Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9](I)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-:25].[Na+].[Na+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:3]([O:25][CH:20]([CH3:19])[CH3:15])([CH3:4])[CH3:8].[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:18]2[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)OC(C)C
Product: COC(=O)c1cc(-c2ccc(Br)cc2)c(Cl)cc1N
Temperature: 80 °C
Reaction time: 72 h
Yield: 55.8 %

Procedure:
A suspension of methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (8.2 g, 26.3 mmol), (4-bromophenyl)boronic acid (5.29 g, 26.3 mmol), tetrakis(triphenylphosphine) palladium (0.304 g, 0.263 mmol) and sodium carbonate (79 mL, 1M in water, 79 mmol) in 1,4-dioxane (300 mL) was stirred 3 days at 80° C. After cooling, the mixture was filtered through celite, the filtrate was then diluted with water and extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in diisopropylether, filtered and washed with acetonitrile then diisopropylether to give the title compound methyl 4-amino-4′-bromo-6-chloro-3-biphenylcarboxylate (2.5 g, 7.34 mmol, 27.9% yield) as an off-white powder. LCMS: (M+H)+=340-342; Rt=4.09 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].[C:14]1([CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:21](=[O:22])[CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:24][CH3:25])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2nc(N)sc2c1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc2nc(NC(=O)C(CC)c3ccccc3)sc2c1
Reaction time: 16 h

Procedure:
6-Ethoxy-benzothiazol-2-ylamine (39 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (17 mg, 0.050 mmol, 25%). ESI-MS m/z calc. 340.1, found 340.9 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: [CH2:1]([C:4]1([CH2:8][OH:9])[CH2:7][O:6][CH2:5]1)[CH2:2][CH3:3].[Br:10][CH:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)[CH2:12][Br:13].B(F)(F)F.CCOCC>>[CH2:1]([C:4]12[CH2:8][O:9][C:18]([C:17]3[CH:21]=[CH:22][C:14]([C:11]#[CH:12])=[CH:15][CH:16]=3)([O:6][CH2:5]1)[O:19][CH2:7]2)[CH2:2][CH3:3].[CH2:1]([C:4]12[CH2:8][O:9][C:18]([C:17]3[CH:21]=[CH:22][C:14]([CH:11]([Br:10])[CH2:12][Br:13])=[CH:15][CH:16]=3)([O:6][CH2:5]1)[O:19][CH2:7]2)[CH2:2][CH3:3]
Reactant: O=C(Cl)c1ccc(C(Br)CBr)cc1
Reactant: CCCC1(CO)COC1
Agent: FB(F)F
Solvent: CCOCC
Product: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Product: CCCC12COC(c3ccc(C(Br)CBr)cc3)(OC1)OC2

Procedure:
The compound 4-n-propyl-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2.2.2]octane was synthesized utilizing the method set forth in Procedure 2. Reaction of the 3-n-propyl-3-hydroxymethyloxetane with 4-(1,2-dibromoethyl)benzoyl chloride led to the production of the corresponding oxetane ester which was characterized by NMR (300 MHz, CDCl3): δ 0.95 (3H, t, CH3), 1.35 (2H, m, CH3CH2), 1.75 (2H, m, CH3CH2CH2), 3.95-4.1 (2H, m, CH2Br), 4.45 (2H, s, CH2O), 4.5-4.6 (4H, d of d, CH2OCH2), 5.1 (1H, d of d, ArCHBr), 7.5 (2H, d, aromatic), 8.05 (2H, d, aromatic). The oxetane ester was reacted with boron trifluoride etherate as described in Procedure 2 to provide 4-n-propyl-1-(4-(1,2-dibromoethyl)phenyl)-2,6,7-trioxabicyclo[2.2.2]octane. This compound was characterized by NMR (300 MHz, CDCl3): δ 0.9 (3H, t, CH3), 1.15-1.35 (4H, m, CH2CH2), 3.9-4.1 (2H, m, CH2Br), 4.1 (6H, s, (CH2O)3), 5.1 (1H, d of d, ArCHBr), 7.35 (2H, d, aromatic), 7.6 (2H, d, aromatic).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]([OH:27])(=O)[CH2:15][CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>C(C(C)=O)C(C)C>[C:23]([O:25][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])(=[O:24])[CH2:22][CH2:21][CH2:20][S:19][S:18][CH2:17][CH2:16][CH2:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[O:27]
Reactant: NCCCCCCO
Reactant: O=C(O)CCCSSCCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: NCCCCCCOC(=O)CCCSSCCCC(=O)OCCCCCCN
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
5.1 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 5.9 g of 6-amino-1-hexanol. After stirring for 10 minutes, 6.0 g of 4,4′-dithiodibutyric acid (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the resulting mixture was heated to 120° C. and then stirred at 110° C. for 4 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 50 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stirring for 2 hours, the precipitated crystals were collected by filtration and washed with acetone, yielding the methanesulfonate salt of di(6-aminohexyl) 4,4′-dithiodibutyrate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[NH2:23])[C:16]=3[N:17]=2)=[CH:9][CH:8]=1)(=O)=O.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O>[C:7]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:16](=[C:18]([C:22]([NH2:23])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1
Reactant: NC(=O)c1cccc2sc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3)nc12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc2sc(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: 0 °C

