Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH:24]=[C:23]([CH3:35])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([CH3:35])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.54 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether) yielded the title compound as a white solid (0.175, 37%). MS (ISP) 471.2 [(M+H)+]; mp 202.5° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH2:28][CH3:29]>C(#N)C>[F:19][C:2]([F:1])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:27][CH2:28][CH3:29])[CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4]
Reactant: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(C(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-iodopropane (0.01 g). MS m/z (rel. intensity, 70 eV) 317 (M+, 3), 289 (15), 288 (bp), 248 (4), 109 (6).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([SH:14])=[N:12][N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].[Cl-].[Na+]>CN(C)C=O>[O:24]([C:22]([NH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([SH:14])=[N:12][N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(-n2nnnc2S)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-n2nnnc2S)c1)Oc1ccccc1
Yield: 92.8 %

Procedure:
After dissolving 391 g of 1-(3-aminophenyl)- 5-mercaptotetrazole hydrochloride in 800 ml of N,N-dimethylformamide in a nitrogen gas atmosphere, the mixture was cooled to a temperature below 0° C. After adding thereto 302 ml of pyridine, 294 g of phenyl chloroformate were added dropwise to the s-lution while cooling with stirring so that the liquid temperature was not over 0° C. After further stirring the mixture for one hour at a temperature below 0° C., the reaction mixture was added dropwise to 5 liters of a saturated aqueous sodium chloride solution followed by stirring for 30 minutes. Crystals formed were collected by filtration and washed with 2 liters of water to provide 495 g of the desired compound with a yield of 93%.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21]CC3C=CC=CC=3)[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([CH:29]([CH3:31])[CH3:30])[N:7]=2>C1COCC1.CO.[Pd]>[ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([CH:29]([CH3:31])[CH3:30])[N:7]=2
Reactant: COc1ccc(Cn2cnc(N)c3nc(C(C)C)nc2-3)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(N)c3nc(C(C)C)nc2-3)cc1O
Yield: 78.6 %

Procedure:
6-Amino-3-(3-benzyloxy-4-methoxy-benzyl)-8-isopropyl-3H-purine hydrochloride (4.04 g, 9.2 mmole), in THF:methanol (1:1) (600 ml) was hydrogenated for 10 hours over 10% Pd-C (0.8 g) at room temperature and pressure. The catalyst was filtered off, the solvents removed in vacuo and the residue crystallized from acetone to give 6-amino-3-(3-hydroxy-4-methoxy-benzyl)-8-isopropyl-3H-purine hydrochloride (2.53 g, 78.8%), mp 125-130/185-195° C.
Reaction SMILES: Cl[Si](C)(C)C.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14].Cl>ClCCl>[CH3:21][O:20][C:18]([C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[S:13]([NH:6][C:11]1[CH:10]=[CH:9][C:8]2[CH2:25][CH2:24][CH2:23][CH2:22][C:7]=2[C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14])=[O:19]
Reactant: c1ccncc1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of Example 418A (1.81 g, 8.35 mmol) in dichloromethane (25.5 mL) was treated with chlorotrimethylsilane (6.7 mL of 1M CH2Cl2 solution, 16.7 mmol) and pyridine (25.5 mL), stirred at room temperature for 10 minutes, treated with methyl 2-(chlorosulfonyl)benzoate (2.61 g, 11.11 mmol), stirred overnight at room temperature, and treated with 1N HCl (50 mL). The aqueous phase was extracted with dichloromethane two times and the combined organic phases were washed with water and brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 404 (M+H)+; 480 (M+Na)+; (ESI(−)) m/e 402 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.77-7.65 (m, 4H), 7.12 (d, 1H), 6.98 (d, 1H), 3.01 (s, 3H), 3.63 (s, 3H), 2.68 (br s, 2H), 2.53 (br s, 2H), 1.66 (br m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]=2[N:5]=[C:4]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:3]=12.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][C:3]2[C:4](=[N:5][C:6]3[C:7]([C:12]([F:14])([F:13])[F:15])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:16][CH2:17]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(nc3c(C(F)(F)F)cccc13)CCNCC2
Product: CCOC(=O)N1CCc2nc3c(C(F)(F)F)cccc3c(C)c2CC1
Yield: 92 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-7-trifluoromethyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 1,2,4,5-tetrahydro-11-methyl-7-trifluoromethyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 155. Yield: 92% of theory; m.p. 136° C.
Reaction SMILES: [CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]=[C:21]=[O:22]>C1(C)C=CC=CC=1>[CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:10][C:21]([NH:20][CH3:19])=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN=C=O
Reactant: NC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 21.7 %

