Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([SH:22])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.S(OC)(O[CH3:29])(=O)=O.[OH-].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([S:22][CH3:29])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Sc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.1 g (3.0 mmole) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-thiol, 1.0 ml (10 mmole) of dimethyl sulfate, 20 ml of 1N sodium hydroxide and 10 ml of ethanol was stirred at room temperature for 15 min. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an oil. Crystallization from ether gave colorless prisms, mp 187°-188° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][N:4]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:32][CH:31]2[NH2:33])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:32][CH:31]2[NH:33][CH2:2][C:3]2[O:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][N:4]=2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1nnc(CCl)o1
Reactant: NC1CC1c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nnc(CNC2CC2c2ccc(OCc3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Tert-butyl (5-(chloromethyl)-1,3,4-oxadiazol-2-yl)carbamate (141 mg, 0.606 mmol) was added to a solution of 2-(4-(benzyloxy)phenyl)cyclopropanamine (enantiomer (−)) (145 mg, 0.606 mmol) and K2CO3 (166 mg, 1.213 mmol) in dry DMF (1.5 mL) and stirred at RT for 2 h. After completion, the reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (4×10 mL). The combined organic extracts were washed with water (3×10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography (SiO2) using MeOH:CHCl3 (1:99) as eluent to afford tert-butyl (5-(((2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate (enantiomer-(−)) (100 mg, 37.7%) as a pale green liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[Li]CCCC.CN([CH:36]=[O:37])C>>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:36]=[O:37])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of 1-(4-bromophenyl)-4-(tert-butoxycarbonyl)piperazine (9.98 g, 29.2 mmol, prepared as described in Example 1) in TI (70 mL) and toluene (70 mL) was added nBuLi (1.6 M in hexanes, 19 mL, 30.4 mmol) at a rate to maintain an internal temperature below −65° C. The resulting solution was stirred 15 min, then treated with DMF (5 mL). The mixture was stirred 30 min at −78° C., then allowed to warm to 0° C., quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated. The crude material was crystalized from dichloromethane/ether/hexanes to give 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzaldehyde. The filtrates were purified by flash chromatography (30% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) to provide an additional 2.16 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]4[CH:26]5[CH2:27][CH2:28][CH:22]4[CH2:23][C:24]([C:30]([F:33])([F:32])[F:31])([OH:29])[CH2:25]5)=[O:20])[CH2:14][C:13]=3[CH:34]=2)[CH:5]=[N:6][C:7]=1[NH2:8].[CH:35](OC)(OC)OC>C(OCC)C>[NH:1]1[C:2]2[C:7](=[N:6][CH:5]=[C:4]([C:9]3[CH:10]=[CH:11][C:12]4[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]5[CH:22]6[CH2:28][CH2:27][CH:26]5[CH2:25][C:24]([C:30]([F:33])([F:32])[F:31])([OH:29])[CH2:23]6)=[O:20])[CH2:14][C:13]=4[CH:34]=3)[CH:3]=2)[N:8]=[CH:35]1
Reactant: Nc1cc(-c2ccc3c(c2)CN(C(=O)N2C4CCC2CC(O)(C(F)(F)F)C4)CCO3)cnc1N
Reactant: COC(OC)OC
Solvent: CCOCC
Product: O=C(N1CCOc2ccc(-c3cnc4nc[nH]c4c3)cc2C1)N1C2CCC1CC(O)(C(F)(F)F)C2
Yield: 29 %

Procedure:
A slurry of 8-{[7-(5,6-diaminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (0.22 g, 0.46 mmol) and trimethyl orthoformate (3.5 mL) was heated (105° C.) for 30 minutes. The reaction mixture was diluted with ethyl ether and the resulting precipitate was collected by filtration. Purification by preparative reverse phase HPLC provided 8-{[7-(1H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (64 mg, 29% yield) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.39 (s, 1H), 8.87 (s, 1H), 8.44 (s, 1H), 7.66 (s, 1H), 7.62 (dd, 1H), 7.07 (d, 1H), 5.81 (bs, 1H), 4.57 (s, 2H), 4.26 (s, 2H), 4.05 (s, 2H), 3.70 (s, 2H), 2.03 (m, 4H), 1.74 (m, 4H); MS (ES) for C24H24F3N5O3: 488 (MH+).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]C)(=O)[CH2:5][C:6](OC)=[O:7].[NH2:13][C:14]1[N:18]=[C:17]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:16][N:15]=1>CO.C(O)C>[CH2:20]([S:19][C:17]1[N:18]=[C:14]2[N:13]=[C:4]([OH:11])[CH:5]=[C:6]([OH:7])[N:15]2[N:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Oc1cc(O)n2nc(SCc3ccccc3)nc2n1
Temperature: 25 °C
Yield: 127.8 %

