Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:35][C:36](OC)=O)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32].CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH:26]=[C:25]([O:24][CH3:23])[C:30]=1[O:31][CH3:32])[CH2:35][C:36]1[NH:22][C:20](=[O:21])[C:3]2[C:4]([CH2:17][CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CCC)n1nc(CCC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1cc(OC)c(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CCC)c2c(=O)[nH]c(Cc3cc(OC)c(OC)c(OC)c3)nc21
Yield: 53.8 %

Procedure:
6 mg (0.019 mmol) of 5-amino-3-propyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.083 mmol) of methyl 3,4,5-trimethoxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate have been added, the phases are separated. Purification by chromatography gives 5.1 mg (56%) of a solid, Rf=0.17 (dichloromethane/methanol=15:1).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH2:42](I)[CH3:43]>C1COCC1>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:28][CH2:29][CH2:30]1)[O:26][CH2:42][CH3:43])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CCI
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCC1
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclobutyl-methanol (23 mg; 0.041 mmol) in THF (1.5 mL) at 0° C. was added sodium hydride (15 mg; 0.375 mmol; 60% dispersion in mineral oil). After stirring at room temperature for 30 minutes ethyl iodide (0.05 mL; 0.625 mmol) was added. Reaction was stirred for 2 hours. More sodium hydride (15 mg; 0.375 mmol; 60% dispersion in mineral oil) and iodoethane (0.05 mL; 0.625 mmol) were added. Reaction stirred for 72 hours. Reaction was quenched with 2 drops of water. The reaction was filtered over a 1 g Bakerbond silica cartridge (Mallinkrodt Baker Inc. Phillipsburg, N.J.) (eluted with ethyl acetate). The crude was purified by RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-30% ethyl acetate in heptane) to give 21 mg (87% yield) of a gum. MS (ES+): Calc: 595.5, Found: 596.4 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.65 (s, 2H), 7.53 (s, 2H), 7.33 (s, 1H), 4.83 (q, J=16.18 Hz, 2H), 4.73 (q, J=16.18, 14.11 Hz, 2H), 4.42 (d, J=6.64 Hz, 1H), 4.22 (s, 3H), 3.20 (m, J=7.05, 6.64 Hz, 2H), 2.49 (m, J=7.88, 7.05 Hz, 1H), 2.07-1.57 (m, 6H), 1.11 (t, J=7.05 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+].[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:67]1[CH2:68][CH2:69][N:64]([C:2]2[C:3]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:13][CH:14]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:65][CH2:66]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Oc2ncccc2Br)cc1)c1ccccn1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(Oc3ncccc3N3CCOCC3)cc2)nc1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
A microwave reaction vessel was charged with tert-butyl 4-(3-bromopyridin-2-yloxy)phenyl(pyridin-2-yl)carbamate (0.6142 g, 1.39 mmol), palladium (II) acetate (0.0306 g, 0.0833 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.0932 g, 0.167 mmol), and sodium tert-butoxide (0.5219 g, 4.17 mmol). The vessel was put under vacuum for 5 min. A solution of morpholine (0.316 mL, 2.78 mmol) in toluene was added to the vessel. The reaction was allowed to heat at 90° C. for 10 min. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 10% to 50% acetone in hexane. Product was taken up in DCM and TFA was added to stir overnight. The solvent was removed and the residue was filtered through a carbonate filter to provide N-(4-(3-morpholinopyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 349.1 (M+1). IC50 (uM) 0.030207.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]#[N:16])[CH2:9][CH2:8]1.[F:21][C:22]1[CH:23]=[C:24]([C@@H:29]2[C:34]([C:35](O)=[O:36])=[C:33]([CH3:38])[NH:32][C:31](=[O:39])[NH:30]2)[CH:25]=[CH:26][C:27]=1[F:28]>>[C:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:35]([C:34]2[C@@H:29]([C:24]3[CH:25]=[CH:26][C:27]([F:28])=[C:22]([F:21])[CH:23]=3)[NH:30][C:31](=[O:39])[NH:32][C:33]=2[CH3:38])=[O:36])[CH2:12][CH2:11]1)#[N:16]
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Reactant: N#Cc1ccccc1C1CCN(CCCN)CC1
Agent: Cl
Product: CC1=C(C(=O)NCCCN2CCC(c3ccccc3C#N)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
2-[1-(3-amino-propyl)-piperidine-4-yl]-benzonitrile dihydrochloride as used in place of 2-[1-(3-amino-propyl)-piperidine-4-yl]-5-fluoro-enzonitnile dihydrochloride and (R)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid was used in place of (4R)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.I[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[CH:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2cccs2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution (7 ml) of 2-(4-trifluoromethylphenyl) thiophene (1.71 g) in tetrahydrofuran was added dropwise n-butyl lithium (1.6 M solution in hexane, 5.00 ml) under an argon atmosphere at −78° C. This mixed solution was heated to room temperature, and a solution (14 ml) of zinc chloride (1.09 g) in tetrahydrofuran was added. This mixture was stirred for 1 hr., and ethyl 4-iodobenzoate (1.16 ml) and tetrakis(triphenylphosphine)palladium (0.202 g) were added. This mixture was stirred overnight under an argon atmosphere and poured into 0.5 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Ethanol (200 ml) was added to the residue, and the mixture was heated under reflux for 10 min. Insoluble materials were filtered off, and the filtrate was concentrated to give ethyl 4-[5-(4-trifluoromethylphenyl)-2-thienyl]benzoate (1.19 g, yield 45%) as a yellow crystalline powder. melting point: 203–204° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][C:36]([F:39])([F:38])[F:37])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]2[O:17][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][C:36]([F:37])([F:38])[F:39])[N:26]=2)[CH:12]=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: COc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1-c1ccccc1C

