Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]1([CH:9]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:31]=[CH:30][C:20]4[N:21]([CH3:29])[C:22]([NH:24]C(=O)OC)=[N:23][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O>[C:32]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:31]=[CH:30][C:20]4[N:21]([CH3:29])[C:22]([NH2:24])=[N:23][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)Nc1nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(N)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Reaction time: 8 h

Procedure:
To a stirred solution of 4 parts of sodium hydroxide in 50 parts of water are added 4.7 parts of methyl {5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-yl]carbamate. The whole is stirred and refluxed for 3.50 hours. The reaction mixture is cooled and allowed to stand overnight. It is acidified with a hydrochloric acid solution 10 N. The precipitated product is filtered off, washed with water and boiled in ethanol. After cooling, the product is filtered off, washed with ethanol and with 2,2'-oxybispropane and dried, yielding 2.5 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-amine; mp. 267.5° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32].O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:31]([O:33][C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[O:32])=[CH:7][CH:8]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (1550 mg, 5590 μmol) and diea (1071 μL, 6149 μmol) in DCM (36 mL) at 0° C. was added 4-nitrophenyl chloroformate (1465 mg, 7267 μmol, Aldrich). After addition, the reaction mixture was stirred at RT for overnight. Then, H2O (60 mL) was added and the mixture was stirred at RT for 15 min. The organic layer was collected and the aqueous was extracted with DCM (1×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was then mixed with silica gel (4:1, residue: silica gel) and the solid mixture was purified by silica gel flash column chromatography using ISCO instrument (solid loading, 0%-100% EtOAc/hexane) to give the compound as an off-white solid. MS (ESI, positive ion) m/z: 443 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:25]1([O:30][C:31](=[O:38])[C@H:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:33][C@H:32]([C:31]([O:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)C[C@H](NC1CCN(C(=O)OC(C)(C)C)C1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-tert-butoxycarbonyl-3-pyrrolidinone (0.382 g, 4.76 mmol) in dichloroethane (20 mL) was added L-leucine cyclopentyl ester tosylate (1.96 g, 5.3 mmol) and sodium triacetoxyborohydride (2.65 g, 12.5 mmol). The mixture was stirred at room temperature for 3 hours, then poured into ethyl acetate (150 mL) and quenched with saturated ammonium chloride solution (50 mL) and washed with saturated sodium hydrogen carbonate solution (3 times 30 mL). The organic extracts were dried (MgSO4), concentrated and purified by flash column chromatography (7:3 ethyl acetate:heptane) to yield the desired product. LC/MS: m/z 369.25 [M+H]+
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[N:18]1([C:22]([C:24]2[CH:25]=[N:26][N:27]([CH3:32])[C:28]=2[C:29](O)=[O:30])=[O:23])[CH2:21][CH2:20][CH2:19]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:1][C:2]1[C:3]([NH:17][C:29]([C:28]2[N:27]([CH3:32])[N:26]=[CH:25][C:24]=2[C:22]([N:18]2[CH2:21][CH2:20][CH2:19]2)=[O:23])=[O:30])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Nc1cc2nc(-c3ccccc3)nn2cc1F
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Yield: 43.5 %

Procedure:
A mixture of 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (50 mg, 219 μmol), 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (45.8 mg, 219 μmol), propylphosphonic anhydride (50% in ethyl acetate, 323 μl, 548 μmol) and diisopropylethyl amine (115 μl, 657 μmol) in tetrahydrofuran (5 ml) was refluxed for 18 hours. The crude material is loaded on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 20-100% as eluent, affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (40 mg: 43.5%) as white solid. Mp.: >250° C. MS: m/z=420.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]1[C:31]([C:36]#[N:37])=[N:32][CH:33]=[CH:34][N:35]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:36]([C:31]1[C:30]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:35][CH:34]=[CH:33][N:32]=1)#[N:37]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: N#Cc1nccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nccnc2C#N)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0506 g, 0.132 mmol) and 3-chloropyrazine-2-carbonitrile (0.0338 g, 0.242 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.80 (s, 1H), 8.50 (d, J=2.2, 1H), 8.21 (d, J=8.7, 2H), 8.15 (d, J=2.2, 1H), 7.50 (d, J=8.7, 2H), 6.30 (t, J=5.5, 1H), 4.86 (s, 2 H), 4.00 (s, 2H), 3.74 (d, J=4.3, 4H), 3.49 (d, J=4.2, 4H), 3.12 (dt, J=13.8, 7.1, 3H), 2.85 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+486.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1.Cl>[Br:8][C:9]1[CH:10]=[C:11]([S:15]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCN(S(=O)(=O)c2cccc(Br)c2)CC1

