IPA (15 mL×2), dried (Na2SO4), filtered and evaporated to obtain a reddish foam (160 mg, theoretical yield), which was used directly in the next step. m/z=236.2 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.55 (d, J=8.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.10-2.90 (m, 4H), 2.85-2.74 (m, 1H), 2.32-2.25 (m, 1H), 2.06-1.95 (m, 1H), 1.51 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([CH3:17])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)=[O:8])[CH3:2].C(O)(=O)C.Br>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([CH3:17])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC(C)C(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of crude 4-(4-methoxy-phenyl)-3-methyl-4-oxo-butyric acid ethyl ester (44 g, 175.8 mmol), acetic acid (300 mL) and 48% aqueous HBr (150 mL) was stirred at reflux for 10 h. The reaction was cooled to rt, concentrated at reduced pressure then partitioned between methylene chloride and water and the aqueous layer was extracted three times with methylene chloride and concentrated to provide a crude material. The crude material was dissolved in ethanol (125 mL) and added amberlyst then heated at 85° C. for 15 h. The reaction mixture was filtered over celite at rt and the filtrate was concentrated at reduced pressure and then partitioned between water and methylene chloride. The aqueous layer was extracted twice with methylene chloride to furnish a crude product and the crude product was purified by ISCO (330 g silica gel column) chromatography using 20 to 30% EtOAc in hexane to obtain a mixture (19 g) of 4-(4-hydroxyphenyl)-3-methyl-4-oxo-butyric acid ethyl ester (MS m/z 235 (M−H) and p-hydroxypropiophenone. The mixture was used for the next reaction without further purification.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Br)cn1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Product: COc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1

Procedure:
Title compound was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 5-bromo-2-methoxypyridine using the protocol outlined for Example 128 (E128); MS (ES+) m/e 325 [M+H]+.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[C:1]1([O:11][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1cccc2c1CCCC2
Product: CN(C(=O)Oc1cccc2c1CCCC2)c1ccccc1

Procedure:
The title product was prepared from 5,6,7,8-tetrahydro-1-naphthol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (42%, colorless oil). HPLC-MS: m/z=282.1 (M+1); Rt: 4.77 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][CH2:12][C@H:11]1[O:19]C1CCCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][CH2:12][C@H:11]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[C@H]1CC[C@@H](OC2CCCCO2)[C@@H]1COCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCC[C@H]1CC[C@@H](O)[C@@H]1COCc1ccccc1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 66.4 %

Procedure:
A mixture of 8.57 g of (1R,2S,3S)-2-benzyloxymethyl-3-butyl-1-(2-tetrahydropyranyloxy)cyclopentane (prepared in Reference Example 6), 50 ml of tetrahydrofuran and 25 ml of 2N hydrochloric acid was stirred for 2.5 hrs at 40° C. The mixture was extracted with 150 ml of diethyl ether, and the extract was washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3:1) as eluent to give 4.31 g of the title compound having the following physical characteristics, in a 66.4% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25](O)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Yield: 53.2 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 184 μmol) and morpholine (16 μl, 184 μmol) as starting materials. The reaction affords 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (44 mg, 53.2%) as white solid. mp.: 212-214° C., MS: m/z=450.0 (M+H+).