Procedure:
Oxalyl chloride (126 μL; 1.49 mmol; 3 eq.), Intermediate 27 (120 mg; 0.5 mmol; 1 eq.), Intermediate 2 (109 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[C:18]([CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=2)[NH2:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:25]([O:29][C:30]([NH:32][C@H:33]([C:35](O)=[O:36])[CH3:34])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[C:18]([CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=2)[NH:19][C:35](=[O:36])[CH:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[CH3:34])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 77.2 %

Procedure:
3-(9-acridinylamino)-5-(hydroxymethyl)aniline and t-butoxycarbonyl-L-alanine were reacted with the same method to the example 38 to give the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.O.C(OCC)(=O)C.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>[NH2:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH:7]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1ccc(Nc2cncc(Br)c2)cc1
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Nc2cncc(-c3cccc(N)c3)c2)cc1

Procedure:
A stirred solution of 3-bromo-5-(p-methoxyphenylamino)pyridine (0.5 g, 1.8 mmol), 3-aminophenyl boronic acid (0.28 g, 1.8 mmol) and Na2CO3 (0.56 g, 5.3 mmol) in dimethoxyethane (10 ml) and water (3.5 ml) is deoxygenated using argon before adding Pd(PPh3)4 (0.06 g) and heating the mixture at reflux for 16 hours. The mixture is diluted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated. The residue is chromatographed on silicagel to afford the product; 1H NMR (400 MHz, d6-DMSO): δ 8.16 (m, 2H), 8.10 (s, 1H), 7.34 (m, 1H), 7.10 (m, 3H), 6.91 (d, J=8.84 Hz, 2H), 6.75 (s, 1H), 6.71 (m, 1H), 6.57 (m, 1H), 5.21 (br s, 2H), 3.73 (s, 3H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.CC[O-].[Na+].[CH3:17][N:18]([CH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26]N)=O)[CH3:19].Cl.CCOCC>C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[NH:10][N:26]=[C:24]([C:23]3[CH:22]=[C:21]([CH:30]=[CH:29][CH:28]=3)[CH2:20][N:18]([CH3:19])[CH3:17])[N:9]=2)=[CH:6][CH:5]=1
Reactant: CN(C)Cc1cccc(C(=O)NN)c1
Reactant: COc1ccc(C(=N)N)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc(-c3cccc(CN(C)C)c3)n[nH]2)cc1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a stirred ethanolic suspension of 4-methoxybenzamidine hydrochloride salt (280 mg, 1.5 mmol, 1.5 eq.) was added over 3 minutes 1.2N NaOEt in ethanol (1.7 ml, 2 eq.) and stirring was continued for 30 min. at r.t. 3-Dimethylaminomethyl-benzoic acid hydrazide (193 mg, 1 mmol) in ethanol was then added at 20° C. and the mixture heated at reflux for 24 hrs. Upon cooling the product mixture was filtered, the solvent was evaporated and the residue subjected to preparative reversed phase-HPLC purification using a YMC ODS-AQ column (20×50 mm) and a (0.1% trifluoroacetic acid) water-acetonitrile gradient (25 ml/min.). The pure fractions were concentrated and the product obtained was converted to the hydrochloride salt by addition of excess 2N HCl/ether solution. Solvent evaporation and high vacuum drying afforded the title compound (86 mg, 0.25 mmol, 25% yield) as a white foam. MS: m/e=309.4 (M+H+).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH2:9]1)C1C=CC=CC=1.CCN(CC)CC.C(Cl)(=O)OC(Cl)C>C(Cl)Cl>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[N:14][CH:15]=1
Reactant: Cc1ccc(C2CCN(Cc3ccccc3)C2)nc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C2CCNC2)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 117 %