Procedure:
A solution of 1-methylpiperazine (0.072 ml, 0.65 mmol) and 3-bromobenzene-1-sulfonyl chloride (0.2 g, 0.78 mmol) in pyridine (3 ml) is stirred at room temperature for 2 hours. The reaction mixture is diluted with 2M HCl, and extracted with DCM. The aqueous layer is made basic with 2M NaOH, and is extracted with DCM. The DCM layers are combined, dried (MgSO4) and the solvent removed in vacuo to afford the title compound as an orange oil. [M+H]+ 345.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[N:17][OH:18])[C:13]([F:16])([F:15])[F:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.O>C1COCC1.CCOC(C)=O>[F:16][C:13]([F:14])([F:15])[C:12]1[C:3]2[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=2[O:18][N:17]=1
Reactant: CCCc1c(O)ccc(C(=NO)C(F)(F)F)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
1-(2,4-Dihydroxy-3-propylphenyl)-2,2,2-trifluoroethanone oxime (4.2 g, 15.96 mmol, prepared by the method described in WO9728137) and PPh3 (8.82 g, 33.6 mmol) were dissolved in THF (250 mL), and the mixture was cooled to 0° C. A solution of DEAD (5.02 mL, 32.0 mmol) in THF (150 mL) was slowly added over a period of 30 min. The reaction mixture was stirred for 1 h at 0° C. After addition of water (500 mL) and extraction with EtOAc (3×300 mL), the combined organic phases were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel flash chromatography (1:6 EtOAc/hexane) to yield 1.96 g (50%) of the title compound as a light yellow powder. 1H NMR (300 MHz, CDCl3): δ 1.00 (t, 3H), 1.73 (m, 2H), 2.88 (t, 2H), 5.34 (s, 1H), 6.93 (d, 1H), 7.48 (d, 1H).
Reaction SMILES: [CH3:1][Sn](C)(C)C.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:32](=[CH:33][CH:34]=2)[O:31][C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:17][C:16]3=[O:35])=[CH:9][C:8]=1[C:36]([O:38][CH3:39])=[O:37]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][O:38][C:36]([C:8]1[CH:9]=[C:10]([C:13]2[CH:14]=[C:15]3[C:32](=[CH:33][CH:34]=2)[O:31][C:18]2([CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH2:17][C:16]3=[O:35])[CH:11]=[N:12][C:7]=1[CH3:1])=[O:37]
Reactant: COC(=O)c1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cnc1Cl
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cnc1C
Temperature: 180 °C
Reaction time: 0.25 h

Procedure:
The mixture of tetramethyltin (1.14 ml), and PdCl2(PPh3)2 (97 mg), tert-butyl 6-[6-chloro-5-(methoxycarbonyl)-3-pyridinyl]-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (1.35 g) in dioxane (13 ml) was stirred at 180° C. for 15 min under microwave irradiation. The reaction mixture was evaporated, and purified by silica gel chromatography (hexane/ethyl acetate) to give the intended compound.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].O>CC(C)=O>[Cl:22][CH2:21][CH2:20][CH2:19][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCCCCl
Yield: 5.9 %

