Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][CH2:13][OH:14])[N:8]=1)[CH3:6].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[C:31]([O:14][CH2:13][CH2:12][C:9]1[N:8]=[C:7]([CH:5]([CH3:6])[C:4]2[CH:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:2]([F:1])[CH:3]=2)[O:11][N:10]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCO)no1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a solution of 1.56 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-hydroxyethyl)-1,2,4-oxadiazole in 40 ml of dry THF were successively added dropwise 0.56 g of triethylamine and 0.43 g of acetyl chloride with ice-cooling. After stirring for 4 hours at room temperature, the reaction mixture was poured into ice-water and extracted with benzene. The organic phase was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel using chloroform to give 1.57 g of 3-(2-acetoxyethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as a colorless oil, nD23 1.5564.
Reaction SMILES: [CH2:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([CH:29]([OH:32])[CH2:30][NH2:31])=[CH:24][C:23]=1[Cl:33]>C1C=CC=CC=1>[NH2:21][C:22]1[C:23]([Cl:33])=[CH:24][C:25]([CH:29]([OH:32])[CH2:30][NH:31][CH:2]([CH3:4])[CH2:1][C:5]2[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]3[O:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=3)=[CH:7][CH:6]=2)=[CH:26][C:27]=1[Cl:28]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CC(=O)Cc1ccc(OCc2cc(=O)c(O)co2)cc1
Solvent: c1ccccc1
Product: CC(Cc1ccc(OCc2cc(=O)c(O)co2)cc1)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-[4-acetonylphenoxymethyl]-5-hydroxy-4H-pyran-4-one (1.0 g) and 2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethylamine (0.75 g) in benzene, was heated to reflux for 3 hours under a Dean and Stark head. After cooling, the solvent was removed in vacuo, the residue dissolved in methanol, treated with sodium cyanoborohydride (0.25 g) and then stirred at ambient temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue taken up in ethyl acetate and washed with water (2×50ml), brine (1×50 ml) and dried (MgSO4). After filtration and evaporation of solvent the residue was purified by column chromatography on silica using 3% methanol:chloroform as eluent to give 2-[4-[2-[(4-amino-3,5-dichloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-4H-pyran-4-one as a (40:60) mixture of diastereoisomers.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:23])[C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:3].C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([C:35](=[O:34])[CH2:36][OH:37])[CH2:29][CH2:30]3)=[O:23])[C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:3]
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)CO)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f17) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][CH:3]([OH:6])[CH2:4]Br.[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+]>O1CCCC1>[CH2:7]([S:14][CH2:2][CH:3]([OH:6])[CH2:4][S:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: SCc1ccccc1
Reactant: OC(CBr)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(CSCc1ccccc1)CSCc1ccccc1
Reaction time: 2 h

Procedure:
1,3-dibromo-2-propanol (2.18 g.) is added to a stirred suspension of the salt obtained by mixing 2.7 g. benzyl mercaptan and sodium hydride (56% dispersion in mineral oil; 900 mg.) in 50 ml. dry tetrahydrofuran. After 2 hours at room temperature, the solvent is removed and 20 ml. of water is added to the residue. The resultant aqueous mixture is extracted with ether and the extracts washed with water, dried over magnesium sulfate and evaporated to yield 1,3-bis(benzylthio)-2-propanol.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH:5]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[BH4-]>O.CO>[CH:16]1[C:12]2[CH:13]=[CH:14][C:15]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH:10]([OH:20])[C:11]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC1c2ccccc2C=Cc2ccccc21
Reaction time: 0.75 h

Procedure:
In this preparation a solution containing 1.5 grams of sodium borohydride in 30 ml. of water containing 1.5 ml. of 3N aqueous sodium hydroxide is added to a solution containing 15.0 g. of dibenzo[a,d]cyclohepten-5-one in 200 ml. of methanol at room temperature, with stirring. The resulting mixture is stirred for 45 minutes and then an additional 0.5 g. of borohydride in 10 ml. of water is added and the mixture stirred at room temperatue for 60 hours. The reaction mixture is then cooled in an ice water bath while 300 ml. of water is slowly added with stirring. The resulting precipitate is collected by filtration and washed repeatedly with water and dried under vacuum affording a residue of 5H-dibenzo[a,d]cyclohepten-5-ol, which is sufficiently pure to use as starting material for subsequent preparations.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C@@H:13]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[CH:29]([CH3:31])[CH3:30])[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:33])[C:20](=[O:32])[NH:21][N:22]=2)[CH3:14])([CH3:12])[CH2:9]1)=O)(C)(C)C.[ClH:34]>>[ClH:34].[CH:29]([C:28]1[CH:27]=[C:26]2[C:17]([N:18]3[C:23]([CH2:24][O:25]2)=[N:22][NH:21][C:20](=[O:32])[C@H:19]3[CH3:33])=[CH:16][C:15]=1[C@H:13]([C:10]1([CH3:12])[CH2:9][NH:8][CH2:11]1)[CH3:14])([CH3:30])[CH3:31]
Reactant: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Agent: Cl
Product: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Yield: 44 %

