Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25](CNC)=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[S:34].[CH2:37]([N:39](CC)[CH2:40]C)C.CN(C)C=O>C(OCC)(=O)C.S([O-])(O)(=O)=O.[K+]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:31][N:32]([CH3:36])[C:33]([N:39]([CH3:40])[CH3:37])=[S:34])=[CH:26][CH:27]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CN(C)C(=S)Cl
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=S)N(C)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
A mixture of the compound (0.1 g) obtained in Example 4, dimethylcarbamothioyl chloride (25 mg), triethylamine (76 mg) and N,N-dimethylformamide (2 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, 5% aqueous potassium hydrogen sulfate solution, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and is concentrated under reduced pressure. The residue was purified by column chromatography [developing solvent:ethyl acetate-hexane (3:1, volume ratio)], and recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (40 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19](=O)[CH2:20]Br)=[CH:17][CH:16]=1)#[N:14].[CH:25]([NH2:27])=O>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH:20]=[C:19]([C:18]3[CH:23]=[CH:24][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[N:27]=[CH:25]2)=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: NC=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cn(-c3ccc(OC(F)(F)F)cc3)cn2)cc1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
4-Trifluoromethoxyaniline (2.20 g, 12.4 mmol) was added dropwise to a solution of 4-cyanophenacyl bromide (1.50 g, 6.7 mmol) in DMF (5 mL). This solution was then added to hot (180° C.) formamide (20 mL) over 5 min, and the combined solution was allowed to stir at 180° C. for 2 h. The cooled solution was then poured onto ice (100 mL), and extracted with ether (2×75 mL). After drying and concentrating, the resulting semi-solid was crystallized from MeOH/H2O. A second recrystallization from MeOH/H2O removed traces of the formanilide impurity and furnished pure product (200 mg): mp 155° C. Anal. Calcd. for C17H10F3N3O: C, 62.01; H, 3.06; N, 12.76. Found: C, 61.53; H, 3.13; N, 12.55.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH2:7][CH3:8])[CH2:4][CH:5]=C.O.I([O-])(=O)(=O)=[O:13].[K+]>CC(C)=O.C(OCC)C.[Os](=O)(=O)(=O)=O>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH2:7][CH3:8])[CH2:4][CH:5]=[O:13]
Reactant: C=CCC(CC)(CF)CF
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CCC(CF)(CF)CC=O
Reaction time: 15 h

Procedure:
To a stirred solution of 4,4-bis(fluoromethyl)hex-1-ene (9.1 g, 62 mmol) in acetone (360 mL)/water (120 mL) at rt was added osmium tetroxide (155 mg, 0.62 mmol) and potassium periodate (29.7 g; 129 mmol) (the latter in portions). After stirring for 15 h, the reaction mixture was diluted with diethyl ether (180 mL). The organic layer was separated, and the aqueous layer was extracted with diethyl ether (3×180 mL). The extracts were washed with saturated sodium thiosulfate (250 mL) and brine (250 mL), dried over sodium sulfate and concentrated to give a residue. The resulting residue was distilled under vacuum to provide 3,3-bis(fluoromethyl)pentanal.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CN(C=O)C>[CH3:21][N:22]([CH3:26])[C:23]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)=[O:24]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OC(=O)N(C)C)cc(C)c21
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 2 mmol) in DMF (5 mL) was slowly added NaH (360 mg, 6 mmol) at 0° C. The mixture was stirred for 20 min and N,N-dimethylcarbamic chloride (430 mg, 4 mmol) was added at 0° C. The mixture was stirred overnight at room temperature and quenched with ice water. The resulting mixture was extracted with EtOAc (2×25 mL) and the combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step reaction without further purification, MS (ESI) m/z=322 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3](Cl)=C[C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.CC[N:28](C(C)C)C(C)C>CCO>[C:21]([O:20][C:19](=[O:25])[NH:18][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][NH:10][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:28]=2)[CH2:17][CH2:16]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Reactant: Fc1cnc(Cl)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2F)CC1
Temperature: 40 °C
Yield: 80.4 %

