Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Zr:6].O>C(O)CC.CC(O)C>[CH3:4][CH2:3][CH2:2][CH2:1][O-:5].[CH3:4][CH2:3][CH2:2][CH2:1][O-:5].[CH3:4][CH2:3][CH2:2][CH2:1][O-:5].[CH3:4][CH2:3][CH2:2][CH2:1][O-:5].[Zr+4:6]
Reactant: CCCCO
Reactant: [Zr]
Solvent: CCCO
Solvent: O
Solvent: CC(C)O
Product: CCCC[O-]
Product: [Zr+4]
Reaction time: 0.03 h

Procedure:
1 butanol (171.6 gm) was mixed with 125 ml of n-propanol and placed in a one liter, three-neck round-bottom flask under nitrogen atmosphere. The concentration of zirconium was 0.95 molar. A solution of 28.8 ml of deionized water in 125 ml of n-propanol was added through an addition funnel under nitrogen atmosphere to the solution in the flask with rapid stirring for two minutes. The stirring was stopped, and the mixture was left to stand for three hours. The mixture was then centrifuged, and the mother liquor was discarded. The solid residue was ultrasonically dispersed in 2-propanol and then centrifuged to harvest the supernatant sol. This procedure was repeated several times.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=[O:25])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:26](O)([C:28]([F:31])(F)F)=O.C(Cl)Cl>FC1C=CC(N=C=O)=CC=1>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([NH:11][C:14]4[CH:23]=[CH:26][C:28]([F:31])=[CH:16][CH:15]=4)=[O:5])[CH2:13][CH2:12]3)=[CH:15][C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloro-2-quinolone (100 mg) is deprotected with TFA-CH2Cl2 1:1 (0.5 mL) and transformed to the title product with 4-fluorophenyl isocyanate (50 μL) according to method C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4]SC.[CH:10]1C(C(O)=O)=CC=C(N)[CH:11]=1.N[C@H](C(O)=O)CC1C=CC=CC=1.N1CCC[C@H]1C(O)=O>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:10][CH3:11])[CH3:4]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
L-methionine 2 g; PABA 0.2 g; L-phenylalanine 2 g; L-proline 2 g;
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][C:22](O)=[O:23])[CH:16]=3)=[N:9][C:8]=2[N:7]([CH2:25][CH2:26][CH3:27])[C:5]1=[O:6])[CH2:2][CH3:3].[CH2:28]1[O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:27][CH2:26][CH2:25][N:7]1[C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[C:13](=[O:14])[C:12]2[C:8]1=[N:9]/[C:10](/[N:11]=2)=[C:15]1/[CH:16]=[C:17]([O:20][CH2:21][C:22]([NH:33][C:32]2[CH:34]=[CH:35][C:36]3[O:37][CH2:28][O:29][C:30]=3[CH:31]=2)=[O:23])[NH:18][O:19]/1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)no3)nc2n(CCC)c1=O
Reactant: Nc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(OCC(=O)Nc3ccc4c(c3)OCO4)NO1)N=2

Procedure:
Condensation of 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yl)oxyacetic acid (0.5 mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presence of EDCl (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1.N12CCCN=C1CCCCC2.[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:37])=[C:33](Cl)[N:34]=2)[C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27]1)[CH3:25]>C(#N)C>[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:37])=[C:33]([N:10]3[CH2:11][CH2:12][C:6]4([CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]4)[CH2:9]3)[N:34]=2)[C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27]1)[CH3:25]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CN1CCC2(CCNC2)C1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCN(C)C4)C3)nc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 53.3 %