Procedure:
A solution of rac-2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-acetamide (116 mg, 0.40 mmol) in toluene (5 mL) was treated with methyl isocyanate (0.04 mL, 0.60 mmol). The resulting solution was heated to reflux for 24 h, then was cooled and was evaporated under reduced pressure. The resulting oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) to furnish 1-[cyclopentyloxy-(3,4-dichloro-phenyl)-acetyl]-3-methyl-urea (30 mg, 41% yield) as a colorless oil: EI-HRMS m/e calcd for C15H18N2Cl2O3 (M+) 288.0558, found 288.0572.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=O)[CH:16]=3)[NH:11][C:10]=2[OH:22])[CH:4]=1)#[N:2].[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH:27][CH2:26][CH2:25][O:24][CH3:23])=[O:20])[CH:16]=3)[NH:11][C:10]=2[OH:22])[CH:4]=1)#[N:2]
Reactant: COCCN
Reactant: COC(=O)c1ccc2[nH]c(O)c(-c3cc(C#N)ccn3)c2c1
Product: COCCNC(=O)c1ccc2[nH]c(O)c(-c3cc(C#N)ccn3)c2c1
Reaction time: 2 h
Yield: 8 %

Procedure:
Starting material: methyl 3-(4-cyanopyridin-2-yl)-2-hydroxy-1H-indole-5-carboxylate and 2-methoxyethanamine. The product was purified on a silica gel column using chloroform/methanol/aqueous NH3, (150:10:1), as the eluent. The combined fractions were concentrated, stirred for 2 h in ethyl acetate (5 mL), and the formed precipitate was filtered off to give 0.012 g (8% yield) of the title compound as a dark-red powder: 1H NMR (DMSO-d6, 300 MHz) δ 14.67 (br s, 1H), 10.83 (s, 1H), 8.46 (br s, 1H), 8.16 (d, J=6.3 Hz, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.86 (d, J=6.3 Hz, 1H), 3.48 (br s, 4H), 3.31 (s, 3H); MS (ES) m/z 337 (M++1).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.Cl[C:9]1[C:14]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:3]1([CH2:6][O:7][C:9]2[C:14]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: NS(=O)(=O)c1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccnc1OCC1CC1
Reaction time: 0.25 h

Procedure:
11.99 g of a 55% dispersion of sodium hydride are suspended in 40 ml of dimethylformamide and 13.04 ml of cyclopropylmethanol are added dropwise at 10° C. under a nitrogen atmosphere. The mixture is stirred for 15 minutes and then a solution of 21.16 g of 2-chloropyridin-3-ylsulfonamide in 40 ml of dimethylformamide is added dropwise. The reaction mixture is stirred for 30 minutes at 35°-40° C. and then taken up in a mixture of 275 ml of ethyl acetate, 275 ml of icewater and 137.5 ml of 2N hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with 3×100 ml of ethyl acetate. The combined organic phases are washed with 4×100 ml of water, dried, concentrated by evaporation and the residue is triturated with ether/hexane (2:1). The crystals so obtained are isolated and dried, affording 22.25 g of 2-cyclopropylmethoxypyridin-3-ylsulfonamide with a melting point of 121°-122° C.
Reaction SMILES: Cl[S:2]([C:5]1[C:6](=[O:22])[C:7]2[C:15](=[CH:16][CH:17]=1)[C:14]1[C:9](=[CH:10][C:11]([S:18](Cl)(=[O:20])=[O:19])=[CH:12][CH:13]=1)[CH:8]=2)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+:27].S([O-])([O-])=O.[Na+:32].[Na+]>O>[Na:27][S:2]([C:5]1[C:6](=[O:22])[C:7]2[C:15](=[CH:16][CH:17]=1)[C:14]1[C:9](=[CH:10][C:11]([S:18]([Na:32])(=[O:20])=[O:19])=[CH:12][CH:13]=1)[CH:8]=2)(=[O:4])=[O:3]
Reactant: [Na+]
Reactant: O=C1C2=Cc3cc(S(=O)(=O)Cl)ccc3C2=CC=C1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: O=C1C2=Cc3cc(S(=O)(=O)[Na])ccc3C2=CC=C1S(=O)(=O)[Na]

