Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.7 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (65 mg, 57%)
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30].O>CCCCCC.C1(C)C=CC=CC=1>[Br:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:16][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30]
Reactant: OCCCCCCCCCCCCO
Reactant: BrCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: BrCCCCCCCCCCCCOCCCCCCCCCCCCOCCCCCCCCCCCCBr
Temperature: 80 °C
Reaction time: 96 h
Yield: 56 %

Procedure:
Sodium hydride (60%, 652 mg, 16.3 mmol) washed with hexane was suspended in toluene (3 ml), 1,12-dodecanediol (1.50 g, 7.41 mmol) was added, 1,12-dibromododecane (6.08 g, 18.5 mmol) was added, and the mixture was stirred at 80° C. for 4 days. The reaction mixture was cooled to room temperature, and pure water (30 ml) was added dropwise thereto in a water bath to quench the reaction. The mixture was extracted with chloroform (100 ml), and washed 3 times with 1N hydrochloric acid (30 ml), 3 times with 5% aqueous sodium hydrogen carbonate solution (30 ml), and once with 20% aqueous sodium chloride solution (30 ml). The organic layer was dried over sodium sulfate and the solvent of the filtrate was evaporated. The residue was isolated and purified by silica gel column chromatography, and precipitated with methanol (50 ml) to give 1,12-bis-(12-bromododecyloxy)-dodecane (yield 56%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.[Br:10]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>N1C=CC=CC=1.ClCCl>[Br:10][C:8]1[CH:9]=[C:4]2[CH2:3][CH2:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: c1cnc2c(c1)CCN2
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1cnc2c(c1)CCN2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.8 %

Procedure:
2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine (4.40 g, 36.6 mmol) in a mixture of pyridine (4.4 mL) and dichloromethane (20 mL) was gradually added dropwise to bromine (7.00 g, 43.8 mmol) in dichloromethane (20 mL) cooled to 0° C., and the resulting reaction mixture was stirred at 0° C. for 20 minutes, after addition of saturated aqueous sodium thiosulfate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1 (v/v)) to give the title compound as a brown solid (2.83 g, yield 39%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:31])=[C:20]3[C:24]=2[N:23](C)[C:22]([C:26]([O:28]CC)=O)=[CH:21]3)=[CH:12][CH:11]=1)=O)(C)(C)C.[ClH:34].[NH2:35][C:36]([NH2:38])=[NH:37].[CH3:39][O-].[Na+]>CO>[ClH:31].[ClH:34].[NH2:8][CH2:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:31])=[C:20]3[C:24]=2[NH:23][C:22]([C:26]([N:37]=[C:36]([NH2:38])[NH:35][CH3:39])=[O:28])=[CH:21]3)=[CH:12][CH:11]=1
Reactant: N=C(N)N
Reactant: C[O-]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccc(CNC(=O)OC(C)(C)C)cc3)c2n1C
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(Cl)ccc(OCc3ccc(CN)cc3)c2[nH]1