Procedure:
To a stirred solution of 2-(1-benzylpyrrolidin-3-yl)-5-methylpyridine (200 mg, 0.79 mmol) in dry CH2Cl2 (3 mL) were added Et3N (80 mg, 0.79 mmol) and 1-chloroethyl carbonochloridate (225 mg, 1.6 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under vacuum and dissolved in CH2Cl2 (5 mL). The organic solution was washed with water (20 mL×3), and the combined aqueous layers were concentrated to give crude 5-methyl-2-(pyrrolidin-3-yl)pyridine (150 mg, 82%) as a solid, which was used for next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:21])[C:17]([OH:20])=[CH:18][CH:19]=3)[S:13][C:6]=12.Br[CH2:30][CH2:31][CH2:32][Cl:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:33][CH2:32][CH2:31][CH2:30][O:21][C:16]1[CH:15]=[C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=3[F:1])[CH:11]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:30][CH2:31][CH2:32][Cl:33]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)c(O)c4)sc23)c(F)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(OCCCCl)c(OCCCCl)c4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a stirred solution of 332 (140 mg, 0.35 mmol) in anhydrous DMF (5 ml) were added 1-bromo-3-chloropropane (553 mg, 3.51 mmol) and cesium carbonate (573 mg, 1.76 mmol), respectively. The reaction mixture was stirred for 2 hrs at room temperature, diluted with AcOEt, and successively washed with water, sat. ammonium chloride, water, and concentrated. The crude material was adsorbed on silica gel and purified by flash column chromatography (eluents AcOEt/CH2Cl2: 10/90 to 20/80) to afford title compound 333 (120 mg, 62% yield) as a yellow solid. MS (m/z): 551.0 and 553.0 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[CH:26]=[C:25]([O:27][CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][O:29]5)[CH:24]=[C:23]([F:34])[CH:22]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[I-:35].[Na+]>CC(C)=O>[F:34][C:23]1[CH:22]=[C:21]([C:16]23[CH2:17][CH2:18][C:13]([CH2:12][I:35])([CH2:20][CH2:19]2)[CH2:14][O:15]3)[CH:26]=[C:25]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4cc(F)cc(OC5CCCCO5)c4)(CC2)OC3)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Fc1cc(OC2CCCCO2)cc(C23CCC(CI)(CC2)CO3)c1
Temperature: 78 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
A mixture of 36C (0.9 g, 1.84 mmol) and sodium iodide (3.8 g, 25.4 mmol) in acetone (15 mL) was stirred at 78° C. for 18 h. The reaction cooled to rt and filtered. The filtrate was concentrated in vacuo, taken up in DCM (10 mL) and filtered. The residual solid was washed with DCM (5 mL×2). The combined organic filtrates were concentrated in vacuo. The residual crude oil was purified by flash chromatography using a 0% to 30% gradient of EtOAc/hexane (15 min) to give the title compound (0.730 g, 1.64 mmol, 89% yield) as a white solid. 1H NMR (CDCl3) δ: 6.88 (t, J=1.7 Hz, 1H), 6.76 (ddd, J=10.1, 2.3, 1.6 Hz, 1H), 6.70 (dt, J=10.5, 2.3 Hz, 1H), 5.41 (t, J=3.1 Hz, 1H), 3.96-3.85 (m, 3H), 3.68-3.60 (m, 1H), 3.07 (s, 2H), 2.10-1.95 (m, 5H), 1.89-1.58 (m, 9H); 19F NMR (CDCl3) δ: −111.9 (s).
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH3:10]>>[CH2:7]([NH:11][C:12]([N:3]1[CH:4]=[CH:5][NH:6][C:2]1=[S:1])=[O:13])[CH2:8][CH2:9][CH3:10]
Reactant: Sc1ncc[nH]1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)n1cc[nH]c1=S
Temperature: 50 °C
Yield: 92.5 %