Procedure:
A mixture of vanillin (30.4 g, 200 mmol), K2CO3 (27.6 g) and acetone (150 ml) was stirred and refluxed for 0.5 hours. Heating was removed and 1-bromo-3-chloropropane (40.8 g, 260 mmol) in acetone was added dropwise. The reaction was stirred and refluxed for 16 hours, and then it was poured into water. The aqueous mixture was extracted with diethyl ether, the extract was dried (MgSO4), and the solution was concentrated to afford an oil, which upon evacuation solidified to a white solid (50.2 g). An 8.0 g sample was flash chromatographed on silica gel with 50% ethyl acetatehexane as eluent. Concentration of appropriate fractions gave 2.7 g (37%) of 4-(3-chloropropoxy)-3-methoxybenzaldehyde as a white solid, m.p.=53°-55° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[CH:8]=1.[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31](O)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([O:1][CH2:2][CH2:3][C:4]4[O:5][C:6]5[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=5[CH:8]=4)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][N:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)noc12
Reactant: COC(=O)Cc1ccc2oc(CCO)cc2c1
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3o2)ccc2c(-c3ccccc3)noc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and 3-phenyl-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless oil.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:18](=[O:19])[CH:17]([CH3:20])[S:16][CH:15]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.CI.P([O-])([O-])([O-])=O>CCCCCC.O1CCCC1>[CH3:20][C:17]1([CH3:1])[S:16][CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:14]([CH3:13])[C:18]1=[O:19]
Reactant: CC(C)NC(C)C
Reactant: CC1SC(c2cccnc2)N(C)C1=O
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)SC1c1cccnc1
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Dry diisopropylamine (0.95 ml, 5.3 mmol) was added to dry tetrahydrofuran (3 ml). Further a butyllithium solution (3.6 ml, 5.8 mmol) in hexane was added dropwise at -40° C. The mixture was kept at -10° C. for 1 hour. Then a solution of 3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one (1 g, 4.8 mmol) in dry tetrahydrofuran (7 ml) was added dropwise at -20° to -10° C. After this reaction mixture had been kept between those temperatures for 1 hour, methyl iodide (0.75 g, 5.3 mmol) dissolved in dry tetrahydrofuran (2 ml) was added at -20° to -10° C. This reaction mixture was heated for 2 hours up to 0° C. and then kept at the same temperature for 2 hours. The resulting mixture, after addition of a phosphate buffer (pH 7.0), was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and subjected to medium-pressure liquid chromatography (hexane-acetone) and then to recrystallization from a 1:1 ether-hexane mixture, giving 5,5,3-trimethyl-2-(3-pyridyl)thiazolidin-4-one (0.42 g, 39% yield). NMR (CDCl3) δ [ppm]; 1.62 (3 H, s), 1.68 (3 H, s), 2.74 (3 H, s), 5.51 (1 H, s). IR (nujol) [cm-1 ]; 1668, 1590, 1390, 1310, 1135, 1071, 1021.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:11]3=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:14]([CH:15]=1)=[C:10]23>C(Cl)Cl.N1C=CC=CC=1>[O:26]=[C:25]1[C:9]2[C:10]3[C:11](=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:14]=3[CH:15]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)[CH:22]=[N:23][NH:24]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Temperature: 22 °C
Reaction time: 24 h
Yield: 26.7 %

Procedure:
Methanesulfonyl Chloride (1.5 eq, 0.003 g) was added to a solution of the title compound of Example 7 (0.005 g, 0.018 mmol) in CH2Cl2 (0.045 M, 0.4 mL) and pyridine (0.045 M, 0.4 mL). The mixture was stirred at 22° C. for 24 hours and concentrated under reduced pressure. Silica gel chromatography (triethylamine/methanol/CH2Cl2; 1:5:94) afforded the title compound (1.7 mg) in 30% yield.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:13]1[C:21]2[C:16](=[C:17]([N:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)([CH3:12])([CH3:11])[CH3:10].[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.Cl>C1COCC1>[C:9]([N:13]1[C:21]2[C:16](=[C:17]([N:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[B:31]([OH:36])[OH:32])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N(c1cccc2c1ccn2C(C)(C)C)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)N(c1cccc2c1cc(B(O)O)n2C(C)(C)C)C(C)(C)C
Reaction time: 1 h

Procedure:
A THF solution of lithium diisopropylamide prepared above was added in an ice bath dropwise to a THF (5 mL) solution of 1-(tert-butyl)-4-(di-tert-butyl)aminoindole (300 mg, 0.694 mmol) and triisopropyl borate (157 mg, 0.832 mmol) which was separately prepared. After the reaction solution was stirred in an ice bath for 1 hour, the solution was adjusted to pH3 with adding a 1M HCl solution. The resulting solution was extracted with ethyl acetate (15 mL×2), and the combined solution was dried over anhydrous magnesium sulfate to afford the crude product 53 of 1-(tert-butyl)-4-(ditert-butyl)amino-2-indoleboronic acid. The crude product was used for the next reaction without any further purification.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[BH4-].[Na+].Cl>C(O)C.O1CCCC1.O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:15]([N:6]2[CH2:7][C@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:9][C@H:5]2[CH2:3][OH:2])=[O:16])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Yield: 70372.7 %

