Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(S(C)(=O)=O)CC4)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a suspension of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (0.16 g, 0.43 mmol) in anhydrous DCM (10.0 mL) were added DMAP (0.011 g, 0.092 mmol) and Et3N (0.15 mL, 1.10 mmol), followed by methanesulfonyl chloride (0.076 g, 0.66 mmol) at 0° C. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a light yellow solid (0.14 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CS(C)=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]1[NH:27][N:28]=[N:29][C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N1CCc2ccc(Cl)c(C#Cc3ccccc3)c2CC1)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(N1CCc2ccc(Cl)c(-c3[nH]nnc3-c3ccccc3)c2CC1)C(F)(F)F
Yield: 39.3 %

Procedure:
Heat 7-chloro-6-phenylethynyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.26 mmol) and sodium azide (69 mg, 1.06 mmol) in anhydrous DMSO (5.3 mL) for 5.5 h. Cool the mixture, add brine and extract ten times with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and evaporate onto silica gel. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 2:3 gradient) to obtain the desired intermediate (43 mg, 39%). MS (ES+) m/z: 421 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]([NH2:12])[CH:6]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[N:14]([C:6]1[C:7]([NH2:12])=[N:8][C:9]([NH2:11])=[N:10][C:5]=1[O:4][CH2:3][CH:2]([CH3:13])[CH3:1])=[O:15]
Reactant: O=N[O-]
Reactant: CC(C)COc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)COc1nc(N)nc(N)c1N=O
Temperature: 32 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a stirred solution of 18.2 g (0.100 mol) 6-(2-methylpropoxy)-2,4-diaminopyrimidine in 100 ml acetic acid (10% conc. in water) at 6° C. was added dropwise over 1 h a solution of 9.11 g (0.132 mol) sodium nitrite in 40 ml water, whereupon the temperature was allowed to increase to 32° C. Stirring was then continued for a further 2 h at room temperature. The resulting precipitate was filtered off with suction, washed with water and dried. 5-Nitroso-2,4-diamino-6-(2-methylpropoxy)-pyrimidine (18.3 g, 81%) was obtained as a violet solid.
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]2[C:3]=1[CH:4](O)[CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[CH3:19][CH:20]([SH:22])[CH3:21].O.C(=O)(O)[O-].[Na+]>O.Cl.C(OCC)(=O)C>[CH:20]([S:22][CH:4]1[C:3]2[C:11](=[C:12]([CH3:17])[C:13]([CH3:16])=[C:14]([OH:15])[C:2]=2[CH3:1])[O:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5]1)([CH3:21])[CH3:19]
Reactant: Cc1c(C)c2c(c(C)c1O)C(O)CC1(CCC1)O2
Reactant: CC(C)S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)C(SC(C)C)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol (290 mg) in acetonitrle (2 mL) was added 2-propanethiol (0.5 mL) and concentrated HCl water solution (5 drops). The solution was stirred at room temperature for 7 hours. The solution was neutralized using sodium bicarbonate water solution to pH about 7. Ethyl acetate was added, washed with water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate 0 to 4%) gave 140 mg of 4-(isopropylthio)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol
Reaction SMILES: [K].[C:2]([C:4]([CH3:17])([C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:5])#[N:3].Cl[C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:25]=2)[N:20]=1.O>CN(C)C=O>[C:2]([C:4]([CH3:17])([C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:28]=[N:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29]([F:30])([F:31])[F:32])[CH:25]=3)[N:20]=2)=[CH:13][CH:14]=1)[CH3:5])#[N:3]
Reactant: FC(F)(F)c1ccc2nc(Cl)cnc2c1
Reactant: CC(C)(C#N)C(=O)COc1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C#N)C(=O)COc1ccc(Oc2cnc3cc(C(F)(F)F)ccc3n2)cc1
Temperature: 100 °C
Yield: 47.1 %