Procedure:
2-Mercaptoimidazole (24.39 g, 0.244 mole) and butyl isocyanate (48.3 g, 0.487 mole) were combined in a round-bottom flask and heated to 50° C. for 30 min or until the reaction was complete by TLC. The reaction mixture was then cooled to room temperature and the solidified mass was triturated with 50 mL of hexane for 30 min. The beige solid was filtered, washed with a minimum amount of hexane and dried under reduced pressure to yield 44.96 g (93%) of 1-(butylcarbamoyl)-1,3-dihydroimidazole-2-thione as beige crystals: mp 66-68° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Cl:12]N1C(=O)CCC1=O>C(O)(C)C>[Cl:12][C:11]1[C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:1]
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Product: Cc1nc2c(Cl)c(N)ccc2s1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-amino-2-methylbenzothiazole (818 mg, 4.99 mmol) in isopropanol (12 mL) was added N-chlorosuccinimide (732 mg, 5.48 mmol). The mixture was stirred at 60° C. for 15 min., partitioned between DCM and 5% sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulphate and concentrated in vacuo to give a residue that was purified with flash chromatography (EtOAc/DCM gradient elution). 4-Chloro-2-methylbenzothiazol-5-ylamine was obtained as off-white crystalline solid (510 mg, 51%). mp 121-122° C. (lit. 124° C.); TLC single spot at Rf 0.51 (20% EtOAc/DCM); 1H NMR (270 MHz, DMSO): δ 7.61 (1H, d, J=8.6 Hz, ArH), 6.91 (1H, d, J=8.6 Hz, ArH), 5.49 (2H, s, NH2), 2.75 (3H, s, CH3); APCI-MS 199 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:21]1([CH:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:21]1([CH:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: c1ccc(C2CCCN2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N4CCCC4c4ccccc4)n3)cc2s1
Temperature: 140 °C
Yield: 20.1 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol), 2-phenylpyrrolidine (0.05 ml, 0.3 mmol), diisopropylethylamine (0.1 ml, 0.7 mmol) in DMSO (1.0 g, 11 mmol) was heated under CEM microwave at 140° C., 130 W (Powermax® off). The resultant was diluted with 5 ml of water and filtered. The solid was diluted with DCM and filtered. The filterate was recrystallized from DCM to give a brown solid (25 mg). MS (ESI pos. ion) Found m/z: 416, (M+H)+.
Reaction SMILES: [N:1]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].O>CC1CCCO1>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:4]1[CH2:5][CH2:6][N:1]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2](=[O:8])[CH:3]=1
Reactant: O=C1CCN(N2CCCCC2)C(=O)C1
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: O
Solvent: CC1CCCO1
Product: O=C1C=C(Nc2ccc(Cl)cc2Cl)CCN1N1CCCCC1
Temperature: 25 °C
Yield: 77 %

Procedure:
1,1′-bipiperidine-2, 4-dione (1,000 g, 4,739 mmol) and 2,4-dichloroaniline (0.921 g, 5.687 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml) and the reaction mixture was boiled under reflux for 22 h whilst the water formed was removed using a Dean and Stark apparatus. Upon cooling to rt the product precipitated and was collected by filtration to yield a white solid (1.490 g, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[C:6](SC)[S:7][CH3:8])[CH3:2].[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([S:7][CH3:8])=[N:21][N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]=1[NH2:12])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Reactant: NNc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(SC)nn(-c2ccccc2)c1N

Procedure:
To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester (5.00 g, 23.0 mmol) in dry ethanol (100 mL) is added phenylhydrazine (2.28 mL, 23.0 mmol). The reaction mixture is heated to reflux for 2 h before removal of the solvent. The resulting solid is recrystallized from EtOH (20 mL) to provide 5-amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid product; HPLC-MS calculated for C13H15N3O2S (M+H+) 278.1, found 278.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])(O)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33][NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CCS(C)(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)CNCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chlorobenzylamine (0.628 mL, 5.14 mmol) and crushed molecular sieves (1.5 g) in dichloroethane (10 mL) under nitrogen at 0° C. was added sodium triacetoxyborohydride (2.73 g, 12.9 mmol), followed the product from Step C (2.73 g, 5.14 mmol). The reaction was stirred overnight, allowing it to warm to room temperature. The solution was poured into EtOAc and sat NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was purified by silica gel chromatography (2.5-5% MeOH/CHCl3) to obtain the titled compound as a white foam.