Procedure:
The reaction was carried out in a manner similar to Example 196 e) except for using 0.60 g (1.27 mmol) of ethyl 7-[4-(tert-butoxycarbonylaminomethyl)-benzyloxy]-4-chloro-1-methyl-2-indolecarboxylate, 2.42 g (25.4 mmol) of guanidine hydrochloride, 1.37 g (25.4 mmol) of sodium methoxide and 50 ml of methanol. Thus, 0.25 9 (43.0%) of 7-[4-(aminomethyl)benzyloxy]-4-chloro-1-methyl-2-indoloylguanidine dihydrochloride was obtained.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].CN(C)/C=[CH:10]/[C:11]1[N:12]=[CH:13][C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:15][CH:16]=1.C([O-])(O)=[O:26].[Na+].CCOC(C)=O>C1COCC1.O>[CH:10]([C:11]1[N:12]=[CH:13][C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:15][CH:16]=1)=[O:26]
Reactant: CN(C)/C=C/c1cnc(C(=O)OC(C)(C)C)cn1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cnc(C=O)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium periodate (1.67 g) was added to a solution of t-butyl 5-((E)-2-dimethylamino-vinyl)-pyrazine-2-carboxylate (645 mg) in 50% THF-water (26 mL), and the mixture was stirred at RT for 4 h. A saturated NaHCO3 solution and EtOAc were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated NaCl solution and dried over anhydrous MgSO4. The insoluble matter was separated by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (249 mg). 1H-NMR (CDCl3) δ (ppm): 1.68 (s, 9H), 9.25 (d, J=1.2 Hz, 1H), 9.36 (d, J=1.6 Hz, 1H), 10.2 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1nc(-c2cccc(CNS(=O)(=O)c3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (400 mg, 1.0 mmol) and benzenesulfonyl chloride (300 mg, 1.7 mmol) were dissolved in ethyl acetate (10 ml) and water (5 ml), and sodium hydrogen carbonate (225 mg, 2.6 mmol) was added thereto. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (162 mg, 38%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH2:9][C:10]3([O:16][C:6]=2[CH:5]=[C:4](O)[CH:3]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-:28].[K+].[K+]>C(#N)C>[OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH2:9][C:10]3([O:16][C:6]=2[CH:5]=[CH:4][C:3]=1[O:28][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1CC2(CCCCC2)Oc2cc(O)cc(O)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ccc2c(c1O)C(=O)CC1(CCCCC1)O2
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.5 %

Procedure:
A mixture of 5,7-dihydroxyspiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 19) (0.248 g, 1.0 mmol), ethyl 2-bromopropionate (0.199 g, 1.1 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), and acetonitrile (3 ml) is stirred at room temperature for 22 hours, and the reaction mixture is concentrated. To the residue is added saturated brine and the mixture is extracted with dichloromethane. The organic layer is separated, dried, and concentrated. Purification by a silica gel column chromatography (eluent: dichloromethane) gives the title compound as an oil (0.284 g, yield 81.6%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C1(C)C(C)=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([NH:27][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:2])[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(F)c1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cccc(F)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 89 %

Procedure:
N-(3-Fluorophenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 3-fluoroaniline. Yield: 89% of theory; m.p. 278°-279° C (decomp.; from xylene).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Si](C=[N+]=[N-])(C)(C)[CH3:14]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(O)c(F)c1
Reaction time: 1 h
Yield: 64.6 %

Procedure:
2-(3-Fluoro-4-hydroxyphenyl)acetic acid (1.0 g, 5.88 mmol) was diluted with THF:MeOH (3:1) (10 mL) followed by the addition of TMSCHN2 (5.88 ml, 11.8 mmol). After stirring for 1 hour, the reaction was quenched with 2N HCl and diluted with DCM. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, eluting with hexanes:ethyl acetate (2:1) to yield methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (700 mg, 64.7% yield) as a clear oil.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].Cl[C:10]1[CH:19]=[C:18]([O:20]CC2C=CC(OC)=CC=2)[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([O:30][CH3:31])=[CH:15][CH:16]=2)[N:11]=1.O>CN1CCCC1=O>[OH:20][C:18]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([O:30][CH3:31])=[CH:15][CH:16]=2)[N:11]=[C:10]([N:6]2[CH:7]=[CH:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)[CH:19]=1
Reactant: CC(C)c1cc[nH]n1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of compound 233b (350 mg, 1 eq.) and compound 221b (480 mg, 6 eq.) in N-methylpyrrolidone (5 mL) was heated at 200° C. for 30 min. After the reaction mixture was cooled to room temperature, water was added. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (EtOAc/DCM). Recrystallisation in diethylether gave compound 236b as a white solid in 49% yield. 1H NMR (CDCl3, 376 MHz) δ (ppm) 1.35 (s, 3H), 1.36 (s, 3H), 2.85 (s, 3H), 3.97 (s, 3H), 6.40 (d, J=2.65 Hz, 2H), 7.01 (d, J=9.00 Hz, 1H), 8.00 (brs, 1H), 8.23 (d, J=9.00 Hz, 1H), 9.81 (brs, 1H); MS (ESI, EI+) m/z=298 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[N:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH2:28]([Cl:30])Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[N:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:28]([Cl:30])=[CH:12][CH:13]=3)[C:3]=12
Reactant: ClCCl
Reactant: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(I)c3c(N)ncnc32)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)nc1
Yield: 291.6 %