Procedure:
2.20 Grams of a potassium salt of 2-cyano-2-methyl-4-(4-hydroxyphenoxy)-3-butanone and 1.69 g of 2-chloro-6-trifluoromethylquinoxaline were refluxed in 50 nl of N,N-dimethylformamide under heat at 100° C. for 4 hours. The reaction mixture was added to water, and after the mixture was subjected to extraction with chloroform, the extract was concentrated. The residue was separated and purified by column chromatography to give 1.67 g of a compound No. 166 which was a light yellow solid (melting point 113°-115° C.). The yield was 47.1%. The compound No. 166 was analyzed, and the results are shown in Tables 1 to 23.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C@H:10]1[CH2:27][CH3:28])(C(C)(C)C)(C)C.C(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:27]([C@H:10]1[C@@H:9]([OH:8])[CH2:13][C:12](=[O:14])[N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=1)[CH3:28]
Reactant: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.1 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (7.76 g) in tetrahydrofuran (60 mL)-ethanol (30 mL) was added 6 mol/L hydrochloric acid (60 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=50/1→1/4), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound as a colorless solid (yield: 2.36 g, 42%).
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=O)[C:11](=O)[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:17]([OH:19])[CH3:18]>>[CH2:17]([O:19][CH:2]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2)[CH3:18]
Reactant: CCO
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Product: CCOC1c2ccccc2-c2nccnc21
Yield: 25 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.50 g, 2.13 mmol) was refluxed in 25 ml dry ethanol for 7 hours. The mixture was evaporated to few ml and the precipitate was filtered off, washed with ethanol and dried to give 0.229 g of the crude compound, which was recrystallized from acetic acid-water to yield 0.131 g (25%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 1.1 (t, 3H), 3.25 (dq, 1H), 3.43 (dq, 1H), 5.22 (s, 1H), 7.17 (t, 1H), 7.33 (t, 1H), 7.42 (d, 1H), 7.51 (d, 1H), 12.1 (s, 1H), 12.31 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[CH:15]([Si:18]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])Cl)([CH3:17])[CH3:16].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][Si:18]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](Oc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Reaction time: 15 h
Yield: 97.4 %

Procedure:
To a mixture of 3,5-dichlorophenol (16.3 g, 100 mmol), imidazole (14.98 g, 220 mmol), and triisopropylchlorosilane (21.21 g, 110 mmol) was added DMF (200 mL) at room temperature. The resulting brown solution was stirred for 15 h and then it was diluted with water (500 mL). The organic compound was extracted into ethyl acetate (2×100 mL) and the combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude residue which was purified using an ISCO (400 g) column chromatography to obtain 31.1 g (97%) of (3,5-dichlorophenoxy)-triisopropylsilane as a colorless oil. EI(+)-HRMS m/e calcd. for C15H24Cl2OSi (M)+ 318.0973, obsd. 318.0971.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:10][C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2][CH2:3]1)([CH3:9])[CH3:8]
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 48 h

Procedure:
2-(Piperidin-4-yl)propan-2-ol (1 g) was reacted with 1.1 eq of benzyl chloroformate and 1.3 eq of triethylamine in 30 mL of chloroform. The reaction was halted after 2 days at room temperature and purified by isco (0-60% Hexanes/Ethyl Acetate over 20 minutes) to afford 1.49 g benzyl 4-(2-hydroxypropan-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][S:2]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:12]=2[N:11]=[CH:10]1)(=[O:4])=[O:3].[NH:21]1[CH:30]2[CH:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl>CN(C=O)C>[CH3:1][S:2]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([N:21]3[CH:30]4[CH:25]([CH2:26][CH2:27][CH2:28][CH2:29]4)[CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:17][C:12]=2[N:11]=[CH:10]1)(=[O:3])=[O:4]
Reactant: C1CCC2NCCCC2C1
Reactant: CS(=O)(=O)COCCn1cnc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)COCCn1cnc2cc(C(=O)N3CCCC4CCCCC43)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
To a solution of 1-(2-methanesulfonylmethoxyethyl)-1H-benzimidazole-5-carboxylic acid (0.5 g, 1.677 mmol) in DMF (5 mL) was added decahydroquinoline (0.257 g, 1.845 mmol) followed by HOBt (0.25 g, 1.845 mmol) and DIPEA (0.65 g, 5 mmol). The reaction mixture was cooled to 0° C. and EDCl.HCl (0.354 g, 1.845 mmol) was added. It was gradually raised to ambient temperature and stirring continued for 12 h. The solvent was then evaporated, the residue diluted with water (5 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic phases were washed with brine solution, dried (Na2SO4) and the solvent evaporated affording the crude amide which was purified by preparative HPLC to give 0.3 g (43%) of [1-(2-methanesulfonylmethoxy-ethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone. MS-ESI m/z 420 (M+1): 1H NMR (300 MHz, DMSO-d6) δ 1.1-1.9 (br, 13H), 2.8 (s, 3H), 3.0-3.3 (m, 2H), 4.15 (t, 2H), 4.5 (t, 2H), 4.65 (s, 2H), 7.3 (m, 1H), 7.6 (m, 1H), 7.7 (d, 1H), 8.3 (s, 1H)
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH2:28][CH2:29][CH3:30])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH:5]([OH:31])[CH:4]1[OH:32].[CH3:33][NH2:34].C(OCC)(=O)C>CS(C)=O>[CH3:33][NH:34][CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH2:28][CH2:29][CH3:30])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH:5]([OH:31])[CH:4]1[OH:32]
Reactant: CN
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CI)C(O)C3O)c2n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CNC)C(O)C3O)c2n1
Reaction time: 18 h