Procedure:
A stirred suspension of 4.40 g (20.7 mmol) of 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 200 ml acetonitrile was treated with 9.42 g (62 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 5.42 g (20 mmol) 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was added. After stirring 23 hours at room temperature the precipitated product was filtered, washed with acetonitrile and ether, and recrystallized from ethanol to afford 3.99 g of the title compound, mp 252°-254° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10]([C:34]3[CH:33]=[CH:32][C:31]([NH:45][C:46]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:52])=[C:30]([O:29][CH3:28])[CH:35]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of benzyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (7.0 g, 0.0146 mol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (6.15 g, 0.0176 mol), tetrakis(triphenylphosphine)palladium (1.0 g, 0.000876 mol) and sodium carbonate (3.9 g, 0.0365 mol) in ethylene glycol dimethyl ether (170 mL) and water (70 mL) was heated at 75° C. for 16 hours under an atmosphere of nitrogen. After addition of tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (6.15 g, 0.0176 mol, 1.2 eq.) and tetrakis(triphenylphosphine)palladium (1.0 g, 0.000876 mol) the mixture was stirred at 85° C. for additional 16 hours. The mixture was allowed to cool to ambient temperature and ethylene glycol dimethyl ether was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 20%-40% ethyl acetate/dichloromethane followed by 2%-5% methanol/dichloromethane as a mobile phase to give benzyl 4-(4-amino-3-{4-[(tert-butoxycarbonyl)amino]-3-methoxyphenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (8.0 g, 0.014 mol).
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8]/[CH:9]=[CH:10]/[C:11]2[C:12]3[C:13]4[CH:25]=[CH:24][S:23][C:14]=4[C:15](=[O:22])[NH:16][C:17]=3[CH:18]=[CH:19][C:20]=2[OH:21])[CH2:3]1.[CH2:26]=O.[C:28]([BH3-])#[N:29].[Na+]>CO>[CH3:26][N:29]([CH3:28])[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8]/[CH:9]=[CH:10]/[C:11]2[C:12]3[C:13]4[CH:25]=[CH:24][S:23][C:14]=4[C:15](=[O:22])[NH:16][C:17]=3[CH:18]=[CH:19][C:20]=2[OH:21])[CH2:3]1
Reactant: C=O
Reactant: NC1CCCN(C/C=C/c2c(O)ccc3[nH]c(=O)c4sccc4c23)C1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CCCN(C/C=C/c2c(O)ccc3[nH]c(=O)c4sccc4c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A solution of (E)-9-[3-(3-aminopiperidin-1-yl)prop-1-enyl]-8-hydroxythieno[2,3-c]quinolin-4(5H)-one (60 mg, 0.15 mmol) and formaldehyde (37% in water, 13 mg, 0.44 mmol) in methanol (1 mL) was stirred at room temperature for 30 min followed by the addition of sodium cyanoborohydride (28 mg, 0.44 mmol). The reaction mixture was stirred at room temperature overnight, concentrated and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparatory HPLC (C18 silica, water/acetonitrile w/0.05% TFA gradient) to afford the desired product (30 mg, 53%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.97 (dd, J=19.4, 5.3 Hz, 2H), 7.30 (d, J=8.9 Hz, 1H), 7.23 (d, J=15.9 Hz, 1H), 7.07 (d, J=8.9 Hz, 1H), 6.33-6.22 (m, 1H), 4.32-4.18 (m, 3H), 3.90-3.77 (m, 2H), 3.47 (t, J=11.6 Hz, 1H), 3.18 (t, J=11.3 Hz, 1H), 3.01 (s, 6H), 2.40-2.23 (m, 2H), 2.10-1.84 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20].C1C(Cl)=CC=C(Cl)C=1>>[Br-:13].[CH3:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][N+:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH3:12])([CH3:11])[C:2]=1[CH3:1]
Reactant: CC1=Nc2ccccc2C1(C)C
Reactant: COCCOCCBr
Solvent: Clc1ccc(Cl)cc1
Product: COCCOCC[N+]1=C(C)C(C)(C)c2ccccc21
Product: [Br-]
Temperature: 70 °C

Procedure:
To 2,3,3-trimethylindolenine (1.59 g) was added 1-bromo-2-(2-methoxyethoxy)ethane (2.75 g) and dichlorobenzene (5 ml). The mixture was heated to 70° C. overnight. The volatiles were stripped and the material purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][C:9]=2[CH3:19])=[CH:4][CH:3]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:36][CH2:37][C:38](Cl)=[O:39]>O1CCCC1>[Cl:36][CH2:37][C:38]([N:11]1[CH2:10][C:9]([CH3:19])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]2[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]12)=[O:39]
Reactant: CC1=C(c2ccc(Cl)cc2)n2ncc(C#N)c2NC1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: C1CCOC1
Product: CC1=C(c2ccc(Cl)cc2)n2ncc(C#N)c2N(C(=O)CCl)C1

Procedure:
A 10 g portion of 7-(4-chlorophenyl)-4,5-dihydro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile and 9 g of [1,8-bis(dimethylamino)naphthalene, N,N,N',N'-tetramethyl-1,8-naphthalenediamine] in 300 ml of dry tetrahydrofuran under nitrogen was mixed and 6 ml of chloroacetyl chloride in 70 ml of dry tetrahydrofuran was added over 15 minutes with stirring. The mixture was stirred at reflux for 5.5 hours, then at room temperature overnight and then filtered. The filtrate was concentrated to an oil. This oil was triturated with ether, the solid collected and dried, giving 10 g of the desired intermediate, mp 138°-140° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C1COCC1.CCOC(C)=O>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:10]([C:9]2[C:4]([S:3][CH2:1][CH3:2])=[N:5][C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:7][C:8]=2[CH3:13])=[O:12])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: NCc1cc(F)cc(F)c1
Reactant: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cc(F)cc(F)c1
Yield: 51.7 %