Procedure:
To a suspension of (E)-N-(6-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridine-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (65) (100 mg, 0.21 mmol), arylboronic acid (0.27 mmol) and K3PO4.3H2O (168 mg, 0.63 mmol) in DME (8 mL) and water (2 mL) was added Pd(dppf)Cl2.DCM (9 mg, 0.02 mmol). The resulting mixture was purged with N2 (3×) before microwaved at 90° C. for 45 min. The solvents were evaporated and the residual was directly loaded to a silica gel column and pre-purified by column chromatography (0 to 10% MeOH in DCM) followed by preparative HPLC purification (RP C18, 10 to 95% acetonitrile in water (0.2% NH3)) to give (E)-N-(6-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (66) (27 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO) δ 9.82 (br, 2H), 8.57 (d, J=2.5 Hz, 1H), 8.40 (s, 1H), 8.33 (d, J=8.7 Hz, 1H), 8.08 (dd, J=8.7, 2.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 6.73-6.65 (m, 1H), 6.34-6.19 (m, 1H), 3.80 (s, 2H), 3.34 (s, 3H), 2.69 (s, 6H). LC-MS (ESI): m/z (M/M+2) 463/465.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (100 mg, 0.32 mmol) and 1-methylpiperazine (65 mg, 0.65 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish N-benzyl-5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (73 mg, 0.22 mmol), 69% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.81 (m, 1H), 7.90 (d, J=9.5 Hz, 1H), 7.44-7.34 (m, 4H), 7.30-7.25 (m, 1H), 6.41 (dd, J=2.5 Hz, 10 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 4.58 (d, J=6 Hz, 2H) 3.4-3.2 (m, 4H), 2.34 (m, 4H), 2.19 (s, 3H).+ESI HRMS (calcd for C18H23N4O2, M+1) 327.1821, found 327.1816
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2[CH2:14][S:15][CH2:16][C:3]1=2.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CN1C2=C(CSC2)C(=O)Nc2ccccc21
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: CN1c2ccccc2NC(=O)c2cscc21

Procedure:
To a suspension of 3.8 g. of 1,3,4,9-tetrahydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one in 15 ml. of dry pyridine is added, in portions, a total of 2.18 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid is collected and recrystallized from methanol, to give a tan solid, m.p. 224°-225°C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>>[Cl:8][C:6]1[CH:5]=[N:4][C:3]2[N:9]3[C:10]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)=[N:11][CH:12]=[C:13]3[C:20](=[O:21])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)cnc1-n1ccnc1C1CCCCC1
Product: O=c1[nH]c2cc(Cl)cnc2n2c(C3CCCCC3)ncc12