Procedure:
Also, for example, 2,7-bis(chlorosulfonyl)fluorenone can be mixed with a heated solution of sodium bicarbonate and sodium sulfite in water to yield 2,7-bis(sodiosulfonyl)fluorenone, which can be refluxed with n-butyl iodide in ethanol to yield 2,7-bis(n-butylsulfonyl)fluorenone, which in turn can be refluxed with malononitrile in methanol in the presence of piperidine to yield 2,7-bis(n-butylsulfonyl)-9-(dicyanomethylene)fluorene.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.C(N1CCC2(CC3C=CC=CC=3O2)CC1)C1C=CC=CC=1.[H][H].CCOCC>C(O)(C)C.[Pd]>[NH:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC3(CC2)Cc2ccccc2O3)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: c1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C

Procedure:
A solution of 5.3 g of 2,3-dihydro-1'-benzylspiro[benzofuran-2,4'-piperidine], free base of Example 1, in 250 ml of isopropyl alcohol is hydrogenated in a Paar shaker, 50 psig, 65°-70° C., with 1 g of a 10% palladium/carbon catalyst until the uptake of hydrogen is completed. Thereafter, the solution is successively permitted to cool to ambient temperature, filtered and concentrated to dryness, leaving a white solid. The solid is dissolved in a benzene-ether mixture, the solution is filtered through celite and then concentrated again, providing a white solid which, upon trituration with ether, provides the product, 2,3-dihydrospiro[benzofuran-2,4'-piperidine], mp 56°-58.5° C.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[C:19]1([C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:30]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccc2)n1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with 6-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 389.14 g/mol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1)#[CH:2].Br[C:18]1[N:22]([CH2:23][CH2:24][F:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1>>[F:25][CH2:24][CH2:23][N:22]1[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=[C:18]1[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][CH:8]=1
Reactant: FCCn1c(Br)nc2ccccc21
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)nc1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nc3ccccc3n2CCF)cn1
Yield: 31.5 %

Procedure:
tert-Butyl (5-ethynylpyridin-2-yl)carbamate (22 mg, 0.1 mmol) and 2-bromo-1-(2-fluoroethyl)-1H-benzo[d]imidazole (24.3 mg, 0.1 mmol) was reacted using general procedure B to afford tert-butyl (5-((1-(2-fluoroethyl)-1H-benzo[d]imidazol-2-yl)ethynyl)pyridin-2-yl)carbamate (12 mg, 31%). 1H NMR (300 MHz, CDCl3): 8.51 (d, J=1.6 Hz, 1H), 8.47 (m, 1H), 7.88 (dd, J=8.8, 2.4 Hz, 7.40-7.34 (m, 3H), 7.31 (d, J=12.8 Hz, 6.22 (s, 1H), 4.80 (t, J=4.8 Hz, 1H), 4.68 (t, J=4.8 Hz, 1H), 4.53 (m, 1H), 4.47 (m, 1H), 1.55 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:29]#[N:30])=[C:16]2[NH:15][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of 6.753 g (15.6 mmol) 4-[(3-chloro-4-thiophenoxyphenyl)amino]-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and 17.66 g (78.0 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 2 hours, added large volume of ice water, and made basic with sodium bicarbonate. Stirred for 2 hours and with mixture still basic, extracted with chloroform. Stirred organic layer with Darco, dried with sodium sulfate, filtered, stripped solvent and dried in vacuo, giving 5.996 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=403.1, 405.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[NH:10][C@H:11]([C:24]([NH:26][C:27]1[CH:28]=[N:29][N:30]([CH3:33])[C:31]=1[NH2:32])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:49]1([C:55](Cl)([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]=[C:9]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[NH:10][C@H:11]([C:24]([NH:26][C:27]1[CH:28]=[N:29][N:30]([CH3:33])[C:31]=1[NH:32][C:55]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude product tert-butyl (5S)-5-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-6-oxohexylcarbamate and triethylamine (1.01 g) in chloroform (100 ml) was added triphenylmethyl chloride (2.78 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give tert-butyl (5S)-5-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-6-oxohexylcarbamate (5.60 g) as an oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11][C:12]([NH:14][C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)=[S:13])[O:4][CH2:3][CH2:2]1.CI.[C:23](OCC)(=O)C>O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11][C:12](=[N:14][C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)[S:13][CH3:23])[O:4][CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: Cc1cscc1NC(=S)NC1CCCCC12OCCO2
Solvent: CI
Solvent: C1CCOC1
Product: CSC(=Nc1cscc1C)NC1CCCCC12OCCO2
Temperature: 70 °C
Reaction time: 48 h