Procedure:
To a solution of 250 mg (0.89 mmol) 2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid in THF (7 ml), 124 μl (0.97 mmol) 3,5-difluorobenzylamine, 335 mg (0.89 mmol) HATU and 367 μl (2.66 mmol) NEt3 were added and the RM was heated at 70° C. for 5d. Subsequently the mixture was diluted with EtOAc and washed with a 4M aq. NH4Cl sol., a 1M aq. NaHCO3 sol. and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 187 mg (0.46 mmol, 52%) N-[(3,5-difluoro-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 1). [M+H]+408.1.
Reaction SMILES: [C:1]([C:3]1[NH:4][N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:6](=[O:22])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17](O)(=[O:19])=[O:18])=[CH:12][C:11]=1[CH3:21])#[N:2].C(#N)C.P(Cl)(Cl)([Cl:35])=O>CN(C)C(=O)C>[Cl:35][S:17]([C:13]1[C:14]([CH3:16])=[CH:15][C:10]([N:9]=[N:8][C:7]2[C:6](=[O:22])[N:5]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[NH:4][C:3]=2[C:1]#[N:2])=[C:11]([CH3:21])[CH:12]=1)(=[O:19])=[O:18]
Reactant: Cc1cc(S(=O)(=O)O)c(C)cc1N=Nc1c(C#N)[nH]n(-c2ccccc2C)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: Cc1cc(S(=O)(=O)Cl)c(C)cc1N=Nc1c(C#N)[nH]n(-c2ccccc2C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8.6 g of the azo obtained in step (2) above, 35 ml of acetonitrile, and 8.6 ml of N,N-dimethylacetamide were put into a 100 ml three-necked flask and 8.6 ml of phosphorus oxychloride was added dropwise to the mixture at a temperature of 50° C. or below. After completion of the dropwise addition, the mixture was stirred for 30 minutes and then poured into ice water. The crystals thus deposited were collected by filtration.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1F)([O-:5])=[O:4].[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:19][C:20]1[CH:16]=[CH:17][C:18]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4])([O-:5])=[O:4]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
This compound was made by the procedure of Example 2 from Compound A (46.5 g, 0.010 mole), NaH (4 g as 60% oil suspension, 0.10 mole) and 2,4-dinitrofluorobenzene (27.9 g, 0.15 mole) in THF (150 ml). The final product was purified by distillation to give a liquid product, yield 45.0 g (71.3%). Bp. 150°-160° C./0.5 mm. H1NMR (CDCl3): δ8.80 (d, J=2.5 Hz, 1H), 8.70 (dd, J=2.5, 10 Hz, 1H), 7.24 (d, J=10 Hz, 1H), 4.68 (t, J=12 Hz, 2H); F19NMR (CDCl3): -71.3 (d, J=10.1 Hz, 2F), -77.4 (m, 1F), -80.2 (q, J=7.6 Hz, 3F), -82.5 to -86.0 (m, 4F), -122.9 (t, J=11.6 Hz, 2F), -145.9 (q, J=19.4 Hz, 1F).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:16])[N:9]2[CH2:12][C:13]([OH:15])=O)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH2:27])[S:25][CH:26]=1>>[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH:27][C:13](=[O:15])[CH2:12][N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:17]([F:19])([F:18])[F:20])=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:16])[S:25][CH:26]=1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)c(F)cc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)c(F)cc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide was synthesized from 2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=6.276, method [7], MS (ESI) 516.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.54 (b s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.20 (d, J=9.34 Hz, 1H), 7.89 (d, J=13.72 Hz, 1H), 7.31 (s, 1H), 6.81 (d, J=9.34 Hz, 1H), 5.28 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(O)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(O)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4'-hydroxyacetophenone (0.657 g, 4.83 mmol), trimethylsilyl triflate (2.05 mL, 10.62 mmol), triethylamine (2.69 mL, 19.32 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol) m.p. 250° C.; (dec.) ; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (d, 6H), 3.40 (m, 1H), 6.70 (s, 1H), 6.90 (t, 3H), 7.05 (t, 1H), 7.10 (t, 1H), 7.26 (d, 1H), 7.70 (d, 2H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH2:9].C(N([CH2:16][CH3:17])CC)C.BrCC[O:21][S:22](Cl)(=O)=[O:23]>C(OCC)C>[C:1]1([CH3:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][S:22]([CH:16]=[CH2:17])(=[O:23])=[O:21]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)OCCBr
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCOCC
Product: C=CS(=O)(=O)Nc1c(C)cc(C)cc1C
Yield: 34.4 %

