Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([SH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:16]=1[C:17]#[N:18]>CN(C)C(=O)C.CCOCC>[Br:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([S:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cccc1Br
Reactant: SC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: N#Cc1c(Br)cccc1SC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of adamantanethiol (1.01 g) in N,N-dimethylacetamide (20 mL) at room temperature was added NaH (0.24 g, 60% in mineral oil) and the reaction was stirred for 10 minutes. 2-Fluoro-6-bromobenzonitrile (1 g) was added and the mixture was heated to 80° C. for 1 hour. The reaction mixture was cooled and diluted with ether (400 mL), and the mixture was washed three times with 1M NaOH solution and once with brine, then dried over sodium sulfate, filtered and concentrated to yield the crude product which was taken on to the next step without purification.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na]>C(Cl)(Cl)Cl>[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([NH:12][S:9]([CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:11])=[O:35])[CH2:32][CH2:33]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NS(=O)(=O)C=Cc1ccccc1
Reactant: O=C(Cl)N1CCC(CCCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: O=C(NS(=O)(=O)C=Cc1ccccc1)N1CCC(CCCc2ccccc2)CC1
Reaction time: 1 h
Yield: 41 %

Procedure:
A stirred mixture of 1.83 g. (0.01 mole) of 2-phenylethenesulfonamide, 3.45 g. (0.025 mole) of potassium carbonate and 4.0 g. (0.015 mole) of 4-(3-phenylpropyl)piperidinocarbonyl chloride, in 75 ml. of chloroform is heated under reflux for 22 hours. The solvent is then removed by evaporation in vacuo, and to the residue is added 75 ml. of 0.5N sodium hydroxide and 35 ml. of ether. The mixture is stirred for 1 hour, and then the solid which remains undissolved is removed by filtration. This affords 1.84 g. (ca. 41% yield) of the title compound as a mixture of its sodium and potassium salts.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[O:6][CH2:5][CH2:4][O:3]1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][C:2]1([CH2:7][CH2:8][C:9]([O:11][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])=[O:10])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(CCC(=O)O)OCCO1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC1(CCC(=O)ON2C(=O)CCC2=O)OCCO1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of 3-(2-methyl-1,3-dioxolan-2-yl)propanoic acid (8.95 g, 55.9 mmol) in dichloromethane (111 mL) was cooled to approximately 0° C. N-hydroxysuccinimide (7.10 g, 61.5 mmol), 4-methylmorpholine (6.22 g, 61.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.8 g, 61.5 mmol) were sequentially added with stirring. The reaction was then allowed to warm to room temperature, stirred for 17 hours, and partitioned between dichloromethane (150 mL) and water (50 mL). The organic layer was separated; sequentially washed with water (50 mL), saturated aqueous sodium bicarbonate (2×50 μL), and brine (50 mL); dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide 13 g of 1-{[3-(2-methyl-1,3-dioxolan-2-yl)propanoyl]oxy}pyrrolidine-2,5-dione as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O)C.[H][H]>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1N1CCOCC1
Yield: 87.7 %

Procedure:
4-(2-Methoxy-5-nitro-phenyl)-morpholine (0.600 g, 2.52 mmol) was dissolved in Ethanol (35.0 mL, 599 mmol) and the solution was carefully poured over 10% Palladium on Carbon (0.300 g, 22.5 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 460 mg of 4-Methoxy-3-morpholin-4-yl-phenylamine without further purification. (M+H)=209.2. 1H NMR (400 MHz, DMSO, d6) δ 6.62 (d, 1H, J=8.36 Hz), 6.15 (m, 1H), 6.13 (m, 1H), 4.56 (s, 2H), 3.69 (m, 4H), 3.65 (s, 3H), 2.89 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C=O)C>[Cl:24][CH2:23][CH2:22][CH2:21][N:3]1[C:2]([CH3:13])([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4]1(=[O:12])=[O:11]
Reactant: ClCCCBr
Reactant: CC1(C)NS(=O)(=O)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2S(=O)(=O)N1CCCCl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.9 g (3 mmol) of 3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide in 150 ml of DMF at room temperature was, after addition of 3.7 g (3.3 mmol) of potassium t-butoxide, heated under nitrogen to 80° C. Then 14.2 g (9 mmol) of 1-bromo-3-chloropropane were rapidly added and the mixture was stirred at 100° C. for 30 min. Pouring into ice-water was followed by extraction with ether, and the organic phases were washed with water, dried with sodium sulfate and then evaporated so that the product resulted as crystals which could be filtered off with suction. 6.7 g (82%) of substance were obtained. Melting point 107° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:16]=[C:15]([F:17])[C:14]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:19])=[C:13]([F:31])[CH:12]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[CH:12]=[C:13]([F:31])[C:14]=1[C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:19]
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1cncnc1
Product: O=C(c1c(F)cc(-c2cncnc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure WW starting from 5-pyrimidine boronic acid and (4-bromo-2,6-difluoro-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone to give 8 mg (8%). MS (ES+) 373 m/z
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[C:16]([O:22][CH3:23])=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:3]=1.[B-](F)(F)(F)[CH:25]=[CH2:26].[K+]>CC(O)C.C1COCC1>[CH3:23][O:22][C:16]1[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:25]=[CH2:26])=[N:3]2)=[CH:20][CH:19]=[C:18]([CH3:21])[N:17]=1
Reactant: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=Cc1nn(Cc2ccc(C)nc2OC)c2cccc([N+](=O)[O-])c12
Temperature: 90 °C
Yield: 52.7 %