Procedure:
A solution of the product from step (c) (0.25 g) in dimethylsulphoxide (3mil) was treated with a 40% solution of aqueous methylamine (1 ml). The reaction mixture was allowed to stand for 18 hours at room temperature then poured into ethyl acetate (200 ml), washed with a saturated solution of aqueous brine (3×100 ml), dried and concentrated. Purification (SiO2, methanol:chloroform 1:4 as eluant) afforded the subtitle compound (0.27 g).
Reaction SMILES: FC1C(F)=CC(C2C=CN=CC=2N([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[C:40]([O:44][C:45](=[O:64])[NH:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][C:52]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[O:59][C:60]([F:63])([F:62])[F:61])([CH3:43])([CH3:42])[CH3:41].ClCCS(C)(=O)=O>CCCCCC.CCOC(C)=O>[C:40]([O:44][C:45](=[O:64])[N:46]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][C:52]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[O:59][C:60]([F:61])([F:62])[F:63])([CH3:43])([CH3:41])[CH3:42]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1-c1ccccc1OC(F)(F)F
Agent: CS(=O)(=O)CCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)c1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 298, intermediate b, from [4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester and 1-chloro-2-(methylsulfonyl)ethane and using a gradient of n-hexane:EtOAc (50:50 to 40:60) for the chromatographic purification. Colourless sticky solid (96%). MS (ESI): m/z=461.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](Cl)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:13]1([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:19]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)CCN(C(=O)Cc1ccc(Cl)c(Cl)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.115.1, starting from 3,4-dichlorophenylacetyl chloride and ethyl N-phenyl-3-aminopropionate, ethyl 3-[2-(3,4-dichlorophenyl)-N-phenyl-acetamido]propanoate was obtained as yellowish oil.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([Si:33]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)[CH2:31][CH3:32].O>C1COCC1>[CH2:30]([Si:33]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH:36]([CH:2]=[O:4])[CH2:35][CH2:34]1)[CH2:31][CH3:32]
Reactant: CC(C)(C)[O-]
Reactant: CCC[Si]1(c2ccccc2)CCC(=O)CC1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[Si]1(c2ccccc2)CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 g of potassium t-butoxide was added to a mixture of 35 g of methoxymethyltriphenylphosphonium chloride and 200 ml of THF to prepare an orange ylide solution. A solution of 23 g of 4-n-propyl-4-phenyl-4-silacyclohexanone in 50 ml of THF was added to the ylide solution and agitated at room temperature for 2 hours. Thereafter, the mixture was poured into iced water and extracted with methylene chloride, followed by washing, drying and concentration by a usual manner. n-Hexane was added to the residue, and the resultant crystals of triphenylphosphine oxide were removed by filtration. The filtrate was concentrated, and the resultant residue was hydrolyzed with 100 ml of 20% hydrochloric acid, followed by washing, drying and concentration by a usual manner to obtain 4-n-propyl-4-phenyl-4-silacyclohexane carbaldehyde.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:13][C:14]=1[CH3:15].O>C(#N)C>[Cl:1][CH2:9][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:13][C:14]=1[CH3:15]
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
N-Chlorosuccinimide (4.5 g) was added to a solution (100 ml) of tert-butyl 4-(4,5-dimethyl-1,3-thiazol-2-yl)piperazine-1-carboxylate (10 g) in acetonitrile at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (0:1-1:4-1:2, v/v) to give tert-butyl 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperazine-1-carboxylate as colorless crystals (6.2 g, yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Clc1ccccc1N1CCNCC1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 85 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.08-3.17 (m, 4H), 3.73-3.86 (m, 4H), 4.13 (s, 3H), 7.00-7.65 (m, 7H), 7.74 (d, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20])(=[O:23])[CH3:22]
Reactant: CC1CCc2c(N)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(Cl)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C