Procedure:
A solution of 125 g (0.58 mol) of a 25% solution of sodium methoxide in methanol dissolved in 100 ml of absolute ethanol was treated with 66.3 ml (0.29 mol) of dimethyl malonate followed by 60.0 g (0.20 mol) of 3-amino-5-benzylthio-1,2,4-triazole. The resulting solution was heated at reflux for 5 days. On cooling to room temperature the solid which had separated was collected by filtration, washed with cold ethanol and dissolved in 1000 ml of water. The resulting yellow solution was acidified with concentrated HCl to precipitate a solid. The solid was collected by filtration and dried to yield 70.1 g (82%) of the desired product as a white solid, m.p. 199°-210° C. (decomposition). IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH:36]([NH2:39])([CH3:38])[CH3:37].[BH4-].[Na+]>C(Cl)Cl.CO>[CH:31]([N:14]([CH2:13][C@H:11]1[C@H:10]([CH2:34][NH:39][CH:36]([CH3:38])[CH3:37])[CH2:9][NH:8][CH2:12]1)[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CNC(C)C)C(C)C)ccc1OC

Procedure:
from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.52 mmol), isopropylamine (0.654 mL, 7.61 mmol) and NaBH4 (0.115 g, 3.04 mmol) and purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4, then CH2Cl2/MeOH (10% NH3 conc.) gradient from 9:1 to 8:2) to give the title compound as colorless oil. MS: 536.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.58 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][OH:22])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:23][CH3:24])[CH:3]=1.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CO)C(C)=CC(C)(C)N2
Reactant: COC(=O)Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(=O)Cc1ccccc1OCc1c(-c2ccc(F)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
6-(4-Fluoro-2-methoxyphenyl)-5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-3, 100.1 mg, 0.31 mmol), methyl 2-hydroxyphenylacetate (76.1 mg, 0.46 mmol), tri-butylphosphine (114 μL, 0.46 mmol), and 1,1′-(azodicarbonyl)dipiperidine (117 mg, 0.46 mmol) were dissolved in anhydrous benzene (2 mL), and the mixture was stirred under argon atmosphere at room temperature for 1 hour. Hexane (5 mL) was added to the reaction mixture and unsoluble materials were filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (107.1 mg) as a colorless amorphous product. (Yield 74%)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=O)[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:31][N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([NH:32][OH:31])=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccs3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)c3cccs3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylic acid (335 mg, 0.75 mmol) in dimethylformamide (7 ml), 1-hydroxybenzotriazole (121 mg, 0.90 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol), N-methylmorpholine (0.124 ml, 1.13 mmol), and hydroxylamine (0.229 ml, 3.75 mmol), 216 mg (62%) of the product was isolated as a solid. HR-MS: m/z Calculated for C21H22N2O6S2 463.0992; Found 463.0988.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[OH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2[C:31]2[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Reactant: OB(O)c1ccc(O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(O)cc2)c1OCC1CC1
Yield: 58.4 %

Procedure:
A solution of Intermediate 2 (500 mg, 1.040 mmol), 4-hydroxyphenylboronic acid (172 mg, 1.249 mmol), Pd[(C6H5)3P]4 (120 mg, 0.104 mmol) and cesium fluoride (506 mg, 3.331 mmol) in dry THF was heated to reflux for 4.0 h. After completion of reaction, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4 to afford a crude residue which was purified using 1% CH3OH in CHCl3 to afford 271 mg of the desired compound as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 2H), 0.48-0.54 (m, 2H), 1.03-1.07 (m, 1H), 3.67-3.70 (m, 2H), 3.76 (s, 3H), 6.81-6.92 (m, 3H), 6.97-7.03 (m, 3H), 7.10-7.13 (m, 2H), 7.47 (d, J=4.5 Hz, 1H), 7.95 (d, J=5.1 Hz, 1H), 8.10 (d, J=15.6 Hz, 1H), 9.57 (s, 1H); ESI-MS (m/z) 447.20 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=[O:17])[CH3:13].CC[O-].[Na+]>>[CH2:12]([O:14][C:15](=[O:21])[C:16](=[O:17])[CH2:10][C:9](=[O:11])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)COc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Temperature: 25 °C
Yield: 16.2 %

Procedure:
Phenoxyacetone (5.0240 g, 33.46 mmol) and diethyloxalate (4.52 mL, 33.29 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 11.1 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 40. The crude material was purified with 1:1 Hexanes:CH2Cl2 to obtain 1.3490 g (15.4%) of 40. 1H (CDCl3, 400 MHz): δ 7.31 (2H, t, J=7.5 Hz), 7.01 (1H, t, J=7.3 Hz), 6.91 (2H, d, J=8.8 Hz), 6.76 (1H, s), 4.67 (2H, s), 4.35 (2H, q, J=7.1 Hz), 1.38 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 199.61, 166.38, 161.55, 157.37, 129.63, 121.89, 114.48, 98.97, 70.13, 62.60, 13.90 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 13.90; CH2 carbons: 70.13, 62.60; CH carbons: 129.63, 121.89, 114.48, 98.97 ppm. HPLC: 10.180 min. (Starting material: 9.053 min)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH2:12]1>>[CH2:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][C:19]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:20])[CH2:12]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)CCC1CCCCC1
Product: O=C(CCC1CCCCC1)Nc1ccc(C(=O)O)cc1