Procedure:
A solution of 3-[(R)-1-((R)-7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.0736 g, 0.162 mmol) in HCl (4M in EtOAc, 0.8 mL) was stirred for 1.5 h at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was purified by prep-HPLC (Table 3, Method 27) to give (R)-7-isopropyl-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (0.026 g, 44%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.01 (s, 1H), 6.83 (s, 1H), 4.87-4.82 (m, 1H), 4.60 (s, 2H), 4.16 (d, J=10.8 Hz, 1H), 4.02 (d, J=10.8 Hz, 1H), 3.64 (d, J=10.8 Hz, 1H), 3.55 (d, J=10.8 Hz, 1H), 3.42-3.37 (m, 1H), 3.18-3.11 (m, 1H), 1.52 (s, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.16 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 5) Rt=2.401 min.; MS m/z: 357 [M+H]+. SFC (Table 1, Method 26) Rt=7.575 min.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH3:25]I>CN(C)C=O>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[N:14]([CH3:25])[C:13]2=[O:20])=[CH:4][C:3]=1[C:2]([F:1])([F:21])[F:22])([O-:11])=[O:10]
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Reaction time: 0.25 h

Procedure:
A solution of 3.17 g of 1-(3-trifluoromethyl-4-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione (French Patent No. 2,329,276) and 32 ml of dimethylformamide were added at 23° C. to 26° C. to a 50% suspension of 492 mg of sodium hydride in oil and 3 ml of dimethylformamide and after stirring for 15 minutes, a solution of 0.7 ml of methyl iodide in 2 ml of dimethylformamide was added. The mixture was stirred for 25 minutes at 24° C. to 28° C. and was then poured into 200 g of a 1--1 water-ice mixture. The mixture was extracted with ether and the organic phase was washed with saturated aqueous sodium chloride, dried, filtered and evaporated to dryness under reduced pressure to obtain 3.6 g of the desired product melting at 116° C. An analytical sample was crystallized from isopropyl alcohol to obtain 2.73 g of the product melting at 116° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[N+](=[CH2:15])=[N-]>CCOCC.CO>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:15])=[O:7]
Reactant: O=C(O)C=Cc1ccccc1O
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a stirred mixture of ortho-hydroxycinnamic acid (1.00 g, 6.09 mmol) in 10 mL of ether and 10 mL of methanol was added etheral diazomethane until the mixture became yellowish. The mixture was stirred at room temperature for 15 minutes, and the excess diazomethane was destroyed with the addition of acetic acid. The mixture was concentrated in vacuo and diluted with 100 mL of ethyl acetate. This ethyl acetate solution was washed with saturated sodium bicarbonate solution (3×60 mL) and brine (1×60 mL). The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo to give 1.02 g (94%) of methyl ortho-hydroxycinnamate B.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].O>CN(C)C(=O)C>[CH3:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH2:25][CH3:26])=[O:23])[N:7]2[CH:8]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1cn2c(Br)cccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nc(C)cn12
Temperature: 100 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 5-bromo-2-methylimidazo[1,2-a]pyridine (5.00 g, 23.7 mmol) in N,N-dimethylacetamide (60 mL) were added sodium acetate trihydrate (3.89 g, 47.4 mmol), ethyl acrylate (3.10 mL, 28.4 mmol) and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (1.73 g, 2.37 mmol) at room temperature, and the mixture was stirred under nitrogen stream at 100° C. for 24 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (3.00 g, yield 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH2:21])([CH3:20])[CH3:19])(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([C:15]1[CH:16]=[C:17]([C:18]([NH:21][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:20])[CH3:19])[CH:22]=[CH:23][CH:24]=1)(=[O:14])[CH3:13]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(C(C)(C)N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(C(C)(C)NC(=O)Cc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
4-Chlorophenylacetylchloride (106 mg, 0.56 mmol) in dichloromethane was added to a solution of 3-acetyl-α, α-dimethylbenzylamine 24 (100 mg, 0.56 mmol) and triethylamine (120 μL, 0.86 mmol) in dichloromethane over a period of 5 to 10 min at 0° C. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane (20 mL) and washed with 1 N HCl, water and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate as eluent to give 26 (146 mg, 80%). 1H NMR (CDCl3, 400 MHz) δ 1.61 (s, 6H), 2.53 (s, 3H), 3.46 (s, 2H), 5.68 (s, 1H), 7.19 (d, J=7.2 Hz, 2H), 7.30-7.38 (m, 3H), 7.46 (d, J=8 Hz, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.87 (s, 1H); 13C NMR (DMSO-d6 100 MHz) δ 27.26, 29.89, 42.54, 55.34, 124.71, 126.76, 128.74, 128.98, 130.23, 131.45, 131.63, 136.22, 137.19, 148.96, 169.54, 198.59; ESI-HRMS for C19H21NO2Cl (M+H)+ calcd. 330.1261. found 330.1270.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:12]=2[S:13][C:14]=1[C:15]([NH2:17])=[O:16].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:12]2[S:13][C:14]([C:15]([NH2:17])=[O:16])=[C:10]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]=2[CH:21]=1
Reactant: SCc1ccccc1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(SCc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Benzylmercaptan (134 μL, 1.14 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (250 mg, 1.03 mmol) in 2 mL of DMF. Diazabicycloundecene (DBU) (170 μL, 1.14 mmol) is added and the mixture is warmed to 50° C. After 1 hour, the reaction mixture is allowed to cool and then is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate: hexane gives 5-methoxy-3-[(phenylmethyl)thio]benzo[b]thiophene-2-carboxamide in 63% yield; mp=151°-153° C.
Reaction SMILES: [CH:1]([OH:6])=[CH:2][CH2:3][CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:6][CH2:1]/[CH:2]=[CH:3]\[CH2:4][OH:5]
Reactant: OC=CCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: OC/C=C\COC1CCCCO1
Reaction time: 21 h
Yield: 33.5 %