Procedure:
To a solution of the above 5-fluoro-2,4-dichloropyridine (67 mg, 0.4 mol) in EtOH (2 mL) were added tert-butyl trans-4-aminomethylcyclohexylcarbamate (100 mg, 0.44 mmol) and DIPEA (77 μL, 0.44 mmol). The reaction mixture was heated at 40° C. for 1 h. The mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc and washed with brine. The aqueous layer was re-extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield 127 mg (89%) of {4-[(2-chloro-5-fluoro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].O>C1COCC1>[CH2:26]([O:25][C:23]([NH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C=NN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Nc1ccc(C=NNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.50 g (1.66 mol) of ethyl (3-(4-(aminoiminomethyl)phenyl)ureido)acetate in 20 ml of THF is treated with 2.7 ml of 1N NaOH and cooled to 0° C. 0.29 ml (1.99 mmol) of benzyl chloroformate is added to this mixture and it is stirred at room temperature for 2 h. The pH is kept between 9 and 10 using 1N NaOH. The mixture is then treated with 50 ml of water and extracted with ethyl acetate. After drying (MgSO4), the solvent is removed in vacuo and the residue is stirred with ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][OH:33])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][CH2:32][OH:33])[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: OCCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CC(=O)N(CCO)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 21 %

Procedure:
The procedure described in Example 5 was repeated using 2-({2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}amino)ethanol and acetyl chloride to give the title compound in 21% yield; NMR spectrum (DMSO-d6) 2.00 (s, 3H), 3.43 (t, 2H), 3.54-3.59 (m, 2H), 3.88-3.97 (m, 2H), 4.41 (t, 2H), 4.85 (t, 1H), 5.31 (s, 2H), 7.16 (d, 1H), 7.25 (d, 1H), 7.33 (d, 1H), 7.35-7.40 (m, 1H), 7.57-7.62 (m, 2H), 7.70-7.75 (m, 1H), 7.86-7.92 (m, 1H), 7.96 (d, 1H), 8.45 (s, 1H), 8.61 (d, 1H), 9.83 (s, 1H); Mass spectrum MH+ 508.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:23]([C:22]2[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]([OH:28])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=2)[NH:32][C:33](=[O:34])[NH:35][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccccc1Cl)c1ccccc1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2Cl)cc([N+](=O)[O-])c1O
Yield: 7 %

Procedure:
To a mixture of 2-(2-chlorophenyl)-1-phenylethanone (Intermediate 10) (85 mg, 0.37 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (94 mg, 0.45 mmol), and urea (67 mg, 1.1 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, and the reaction mixture was concentrated. The residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 28 as a yellow solid (12 mg, yield: 7.0%). 1H NMR (CD3OD 400 MHz): δ 7.47 (s, 1H), 7.34-7.40 (m, 1H), 7.20 (s, 5H), 7.10-7.13 (m, 1H), 7.05 (s, 1H), 6.80-6.87 (m, 1H), 6.40-6.45 (m, 1H), 5.45 (s, 1H), 3.95-4.10 (m, 2H), 1.37-1.42 (m, 3H); MS (ESI): m/z 466.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=O)[CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:7](=O)[CH2:6]1)=[O:4].[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl>CO>[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:7]2[CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:11]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(Nc2ccc(C)cc2)CC(C(=O)OC)=C(Nc2ccc(C)cc2)C1
Yield: 97.4 %

Procedure:
Dimethyl 1,4-cyclohexanedione-2,5-dicarboxylate (4.56 gm; 20 mmol) and methanol (100 ml) were heated to boiling; then 4-methylaniline (4.5 gm; 42 mmol) was added followed by conc. hydrochloric acid (200 μl). The mixture was refluxed for 5 hours under a nitrogen atmosphere. On cooling a cream solid precipitated out which was collected by filtration, washed with methanol and dried under vacuum to give 7.92 gm (97%) of dimethyl 2,5-bis{(4-methylphenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate.
Reaction SMILES: [CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16](SC)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:26]([O:28][CH3:29])=[O:27])=[O:6])[CH:2]=[CH2:3].[C:30]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])#[CH:31].C(OC([C@@H]1CCN(CC2C=CC=C3C=2C(NC2C=CC=C(OC)C=2)=NC=N3)C[C@@H]1C(OC)=O)=O)C=C>CO>[CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[C:32]([C:30]#[CH:31])[CH:33]=2)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:26]([O:28][CH3:29])=[O:27])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(SC)c23)C[C@@H]1C(=O)OC
Reactant: C#Cc1cccc(N)c1
Agent: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(Nc4cccc(OC)c4)c23)C[C@@H]1C(=O)OC
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cccc(CN4CC[C@@H](C(=O)OCC=C)[C@@H](C(=O)OC)C4)c23)c1