Procedure:
Using the method of Example 49, 8-amino-9-chloro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is reacted with acetic anhydride to provide 8-acetamido-9-chloro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 234°-236° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([N:32]1[CH2:35][CH:34](O)[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:19]([N:32]1[CH2:35][CH:34]([O:17][C:16]2[C:11]3[NH:10][C:9](=[O:18])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:33]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c2c(O)cccc2n1Cc1ccccc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c2c(OC3CN(C(c4ccccc4)c4ccccc4)C3)cccc2n1Cc1ccccc1
Yield: 39.3 %

Procedure:
To a suspension of 1-benzyl-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (0.104 g., 0.433 mmol) and 1-benzhydryl-azetidin-3-ol (0.114 g., 0.477 mmol) in 0.5 mL anhydrous THF was added triphenyl phosphine (0.125 g., 0.477 mmol) and diisopropyl azodicarboxylate (0.093 mL, 0.477 mmol). The reaction mixture was refluxed for 2 hours, then concentrated in vacuo and purified by preparative TLC (2% methanol in dichloromethane) to give 78 mg (0.17 mmol, 39.5%) of 4-(1-benzhydryl-azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzoimidazol-2-one as a yellow glass. MS: 462 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:13])([CH3:12])[C:5](=[O:11])[NH:6]2.C(O)(=O)C.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:18][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[C:4]2([CH3:13])[CH3:12]
Reactant: BrBr
Reactant: CC1(C)C(=O)Nc2cccc(F)c21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2ccc(Br)c(F)c21
Reaction time: 24 h
Yield: 64.6 %

Procedure:
4-Fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1 g, 22.9 mmol) was dissolved in dichloromethane (DCM) (50 mL) and acetic acid (2 mL) at room temperature. Bromine (0.386 mL, 7.5 mmol) was added and the solution allowed to stir 24 hours. The reaction mixture was poured into sodium thiosulfate solution, extracted with diethyl ether, the combined organic layers were dried over magnesium sulfate and evaporated. Trituration of the crude product with hexane gave 5-bromo-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.25 g, 87%): HRMS [M−H]− 255.9781
Reaction SMILES: C[C@@H](N(C)C)[C@@H](O)C1C=CC=CC=1.C(N(CC)CC)C.C[Si]([C:25]#[CH:26])(C)C.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[C:35]=2[CH:40]=[O:41])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[C:35]=2[C@@H:40]([OH:41])[C:25]#[CH:26])=[CH:32][CH:33]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C#C[Si](C)(C)C
Agent: C[C@H]([C@@H](O)c1ccccc1)N(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#C[C@H](O)c1c(C)noc1-c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
Zinc triflate (0.75 g, 2.1 mmol), (1S,2R)-(+)-N-methylephedrine (0.41 g, 2.3 mmol) and triethylamine (0.23 g, 2.3 mmol) were stirred in toluene (10 mL) at room temperature for 2 hours. (Trimethylsilyl)acetylene (0.32 g, 2.3 mmol) was added and the reaction stirred for 15 minute then 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.5 g, 1.9 mmol) was added and the reaction stirred at room temperature for 2 weeks. The reaction mixture was purified on by silica gel chromatography (0-20% EtOAc in hexanes) to afford the title product with 97.5% ee as measured by analytical chiral HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[NH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][N:15]=1.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[S:33]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[NH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[N:14][N:15]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2N)[nH]1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)[nH]1

Procedure:
Following General Procedure B, the title compound was prepared from tert-butyl (5-(((2-amino-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate (330 mg, 0.925 mmol) and benzofuran-2-sulfonyl chloride (200 mg, 0.925 mmol) in pyridine (2 ml).