Procedure:
50 g of 1,4-butenediol was dissolved in 200 ml of tetrahydrofuran and 280 mg of pyridinium p-toluenesulfonate was added and a solution prepared by dissolving 10.27 g of 3,4-dihydro-2H-pyrane in 50 ml of tetrahydrofuran was added dropwise under ice cooling. After the temperature was returned to room temperature, the reaction solution was stirred for 21 hours. The solvent was evaporated under reduced pressure and the residue was extracted with diethyl ether after adding water. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 7.05 g of a desired crude product as a colorless oily substance.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.O1CCOCC1>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[N:7][C:6]=1[O:8][CH3:9]
Reactant: COc1nc(Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Yield: 97 %

Procedure:
To a 1,4-dioxane (50 mL)-water (10 mL) solution of 6-bromo-3-chloro-2-methoxypyridine (1.98 g, 8.90 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.50 g, 8.09 mmol), and sodium carbonate (1.71 g, 16.1 mmol), tetrakis(triphenylphosphine)palladium (0) (467 mg, 0.400 mmol) was added under argon atmosphere and the resultant mixture was stirred at 100° C. for 3 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain the title compound (2.55 g, yield 97%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4](S(C)=O)[N:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)CC(C)C>[NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: CS(=O)c1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Reactant: C1CCNC1
Solvent: CC(C)CCO
Product: Nc1nc(N2CCCC2)nc2c1CC(c1ccccc1Cl)CC2
Temperature: 200 °C

Procedure:
This compound is prepared in a manner analogous to that of Example 18, using 1.60 grams (0.005 mole) of 4-amino-2-methylsulfinyl-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (prepared as in Example 17) and 0.71 gram (0.010 mole) of pyrrolidine in 50 mL of isoamyl alcohol. The sealed tube is heated at about 200° C. for 7 hours. The reaction mixture is subjected to column chromatography on silica gel, yielding 4-amino-2-(pyrrolidin-1-yl)-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [CH2:1]([N:8]1[CH:15](O)[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Si:25]([CH3:39])([CH3:38])[O:26][C:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=1[O:33][Si](C)(C)C.B(F)(F)F.CCOCC>ClCCl.CCOCC>[CH2:1]([N:8]1[C@@H:15]([C:27]2([O:26][Si:25]([CH3:39])([CH3:38])[CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29][C:28]2=[O:33])[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CS[C@@H](c3ccccc3)N12
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CCCC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C[Si](C)(C)OC1([C@H]2[C@@H]3CS[C@@H](c4ccccc4)N3C(=O)N2Cc2ccccc2)CCCCC1=O
Temperature: 0 °C
Yield: 76 %