Procedure:
A mixture of EXAMPLE 1G (25 mg), dichlorobis(triphenylphosphine) palladium(II) (4.36 mg), phenylboronic acid (8.33 mg), 1M sodium carbonate (0.087 mL) and 7:2:3 dimethoxyethane/ethanol/water (1 mL) was heated in a microwave at 160° C. for 10 minutes. The mixture was concentrated and diluted with 1:1 dimethylsulfoxide/methanol. The solid was filtered, dissolved in N,N-dimethylformamide, cooled at 0° C. for 18 hours and filtered to afford the title compound. 1H NMR (DMSO-d6) δ 9.24 (d, J=2.1 Hz, 1H), 8.40 (dd, J=7.9, 1.2 Hz, 1H), 8.27 (d, J=8.2 Hz, 2H), 8.23 (dd, J=7.6, 1.2 Hz, 1H), 8.00 (s, 1H), 7.94 (d, J=8.2 Hz, 2H), 7.79 (d, J=7.0 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.46 (t, J=7.3 Hz, 1H).
Reaction SMILES: [I:1]C1C=CC2C3(C)CCN(C(OC(C)(C)C)=O)CC3OC=2C=1.O[C:24]1[CH:25]=[CH:26][C:27]2[O:43][CH:31]3[CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35][C:30]3([CH3:44])[C:28]=2[CH:29]=1>>[I:1][C:24]1[CH:25]=[CH:26][C:27]2[O:43][CH:31]3[CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35][C:30]3([CH3:44])[C:28]=2[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(I)cc3OC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3cc(O)ccc3OC2C1
Product: CC(C)(C)OC(=O)N1CCC2(C)c3cc(I)ccc3OC2C1

Procedure:
Synthesized as described for tert-butyl 7-iodo-4a-methyl-3,4,4a,9a tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from tert-butyl 6-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate. MS m/z 360 [M-tBu+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>CS(C)=O.O>[Br:8][C:4]1[N:3]=[C:2]([NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)N
Reactant: Brc1cccc(Br)n1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Nc1cccc(Br)n1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
A stirred solution of 2,6-dibromopyridine (4.0 g, 16.5 mmol) and tert-butylamine (1.8 ml, 17.2 mmol) in dimethylsulfoxide (10 ml) was heated at 100° C. in a sealed tube for 20 h. After cooling to ambient temperature the reaction was diluted with water and extracted into dichloromethane. Combined organic extracts were washed with water and saturated brine then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with 20% diethyl ether in isohexane gave 6-bromo-N-(tert-butyl)pyridin-2-ylamine (0.4 g) as a solid: δH (360 MHz, CDCl3) 1.40 (9H, s), 6.34 (1H, d, J 8), 6.66 (1H, d, J 8), 7.18 (1H, dd, J 8 and 8); m/z (ES+) 229/231 (M++H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12](O)=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([Cl:22])=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1
Reactant: CCCCCC(CC(=O)O)c1cccc2c1OCO2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCC(CC(=O)Cl)c1cccc2c1OCO2

Procedure:
To a solution of 2.64 g (10 mmol) of 3-(2, 3-methylenedioxyphenyl)octanoic acid in 25 ml of methylene chloride were added 1.46 ml (20 mmol) of thionyl chloride and 0.1 ml of N, N-dimethylformamide, and the resultant mixture was stirred at room temperature for 4 hours and concentrated in vacuo to give 3-(2, 3-methylenedioxyphenyl)octanoic acid chloride as a crude oil. A solution of this acid chloride in 15 ml of methylene chloride was dropwise added to a solution of 1.95 g (11 mmol) of 2, 6-diisopropylaniline and 1.67 ml (12 mmol) of triethylamine in 40 ml of methylene chloride chilled with water under stirring. Stirring was continued for 2 hours, and the reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/6) and crystallized from hexane to give 3.60 g (Yield, 85%) of N-(2, 6-diisopropylphenyl)-3-(2, 3-methylenedioxyphenyl)octanamide as white crystals,
Reaction SMILES: [CH:1](F)(F)F.[CH2:5]([O:7][C:8](=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([O:17][C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[CH:19]=2)[C:11]=1[F:27])[CH3:6].C([Zn]CC)C>>[CH2:5]([O:7][C:8](=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:1])=[C:12]([O:17][C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[CH:19]=2)[C:11]=1[F:27])[CH3:6]
Reactant: CCOC(=O)Cc1ccc(C)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: FC(F)F
Agent: CC[Zn]CC
Product: CCOC(=O)Cc1ccc(CC)c(Oc2cc(Cl)cc(C#N)c2)c1F