Procedure:
Compound 18A was prepared from 15B and 3-ethynylaniline in a similar way as 15C. It has an analytical HPLC retention time=2.353 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=500+.
Reaction SMILES: Br[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:4]1(=[O:6])=[O:5].[Na].[SH:16][C:17]1[N:21](C)[N:20]=[N:19][N:18]=1.[CH2:23](C(C)=O)C>>[CH3:23][CH:2]([S:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1)[N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:4]1(=[O:6])=[O:5]
Reactant: O=C1c2ccccc2S(=O)(=O)N1CBr
Reactant: Cn1nnnc1S
Reactant: CCC(C)=O
Agent: [Na]
Product: CC(Sc1nnn[nH]1)N1C(=O)c2ccccc2S1(=O)=O
Yield: 80 %

Procedure:
A mixture of 2-(bromomethyl) saccharin (3 g, 10.8 mmol) and the sodium salt of 5-mercapto-1-methyl-1H-tetrazole (1.49 g, 10.8 mmol) was heated under reflux in methyl ethyl ketone (75 ml) for 2 hours. The reaction mixture was cooled, poured into dilute sodium bicarbonate/ice solution and extracted with MDC (2x's). The combined organic extracts were dried (Na2SO4) and freed of solvent under vacuum. The crude product was chromatographed (silica gel-95:5 CH2Cl2 :ether), and the resultant oil was crystallized from hot isopropanol to afford 2.7 g (80%) of 2-(1-methyl-1H-tetrazol-5-ylthiomethyl)saccharin as a white solid, mp 106°-110° C. 1H nmr (90 MHz, CDCl3):5.55 (2H, s). FDMS: m/e 311 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]([Si:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([CH3:10])[CH3:9])([CH3:7])[CH:6]=1.C([Li:26])CCC.CCCCC>C(OCC)C.CCCCCC>[CH3:1][C:2]1[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]([Si:8]([N-:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([CH3:10])[CH3:9])([CH3:7])[CH:6]=1.[Li+:26].[Li+:26].[CH3:1][C:2]1[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]([Si:8]([N-:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([CH3:10])[CH3:9])([CH3:7])[CH:6]=1
Reactant: COc1ccccc1N[Si](C)(C)C1(C)C=C(C)C(C)=C1C
Reactant: [Li]CCCC
Solvent: CCCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccccc1[N-][Si](C)(C)C1(C)C=C(C)C(C)=C1C
Product: [Li+]

Procedure:
To 1.4 g (4.6 mmol) ((tetramethylcyclopentadienyl)dimethylsilyl)(2-methoxyphenyl)amine in diethyl ether was added dropwise 3.9 mL of 2.5 M butyl lithium (9.8 mmol) in hexane solvent. A white precipitate formed. Pentane was added to the mixture. The slurry was filtered and the solids washed with pentane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][NH:26][CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:26]([CH:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH:28]2[N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CNC1c2ccccc2CC1N1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)C1c2ccccc2CC1N1CCCC1
Reaction time: 1 h

Procedure:
A mixture of 2.66 g of 3,4-dichlorophenylacetic acid, 2.11 g of carbonyldiimidazole and 20 ml of tetrahydrofuran was stirred for 1 hour and then a solution of 2.16 g of the product of Step B in 5 ml of tetrahydrofuran was added slowly. The mixture was stirred for 3 hours 30 minutes and then the tetrahydrofuran was distilled off under reduced pressure. The residue was taken up in 100 ml of ether and after washing with a saturated solution of sodium bicarbonate, then with saturated salt water, drying and concentrating to dryness under reduced pressure, 4.68 g of [Trans (±)] 3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamide in the form of a base were obtained.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].N1C(C)=CC=CC=1C.[N:14]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[ClH:3].[N:14]1([CH:19]2[CH2:24][CH2:23][N:22]([P:1]([Cl:5])([Cl:3])=[O:2])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cl
Product: O=P(Cl)(Cl)N1CCC(N2CCCC2)CC1
Temperature: 0 °C
Yield: 207 %