Procedure:
To a solution of compound 6-benzyl-7-hydroxy-3-phenyl-(3S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-5-one of formula (6) (0.326 parts, 1 mmol) in dichloromethane (10 parts) was added 1,2-bistrimethylsilyloxy cyclohexene (0.516 parts, 2 mmol). Then the solution was cooled to 0° C. and Lewis acid for example BF3.Et2O (0.142 parts, 1 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 10 mints. and the reaction mixture was quenched with saturated ammonium chloride (10 parts). Then the organic layer was separated, concentrated and column purification with ethylacetate:pet.ether (15:85) as eluent provided compound 6-benzyl-7-(1-trimethylsilyloxy-2-oxocyclohexyl)-3-phenyl-(3S, 7R, 7aR)-perhydroimidazo[1,5-C][1,3]thiazole-5-one of formula (7e) (viscous liquid, 0.376 parts, 0.76 mmol) in 76% yield. And with ethyl acetate:pet.ether (25:75) as eluent provided the compound 6-benzyl-7-(1-hydroxy-2-oxocyclohexyi)-3-phenyl-(3S, 7R, 7aR)-perhydroimidazo[1,5-C][1,3]thiazole-5-one of formula (7e′) (highly viscous liquid, 0.093 parts. 0.22 mmol) in 22% yield.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[N:22]=[CH:21][C:20]([O:23][C:24]5[CH:40]=[CH:39][C:27]([C:28]([NH:30][NH:31]C(OC(C)(C)C)=O)=[O:29])=[CH:26][CH:25]=5)=[CH:19][CH:18]=4)=[O:15])[C@@H:7]3[C:6]=2[C:5]([F:41])=[CH:4][CH:3]=1>ClCCl>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][C:24]5[CH:40]=[CH:39][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=5)=[CH:21][N:22]=4)=[O:15])[C@@H:7]3[C:6]=2[C:5]([F:41])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(Oc2ccc(NC(=O)N[C@@H]3[C@H]4COc5c(F)ccc(F)c5[C@H]43)nc2)cc1
Solvent: ClCCl
Product: NNC(=O)c1ccc(Oc2ccc(NC(=O)N[C@@H]3[C@H]4COc5c(F)ccc(F)c5[C@H]43)nc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
The tert-butyl 2-[4-({6-[({[(1S,1aS,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]amino}carbonyl)amino]-3-pyridinyl}oxy)benzoyl]hydrazine carboxylate (49 mg, 0.089 mmol) in a mixture of dichloromethane (0.5 mL) and trifluoroacetic (0.5 mL) was stirred at room temperature for 30 min. The reaction was concentrated and purified on column chromatography (silica gel, 2% MeOH in CH2Cl2) to give the compound N-[(1S,1aS,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-{5-[4-(hydrazinocarbonyl)phenoxy]-2-pyridinyl}urea (17.6 mg, yield: 42%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]([CH3:32])[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]1)=[O:19])[CH2:12][CH2:11][CH2:10]2>>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]([CH3:32])[C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][C:29]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:30][CH:31]=3)[CH2:24][CH2:25]1)=[O:19])[CH2:12][CH2:11][CH2:10]2
Reactant: C[C@H](C(=O)N1CCN(c2ccccc2)CC1)N1CCCc2cc(F)ccc21
Reactant: O=S(=O)(O)Cl
Product: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Cl)cc2)CC1)N1CCCc2cc(F)ccc21
Temperature: 25 °C

Procedure:
After cooling chlorosulfonic acid (5.5 ml, 3 eq) to 0° C. under N2, (R)-2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-1-(4-phenylpiperazin-1-yl)propan-1-one (1 g, 2.72 mmol) was added and then allowed to warm up to rt. The solution was poured into an ice-water mixture (250 ml), followed by an extraction with CH2Cl2 (3×100 mL). The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was used without further purification for next step. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=466.3; tR=3.49 min.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (126 mg, 92%), MS (ISP) m/z=457.4 [(M+H)+], mp 222.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and tetrahydropyran-4-yl-acetic acid.