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (79.4 g: 0.197 mmole) in a mixture of ethanol (300 ml) and tetrahydrofuran (150 ml), sodium borohydride (10.44 g: 1.4 eq.) is added in small portions with stirring at 0° C. The mixture is stirred at 0° C. for 1.5 hours and at room temperature for 5 hours. To the reaction mixture under ice cooling, 5N-hydrochloric acid (100 ml) is added. The mixture is diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is recrystallized from a mixture of dichloromethane and ether to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (51.9 g). Yield: 70%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[C:4]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>C(N(CC)CC)C>[CH:26]1([C:29]([N:9]2[CH2:8][CH2:7][C:6]3[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[C:4]([S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:5]=3[CH2:11][CH2:10]2)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc2c(c(Sc3ccccc3)c1OC)CCNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(c(Sc3ccccc3)c1OC)CCN(C(=O)C1CC1)CC2

Procedure:
To a solution of 1.58 g. (0.005 mole) of 7,8-dimethoxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine in 25 ml. of methylene chloride and 1.0 g. of triethylamine is added dropwise 1.05 g. (0.010 mole) of cyclopropanecarboxylic acid chloride at 5° C. and the mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered and the filtrate is washed with water, 5% potassium carbonate solution and then with water, dried and subsequently concentrated to give 3-cyclopropanecarbonyl-7,8-dimethoxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[CH:14][NH:15]2)=[CH:11][CH:10]=1.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1.Cl>CC(N(C)C)=O.C1(C)C=CC=CC=1.O>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[CH:14][N:15]2[CH2:22][CH2:21][CH2:20][C:19]([OH:24])=[O:23])=[CH:11][CH:10]=1
Reactant: O=C1CCCO1
Reactant: COc1ccc2c(C)c[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: COc1ccc2c(C)cn(CCCC(=O)O)c2c1
Reaction time: 12 h
Yield: 73.6 %

Procedure:
Anhydrous potassium carbonate (34.5 g, 0.25 mol) was added to a solution of 6-methoxy-3-methylindole (16.1 g, 0.1 mol) and γ-butyrolactone (43 g, 0.5 mol) in dimethylacetamide (750 mL). Under mechanical stirring and protected with a drying tube, the reaction mixture was refluxed for 18 hours, more γ-butyrolactone (21.5 g, 0.25 mol) was added, and the reflux was continued for 12 hours. A final portion of γ-butyrolactone (21.5 g, 0.25 mol) was added and the thick suspension was refluxed for another 12 hours, cooled to ~30° C., and poured into water (600 mL). Toluene (600 mL) was added and the 2 layer system was stirred for 15 minutes. The aqueous layer was separted and acidified with concentrated hydrochloric acid. The product was extracted with toluene (3×250 mL). The combined extracts were washed with water (600 mL), dried over MgSO4, filtered, evaporated, and the dark oily residue was chromatographed on silica gel (480 g). Elution with chloroform/hexane (1:1) afforded 18.2 g (74%) of the title compound as a yellowish oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[NH:8][S:7]1(=[O:15])=[O:14].Cl.[Cl:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[N:20][CH:19]=1>CN(C)C=O.C(N(CC)CC)C>[Cl:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[NH:8][S:7]3(=[O:15])=[O:14])[CH2:28][CH2:29]2)[CH:21]=[N:20][CH:19]=1
Reactant: CC1CC(=O)N(CCCCBr)S(=O)(=O)N1
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CC(=O)N(CCCCN2CCN(c3cncc(Cl)n3)CC2)S(=O)(=O)N1

Procedure:
The title compound is prepared by adding to a stirred solution of 2 g (0.006 mol) of 2-(4-bromobutyl)-5,6-dihydro-5-methyl-2H-1,2,6-thiadiazin-3(4H)-one 1,1-dioxide in 50 mL of dimethylformamide, 4 mL of triethylamine and 1.41 g (0.006 mol) of 1-(6-chloro-2-pyrazinyl)piperazine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>C(Cl)Cl>[Br:8][C:4]1[N:3]=[C:2]([NH:1][C:15]([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[S:16])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)n1
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Product: CCOC(=O)NC(=S)Nc1cccc(Br)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5 ° C. is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture is then allowed to warm to room temp. (20° C.) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea may be used as such for the next step without any purification. 1H (400 MHz, CDCl3) δ 12.03 (1H, br s, NH), 8.81 (1H, d, J 7.8 Hz, H-3), 8.15 (1H, br s, NH), 7.60 (1H, t, J 8.0 Hz, H-4), 7.32 (1H, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH2), 1.35 (3H, t, J 7.1 Hz, CH3).