Procedure:
To a cooled (ice/water bath) solution of phosphorus oxychloride (5.70 mL, 55.6 mmol) in DCM (30 mL) was added 2,6-lutidine (19.4 mL, 167 mmol) and a DCM solution (30 mL) of 4-(1-pyrrolidinyl)-piperidine (8.58 g, 55.6 mmol) and stirred for 1 hour. The suspension was filtered and solid washed with excess diethyl ether to afford the title pyrrolidine (17.7 g, 91% yield) as a white solid. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C19H30N5O4P 423.2. found m/z=422.2 (M−1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.C1N2CCN(CC2)C1.C1C(=O)N(Cl)C(=O)C1.[Cl:30][CH2:31][CH2:32][CH2:33][OH:34].CS(O)(=O)=O>C(Cl)Cl>[Cl:30][CH2:31][CH2:32][CH2:33][O:34][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: OCCCCl
Agent: C1CN2CCN1CC2
Agent: CS(=O)(=O)O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)c1c(OCCCCl)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A suspension of methyl indole-3-carboxylate (5.25 g, 30.0 mmol) and DABCO (1.84 g, 16.4 mmol) in dry CH2Cl2 (25 ml) was cooled to 0° C. under argon atmosphere, treated in one portion with NCS (4.41 g, 33.0 mmol) and the mixture stirred for 10 min. The resulting solution was added to a solution of 3-chloropropan-1-ol (3.12 g, 33.0 mmol) in dry CH2Cl2 (25 ml) containing anhydrous methane sulphonic acid (0.23 ml). The resulting suspension was stirred for 30 min and then washed with 10% aqueous Na2CO3 solution (3×25 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was triturated with toluene (10 ml) at 0° C. for 1 h and the solid precipitate filtered, washed with a small amount of toluene and dried in vacuo to leave the product as an off-white solid (5.22 g, 65.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:26][N:27]1[C:31]([SH:32])=[N:30][N:29]=[N:28]1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[CH3:26][N:27]1[C:31]([S:32][CH2:1][O:2][C:3](=[O:6])[CH3:4])=[N:30][N:29]=[N:28]1
Reactant: COC(=O)CO
Reactant: Cn1nnnc1S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCSc1nnnn1C
Reaction time: 3 h

Procedure:
After glycolic acid methyl ester (300 mg, 3.33 mmol), triphenylphosphine (1050 mg, 4.00 mmol), 1-methyl-5-mercapto-1H-tetrazole (465 mg, 4.00 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (2.10 ml, 4.00 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for three hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using ethyl acetate (10 ml,×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 70% ethyl acetate-hexane solution) to give acetic acid (1-methyl-1H-tetrazole-5-ylsulfanyl)methyl ester containing 1,2-hydrazinedicarboxylic acid diisopropyl ester as 610 mg of a colorless oily substance. Measurement of 1H-NMR showed that 406 mg of acetic acid (1-methyl-1H-tetrazole-5-ylsulfanyl)methyl ester (yield: 65%/glycolic acid methyl ester), and 204 mg of 1,2-hydrazinedicarboxylic acid diisopropyl ester were contained.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][N:19]1[CH:23]=[C:22]([CH:24]2[CH2:26][O:25]2)[CH:21]=[N:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH:24]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[OH:25])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cn1cc(C2CO2)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cnn(C)c2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (160 mg, 0.8 mmol) in DMF (3 mL) was added NaH (60%, 96 mg, 2.4 mmol). After stirring for 5 min at RT, 1-methyl-4-(oxiran-2-yl)-1H-pyrazole (150 mg, 1.2 mmol) was added into the reaction mixture, which was stirred at RT for 26 h. The progress of reaction was monitored by TLC, NMR and LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOH-Hex) to yield 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethanol. The product was further purified by chiral HPLC separation. 1H NMR (CDCl3, freebase) δ (ppm): 7.46 (s, 1H), 7.2 (s, 1H), 7.19 (s, 1H), 7.15 (d, 1H), 6.98 (d, 1H), 5.0 (t, 1H), 4.2 (d, 2H), 3.82 (s, 3H), 3.6 (s, 2H), 2.9 (m, 1H), 2.8 (m, 2H), 2.7 (m, 1H), 2.5 (s. 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CN(C)C=O>[NH2:1][C:2]1[N:6]([C:19]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[F:11])[N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Nc1nc(C(F)(F)F)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)nc2N)c(F)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 58.6 %

Procedure:
In a 50-ml eggplant flask provided with a magnetic stirrer were placed 3.04 g (20 mmol) of 5-amino-3-trifluoromethyl-1H-1,2,4-triazole, 3.06 g (22 mmol) of 3,4-difluorobenzonitrile, 2.76 g (20 mmol) of potassium carbonate and then 10 ml of N,N-dimethylformamide. The mixture was stirred at 60° C. for 6 hours. Thereto were added 50 ml of ethyl acetate and 50 ml of water to give rise to phase separation. The aqueous phase was extracted with 50 mol of ethyl acetate. The ethyl acetate phase was washed with water and then with a saturated aqueous sodium chloride solution. The ethyl acetate phase was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to distill off ethyl acetate. To the residue was added 5 ml of toluene. The mixture was stirred with heating, cooled and then filtered to obtain 3.18 g of a crystal. Yield: 58.6%