Procedure:
4-(3-Cyclohexanepropionylamino)-benzoic acid was prepared as described in Example 3 from 10.0 g (0.073 mol) of p-aminobenzoic acid and 14.0 g (0.08 mol) of 3-cyclohexanepropionyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]3[OH:19])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].I[CH2:29][CH3:30]>>[CH2:29]([N:13]1[C:14]([CH3:15])=[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:11]([O:16][C@@H:17]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]2[OH:19])=[N:12]1)[CH3:30]
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Reactant: CCI
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CC)c2C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 61 using 4-[(4-ethylphenyl)methyl]-5-methyl-3-(β-D-glucopyranosyloxy)-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole and using iodoethane instead of iodopropane.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:18]=[C:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1[nH]sc2ccccc12
Reactant: O=C=NCc1ccccc1
Product: O=C(NCc1ccccc1)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6i (88% yield) was synthesized from benzo[d]isothiazol-3-one and benzyl isocyanate as a white solid. mp 169-170° C.; IR(CHCl3) 3281, 1711, 1663, 1536 cm−1; 1H-NMR (CDCl3) δ4.64 (d, J=5.9 Hz, 2H), 7.28-7.45 (m, 5H), 7.58 (d, J=7.2 Hz, 1H), 7.70 (t, J=7.2 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 9.26 (br s, 1H); ESIMS m/e 285 (M++1).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:11]1[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:22])([F:1])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:12]=1
Reactant: Cc1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 115 °C
Yield: 98.4 %

Procedure:
To 2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methyl-3H-quinazolin-4-one (0.23 g, 0.76 mmol) were added DIEA (0.27 mL, 1.5 mmol) and POCl3 (5 mL, 55 mmol) and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and the mixture was concentrated under reduced pressure. The residue was treated with toluene and concentrated to dryness twice. The residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL). The separated EtOAc layer was diluted with of EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL) and brine (10 mL×2), dried over MgSO4, filtered and concentrated under reduced pressure to afford 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methyl-quinazoline as a brown viscous oil (242 mg, 99%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2cccc(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2cccc(OC)c2)cc1
Temperature: 50 °C
Yield: 102.9 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.16 g). To the solution was added 1N sodium hydroxide solution (2.8 ml), and the mixture was heated at 50° C. overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.16 g) as yellow crystals.
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:25]1[N:26]=[C:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[CH3:35])[O:28][CH:29]=1)[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[O:15][C:16]=1[C:17]1[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:37][C:34]([F:36])([CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:27]1[O:28][CH:29]=[C:25]([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH3:24])[O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[N:26]=1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)N(C(=O)OC(C)(C)C)c2coc(CCCCC(C)(F)F)n2)c1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2coc(CCCCC(C)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5,5-difluoro-hexyl)-oxazol-4-yl]-(2-methyl-5-m-tolyl-oxazole-4-carbonyl)-carbamic acid tert-butyl ester (32 mg, 0.06 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.05 mL, 0.65 mmol). After stirring at rt for 16 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a light brown solid. TLC: rf (4:1 hept-EA)=0.21. LC-MS-conditions 02: tR=1.17 min, [M+H]+=404.43.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=O>C(O)C>[Cl:26][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:14][CH:16]=2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(CC(N)=S)cc1
Solvent: CCO
Product: COC(=O)c1ccc(Cc2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1
Yield: 93.1 %

Procedure:
To a solution of the compound (209 mg, 1.0 mmol) obtained in Example 178a in ethanol (4 ml) was added 2-bromo-1-(3,4-dichlorophenyl)ethanone (268 mg, 1.00 mmol), and the mixture was heated under reflux for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diluted aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (352 mg, 93%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[C:20](OCCBr)(=[O:22])C>>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH2:19][CH2:20][OH:22])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC(=O)OCCBr
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Product: CCOC(=O)c1cc(OCCO)c2ccn(C3CC3)c2c1

Procedure:
The compound was prepared according to the procedure for ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate but using bromoethyl acetate in place of MeI.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH:12]=[C:13]([CH3:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:18][NH2:19]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][C:13]([CH3:15])([CH3:14])[NH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)C=C(C)C)cc1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNC(C)(C)C2)cc1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar, Vigreux column and nitrogen inlet was charged with 1-(3,4-dimethoxy-phenyl)-3-methyl-but-2-en-1-one (1.4 g, 10 mmol), EtOH (40 mL) and hydrazine monohydrate (0.58 mL, 12 mmol). The mixture was heated at 80° C. for 2 h. LC-MS and TLC analysis showed consumption of SM. The solvent was evaporated under reduced pressure and trace hydrazine and EtOH was removed under high vacuum for 30 min. The material was used as in the next step. Amount obtained: 2.3 g, 10 mmol, 100% yield. LC-MS (ESI) m/e 235 (M+H). Step 3