Procedure:
3-Amino-5-chloro-2-(2-cyclohexyl-1H-imidazol-1-yl)pyridine as synthesized in Production Example 103, 838 mg, 1,1′-carbonyldi-imidazole 983 mg and 1,2-chlorobenzene 25 mL were mixed and heated under reflux for 15 hours. Cooling the reaction liquid off, the precipitate was recovered by filtration and washed with methanol. The resulting crystals were dissolved in a liquid mixture of 2N hydrochloric acid and methanol, and the insoluble matter was separated by filtration. The filtrate was made weakly alkaline with saturated aqueous sodium hydrogencarbonate solution, and the precipitate was recovered by filtration. Drying the same in flowing air under heating, 620 mg of the title compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CCCC(C)C2CN)c(-c2ccc(F)cc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chloro-5-(trifluoromethyl)pyridine, and K2CO3 in DMAC was stirred at 120° C. overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a pale yellow oil which solidified. MS (ESI) 493.01 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:28]=[C:27]([C:29]2[S:30][C:31]3[CH2:37][CH2:36][CH2:35][CH2:34][C:32]=3[N:33]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>C(Cl)Cl>[OH:2][C:3]1[CH:28]=[C:27]([C:29]2[S:30][C:31]3[CH2:37][CH2:36][CH2:35][CH2:34][C:32]=3[N:33]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3O)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[2-methoxy-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 164, 400 mg, 0.787 mmol) dissolved in CH2Cl2 (10 mL) was added AlCl3 (511.2 mg, 3.834 mmol), and then the solution was cooled to 0° C. Ethanethiol (0.284 mL, 3.834 mmol) was added dropwise to the solution which was stirred at 0° C. for 3 h. The reaction mixture was poured onto ice-water (20 mL) with vigorous stirring. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by preparative HPLC, giving the desired product as a white solid (180.0 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.28 (d, 1H), 7.20 (dd, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.79 (s, 1H), 6.69 (dd, 1H), 4.07-4.18 (m, 6H), 3.39 (m, 1H), 2.72 (dd, 6H), 2.09-2.20 (m, 5H), 1.80-1.59 (m, 5H), 1.18 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:11].[CH2:12]1CCN2C(=NCCC2)CC1.IC>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:11]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1cncc(F)c1Cl
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cncc(F)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
A solution of 4-chloro-5-fluoronicotinic acid (1.7 g, 9.68 mmol) in acetonitrile (18 mL) was cooled to 0° C. To this solution was added DBU (3.65 mL, 24.21 mmol) dropwise and the resultant solution stirred for 30 min. Iodomethane (3.03 mL, 48.4 mmol) was added dropwise and stirred at room temperature for 12 h. The volatiles were removed completely under reduced pressure and the residue purified via silica gel chromatography using a gradient of ethyl acetate in hexane to afford methyl 4-chloro-5-fluoronicotinate (1.2 g, 6.33 mmol, 65% yield) as a yellow solid. LCMS (ESI) m/e 190.0 [(M+H)+, calcd for C7H6ClFNO2 190.0]; LC/MS retention time (Method F): tR=0.77 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][SH:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S-:16].[Na+].II.Cl>O.C1COCC1.CCO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14][S:16][CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CS)C(=O)O
Reactant: C[S-]
Agent: Cl
Agent: II
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CSSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 67.9 %

Procedure:
(R)-2-((tert-butoxycarbonyl)amino)-3-mercaptopropanoic acid (Boc-L-Cys-OH) (110 mg, 0.5 mmol) was dissolved in H2O/THF (50% v/v, 20 mL). To the solution was added sodium thiomethoxide (350 mg, 5.0 mmol) at 0° C. Then, a solution of iodine in 95% EtOH was added dropwise until the color of the reaction system changed from colorless to brown. The mixture was stirred for 5.5 h with warming to room temperature. After removing THF under reduced pressure, reaction mixture was neutralized by 1 N HCl aq. until pH 2-3. The solution was extracted with EtOAc. The extract was washed with saturated NaS2O4 aq. and brine, and dried over MgSO4. Concentration under reduced pressure followed by flash chromatography over silica gel in EtOAc/Hexanes/AcOH (75:25:1) gave Boc-L-Csm-OH (90.8 mg, 68% yield). 1H NMR (360 MHz, CDCl3) δ 5.34 (s, 1H), 4.63 (br, s, 1H), 3.26-3.16 (m, 2H), 2.43 (m, 3H), 1.47 (s, 9H); LRMS (ESI) m/z calcd for C9H18NO4S2 (M+H)+ 268.1. found 268.2.