Procedure:
1-(1,4-Dioxaspiro[4.5]dec-6-yl)-3-(4-methylthiophen-3-yl)thiourea (393 mg) was dissolved in absolute tetrahydrofuran (8.5 ml), and a solution of methyl iodide (179 mg) in absolute tetrahydrofuran (0.5 ml) was added. The mixture was then stirred at 70° C. in sand bath for 2 days. Ethyl acetate was then added to the reaction mixture, and the mixture was washed twice with water. The organic phase was dried over magnesium sulfate and the solvent was removed after filtration. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. This gave 59 mg of the desired product which was used directly for the next step.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[H-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: NC(=O)c1c(N)[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(N)n(-c2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 85 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
A solution of 2-aminoindole-3-carboxamide (Reference compound 18-1, 0.20 g, 1.1 mmol) in anhydrous N,N-dimethylformamide (2 mL) and a solution of 4-fluoronitrobenzene (0.13 mL, 1.3 mmol) in anhydrous N,N-dimethylformamide (2 mL) were successively added to a suspension of sodium hydride (purity 60%, g, 1.3 mmol) in anhydrous N,N-dimethylformamide (3 mL) under ice-cooling, and the mixture was stirred at 85° C. for 3 hours. The reaction mixture was poured into ice-water (20 mL), the precipitated solid was washed with ethyl acetate (4 mL). The resultant solid was dried under reduced pressure to give the title reference compound (0.087 g) as a brown solid (yield 26%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][S:10][CH2:11][C:12]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:14])[CH3:13]>C(Cl)(Cl)(Cl)Cl>[CH3:9][S:10][CH:11]([Cl:1])[C:12]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:14])[CH3:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Br)cc1C(C)(C)CSC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)cc1C(C)(C)C(Cl)SC
Temperature: 40 °C
Yield: 98.9 %

Procedure:
N-Chlorosuccinimide (37.4 g, 0.28 mole) was added portionwise to 2-(2-methoxy-5-bromophenyl)-2-methyl-1-propyl methyl sulphide (79.3 g, 0.275 mole) in carbon tetrachloride (250 ml) at room temperature. An exothermic reaction ensued, the temperature being allowed to rise to 40° C. before control with an external cooling bath was applied. After addition, the reaction mixture was heated at about 40° C. for 4 hours, then cooled, filtered and run down yielding 88 g crude title product (99%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13](N)=[O:14]>>[Br:11][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([F:10])[CH:8]=1)[N:1]=[C:13]([OH:14])[N:12]=[CH:4]2
Reactant: Nc1c(F)cc(Br)cc1C=O
Reactant: NC(N)=O
Product: Oc1ncc2cc(Br)cc(F)c2n1
Temperature: 180 °C
Yield: 82.3 %

Procedure:
A stirred mixture of 2-amino-5-bromo-3-fluorobenzaldehyde (2.17 g, 10 mmol) and urea (9 g, 150 mmol) was heated at 180° C. for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT, and the resulting precipitate was filtered and washed with water (500 mL*3). The moisture trapped was completely removed by the co-evaporation with toluene three times. The title compound (2 g, 83%) was obtained as a yellow solid. MS (ES+) C8H4BrFN2O requires: 242, 244. found: 243, 245 [M+H]+.
Reaction SMILES: CS/[C:3](=[N:9]\[C:10](=O)[CH:11]=[C:12]([CH3:14])[CH3:13])/[N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[NH2:16][NH2:17]>>[CH3:13][C:12]([CH3:14])=[CH:11][C:10]1[NH:17][N:16]=[C:3]([N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)[N:9]=1
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Reactant: NN
Product: CC(C)=Cc1nc(N2CCCC2)n[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 29.39 %

Procedure:
A mixture of 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylidene amide (1.2 g, 5.3 mmol) and hydrazine solution was stirred for 2 hours at 100° C. in a sealed tube. The mixture was cooled and concentrated. The crude material was purified by combiflash column chromatography using 50% ethyl acetate in hexane to give 5-(2-methyl-propenyl)-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (300 mg, 29.39%) as a white solid. MS: m/z=193 (M+H+)