Procedure:
[3-(3-Chloro-5-cyano-phenoxy)-4-ethyl-2-fluoro-phenyl]-acetic acid ethyl ester (R-32) was prepared from R-23 using the procedure described for R-31 except diethylzinc was used in place of dimethylzinc.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:11][C:12]#[CH:13])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[BrH:14].C(OCC)(=O)C>C(OCCC)(=O)C>[Br:14][CH2:13][C:12]1[C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[S:9][CH:11]=1
Reactant: Br
Reactant: C#CCS(=O)c1cc(C)cc(C)c1
Solvent: CCCOC(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2c(CBr)csc2c1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In 40 mL of propyl acetate, was dissolved 2.26 g (11.7 mmol) of the compound obtained in Example 13. The refluxing was carried out for 30 minutes. The solution was then cooled, and 1.59 mL (14 mmol) of a 48% hydrobromic acid was added. The resulting mixture was allowed to stand at room temperature for 30 minutes. Ethyl acetate was subsequently added, and the obtained mixture was washed with water, dried with magnesium sulfate and vacuum concentrated to obtain 2.49 g of 3-(bromomethyl)-4,6-dimethylbenzo[b]thiophene. The yield was 84%.
Reaction SMILES: I[C:2]1[N:3]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=[C:5]([C:7]([NH:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:8])[N:6]=1.[C:40]([NH:46][C:47]1[N:48]=[C:49]([OH:59])[C:50]2[CH:56]=[C:55]([C:57]#[CH:58])[CH:54]=[N:53][C:51]=2[N:52]=1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].C(N(CC)CC)C>C(#N)C>[C:40]([NH:46][C:47]1[N:48]=[C:49]([OH:59])[C:50]2[CH:56]=[C:55]([C:57]#[C:58][C:2]3[N:3]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:4]=[C:5]([C:7]([NH:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:8])[N:6]=3)[CH:54]=[N:53][C:51]=2[N:52]=1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1)C(=O)OC
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)n1)C(=O)OC
Yield: 66 %