Procedure:
27.0 g (0.20 mole) mesitylamine were dissolved in 80 ml diethyl ether and mixed with 66.8 g (0.66 mole) triethylamine. The mixture was added dropwise to a stirred solution of 45.6 g (0.22 mole) bromoethylsulphochloride in 160 ml diethyl ether. The mixture was then refluxed for 5.5 hours and evaporated to dryness. The residue was treated with chloroform and 2 N hydrochloric acid and shaken. The chloroform phase was separated and extracted with 2 N sodium hydroxide solution. The alkaline aqueous phase was washed with chloroform, acidified with concentrated hydrochloric acid, and extracted with chloroform. The chloroform phase was dried over anhydrous magnesium sulphate and evaporated to dryness. 15.5 g of the crude title compound was obtained, which, after recrystallization from a mixture of di-isopropylether and hexane, melted at 117°-120° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C(O[C:24](OCC)(OCC)[CH2:25][CH3:26])C>C(O)(=O)C.CO>[CH2:25]([C:26]1[N:11]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][C:19]#[N:20])[CH2:16][CH2:17]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1)[CH3:24]
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: CCOC(CC)(OCC)OCC
Solvent: CC(=O)O
Solvent: CO
Product: CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (20.1 mg, 0.0702 mmol) and 1,1,1-triethoxypropane (0.0428 mL, 0.213 mmol) in acetic acid (0.2 mL) was stirred at 120° C. for 30 min. The mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (13 mg, 57%). LCMS calculated for C18H21N4S (M+H)+: m/z=325.1. Found: 325.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Fc1ccccc1CBr
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1F

Procedure:
The preparation is carried out as described for Example I using 940 mg (4.00 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate and 780 mg (4.15 mmol) of 2-fluorobenzyl bromide, reaction time 6 h.
Reaction SMILES: O[CH:2]([CH3:14])[CH:3](C)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.NN.[C:17]([O-:20])([O-])=O.[K+].[K+]>C(O)COCCO>[CH2:5]([C:7]1[CH:12]=[CH:11][C:17]([OH:20])=[C:9]([CH3:10])[CH:8]=1)[CH2:4][CH2:3][CH2:2][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(O)C(C)CC(=O)c1ccccc1
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Product: CCCCCc1ccc(O)c(C)c1
Temperature: 135 °C
Yield: 85.3 %

Procedure:
153.6 g (0.8 moles) of 4-hydroxy-3-methyl-pentanophenone are added to 500 ml of diethylene glycol, 120 g (3.8 moles) of hydrazine and 196 g (3.5 moles) of potash. The solution is refluxed at 135° C. in the mass for 2 hours and then the excess hydrozine and water are distilled until the temperature of the mass is 230° C. The solution is allowed to cool and then poured into 2.5 l of deionized water. It is then acidified with concentrated hydrochloric acid to pH1. The product precipitates. It is extracted with ether. The ethereal extract is washed with deionized water and then dried on magnesium sulphate. The ether is distilled and the product is purified by distillation. It distills at 97.5° C. at 0.4 mm of mercury. 121.6 g of pure compound is obtained, namely a yield of 85%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([C:17](O)=[O:18])[CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.O.CCOC(C)=O>C1COCC1>[OH:18][CH2:17][C@H:13]1[CH2:12][N:11]([C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH3:10])[C:15](=[O:16])[CH2:14]1
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)O)CC2=O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H](CO)CC2=O)cc1
Reaction time: 3 h

Procedure:
To a solution of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid 1.01 (610 mg, 2.32 mmol) in THF (6 mL) at 0° C. was added BH3-Me2S (2M, 1.74 mL, 3.48 mmol) and the reaction was stirred for 3 hours. Water and EtOAc were added, the layers were separated and the aqueous layer was extracted with EtOAc (4×25 mL). The residue was purified by flash chromatography (EtOAc→15% MeOH in EtOAc) to afford (R)-4-(hydroxymethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.06.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].O=[CH:6][C@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])[OH:8].[Sb](Cl)(Cl)(Cl)(Cl)Cl.N1C=C[CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1([CH3:4])[O:8][C@@H:7]([C@H:9]2[O:10][C@H:15]([OH:16])[C@H:13]3[O:14][C:25]([CH3:26])([CH3:24])[O:12][C@@H:11]23)[CH2:6][O:3]1
Reactant: CC(C)=O
Reactant: c1ccncc1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)O[C@@H]2[C@H]1COC(C)(C)O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-mannose and 89.7 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 60° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, a small amount of pyridine was added to the reaction mixture, and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene, and the solution was washed with aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The benzene was distilled off under reduced pressure to give 11.61 g (80.4%) of 2,3:5,6-di-O-isopropylidene-α-D-mannofuranose as a residue. The compound, when recrystallized from petroleum ether, showed m.p. 122°-123° C.