Procedure:
Following the procedure of Example 1, dimethyl N-(2-iodo-1-triphenylmethylimidazol-4-ylcarbonyl)-L-glutamate (638 mg, 1.0 mmol), 2-pivaloylamino4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine (541 mg, 2.0 mmol), Pd(PPh)2Cl2 (35 mg, 0.05 mmol), cuprous iodide (19 mg, 0.1 mmol), triethylamine (0.7 mL), and acetonitrile (50 mL) yield dimethyl N-(2-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethynyl]-1-triphenylmethylimidazol-4-ylcarbonyl}-L-glutamate [515 mg, 66% after flash column chromatography (ethyl acetate:hexanes, 2:1), mp 93-95° C]: 1H NMR (CDCl3) δ 12.05 (br s, 1H), 8.43 (br s, 1H), 8.26 (s, 1H), 7.93 (d, 1H, J=2.2 Hz), 7.61 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.33-7.28 (m, 9H), 7.18-7.12 (m, 6H), 4.77 (m, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 2.45 (m, 2H), 2.32 (m, 1H), 2.05 (m, 1H), 1.30 (s, 9H). HRMS calcd for C44H41N7O7 779.3067, found 779.3088.
Reaction SMILES: [C:1]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([OH:33])[CH2:28][CH2:29][CH2:30][C:31]#[CH:32].N1CCCCC1>C1COCC1.CCOCC.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.[Cu]I>[Si:5]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:32]#[C:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:33])[CH:11]=[CH:12][CH:13]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#CCCCCO
Reactant: CC(C)(C)[Si](OCc1cccc(I)c1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](OCc1cccc(C#CCCCCO)c1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a solution of t-Butyl-diphenyl(3-iodo-benzyloxy)silane (8.49 g, 18 mmol) in THF (70 mL) is added hex-5-ynol (2.5 mL, 22 mmol) and (Ph3P)4Pd (990 mg, 0.85 mmol) and CuI (171 mg, 0.9 mmol). This solution is degassed and placed under an argon atmosphere. To this solution is added piperidine (5.4 mL, 54 mmol) and stirring continued for 4 h. The reaction mixture is diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound as an oil (6.84 g). 1H NMR (300 MHz, CDCl3): δ 7.70 (m, 4H), 7.40 (m, 6H), 7.27 (m, 4H), 4.71 (s, 2H), 3.71 (t, 2H), 2.47 (t, 2H), 1.74 (m, 4H), 1.10 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Li+].[CH3:10][CH:11]([N-]C(C)C)[CH3:12].C(Br)C=C.[NH4+].[Cl-]>C1COCC1>[CH2:12]([C:7]1[C:6]([Br:8])=[CH:5][N:4]=[CH:3][C:2]=1[Br:1])[CH:11]=[CH2:10]
Reactant: CC(C)[N-]C(C)C
Reactant: Brc1cncc(Br)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1c(Br)cncc1Br
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A THF (100 mL) solution of 3,5-dibromopyridine (5 g, 21.1 mmol) at −78° C. was added via cannula to a solution of LDA (22.2 mmol) in THF (700 mL) at −78° C. keeping the temperature <60° C. After stirring for 10 min. at −78° C., allyl bromide (2.56 mL, 29.5 mmol) was added via syringe and the reaction mixture was stirred for 2 hr at −78° C. Saturated NH4Cl (100 mL) was added slowly to quench the reaction. The organic layer was separated, washed with brine and dried (MgSO4). Filtration and concentration in vacuo gave the title compound as an oil which was purified by chromatography on silica gel with hexane:ethyl acetate 9:1.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[C:8]([C:12]([NH2:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[C:8]([C:12]([NH2:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1[nH]c2cc(O)ccc2c1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 5 (134 mg, 0.395 mmol) in 5 mL of dichloromethane at −78° C. was added boron tribromide solution (1 M in dichloromethane, 1.97 mmol). After 10 minutes the mixture was allowed to warm to room temperature, and stir for an additional 4 hours. The reaction was poured into a mixture of EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water and brine, dried with Na2SO4, filtered, and concentrated in vacuo. Trituration with chloroform gave the titled compound as a brown powder. HRMS (ES) exact mass calculated for C13H16N3O5S (M+H+): 326.0805. Found 326.0794.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6]I.[Cl:8][C:9]1[C:22]2[S:21][C:20]3C(=[CH:16][CH:17]=[CH:18][CH:19]=3)NC=2[CH:12]=[CH:11][C:10]=1[OH:23].[H-].[Na+]>CO>[Cl:8][C:9]1[C:22]2[S:21][C:20]3[C:3](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:2]([CH3:1])[C:4]=2[CH:12]=[CH:11][C:10]=1[O:23][CH3:6]
Reactant: CN(C)C=O
Reactant: CI
Reactant: Oc1ccc2c(c1Cl)Sc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1Cl)Sc1ccccc1N2C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 25 ml of DMF was added methyl iodide (2.9 ml), 4-chloro-3-hydroxy-10H-phenothiazine (see Example 3) (2.3 g) and sodium hydride (0.672 g). The resulting reaction mixture was stirred at ambient temperature for 12 hours. At 0° C., MeOH was added to destroy the remaining hydride, then H2O. The resulting solution was extracted with ethyl acetate and the organic phase, dried and evaporated. The resulting residue was then purified by chromatography on silica gel to give 1.5 g of 4-chloro-3-methoxy-10-methyl-10H-phenothiazine (m.p.: 136° C.).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][S:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1.O>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:17][N:18]([CH2:33][CH2:34][S:35][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[CH2:19][CH2:20]1
Reactant: BrCCSc1cccs1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCN(CCSc2cccs2)CC1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 0.46 g of ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylate in 10 mL of N,N-dimethylformamide, 0.37 g of potassium carbonate and 0.31 g of 2-((2-bromoethyl)thio)thiophene were added, and the mixture was stirred at 50 to 70° C. for 2 hours 10 minutes. The reaction mixture was cooled to room temperature, then, water and ethyl acetate were added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=50:1 to obtain 0.39 g of ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:28]([N:33]=[C:34]=[S:35])(=[O:32])[O:29][CH2:30][CH3:31].O>CS(C)=O>[F:25][C:23]([F:26])([F:24])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:28](=[O:32])[O:29][CH2:30][CH3:31])=[S:35])=[N:7][CH:6]=1)=[O:27]
Reactant: Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (600 mg, 1.61 mmol) in DMSO (30 mL) was added ethyl isothiocyanatocarbonate (230 μL, 1.95 mmol), and the mixture was stirred at room temperature for 12 hr. Water (150 mL) was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl ({[5-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (485 mg, 59%) as a brown oil.