Procedure:
A mixture of 3-iodo-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (982 mg, 2.31 mmol) in 10 mL of 4:1 IPA/THF was degassed for 20 minutes with an argon balloon, to which TEA (968 μL, 6.94 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (189 mg, 0.231 mmol) and potassium trifluoro(vinyl)borate (659 mg, 6.94 mmol) were added. The reaction mixture was heated at 90° C. for 3 hours. The mixture was filtered through Celite, and the filter pad was rinsed with ethyl acetate. The filtrate was washed with water and brine 3 times. The organic phase was concentrated to a residue under vacuum. The residue was purified by silica gel chromatography eluting with 15-20% EtOAc/hexanes to give the product (395 mg).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][C@H:34]1[C:64]1[CH:69]=[C:68](CO)[CH:67]=[CH:66][C:65]=1[CH3:72])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[O:35][C@H:34]1[C:64]1[CH:69]=[C:68]([CH2:1][Br:5])[CH:67]=[CH:66][C:65]=1[CH3:72])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(CO)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CBr)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Carbon tetrabromide (0.62 g) and triphenylphosphine (0.49 g) were added to a solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[5-(hydroxymethyl)-2-methylphenyl]-D-glucitol (1.0 g) in methylene chloride (10 ml) at room temperature and the mixture was stirred for one hour. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[5-(bromomethyl)-2-methylphenyl]-D-glucitol (0.8 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([CH2:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.CC(O)=O>CCO.[Pd]>[F:20][C:17]([F:18])([F:19])[CH:15]([CH3:16])[CH2:14][C:11]1([OH:21])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C=C(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(CC1(O)CCNCC1)C(F)(F)F
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl-4-hydroxy-4-(2-(trifluoromethyl)allyl)piperidine-1-carboxylate (100 mg, 0.32 mmol) in EtOH (5 mL) was added 10% Pd/C (20 mg) and a drop of AcOH. The mixture was stirred at 40° C. for 16 hrs under H2 atmosphere. The reaction mixture was filtered through a celite pad; the filtrate was concentrated to get the title compound which was used directly for the next step without purification. LC-MS: m/z 212.2 (M+H)+
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9](C(Cl)(Cl)Cl)[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[N:6]=1.O.Cl>CO>[NH2:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[N:6]=1
Reactant: C[O-]
Reactant: Nc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(N)nc(C(F)(F)F)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1.8 g of a 30% by weight solution of sodium methanolate in methanol (corresponding to 0.01 mol of sodium methanolate) were added at 22° C. to a solution of 28.8 g (0.1 mol) of 2-amino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine in 100 ml of methanol. The pale yellow solution was then refluxed for 30 minutes. The progress of the reaction was followed by thin-layer chromatography on silica gel (mobile phase: diethyl ether/hexane 1:1). After the reaction was complete, 20 ml of water were added, followed by 2 normal hydrochloric acid until the pH was 6-7. After this most of the methanol was removed at 40° C. under reduced pressure, adding 150 ml of water a little at a time so that the product did not agglomerate. To complete precipitation of the product, the resulting mixture was then stirred at 5° C. for 1 hour, after which the product was separated off, washed with a little water and dried at 40° C. under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:25][CH2:26][CH:27]([NH2:29])[CH3:28]>>[OH:25][CH2:26][CH:27]([NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])[CH3:28]
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: CC(N)CO
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC(C)CO)n(C)n1
Yield: 42 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1-methylethylamine instead of 2-hydroxy-2-methylpropylamine, to the title compound (22 mg, 42%) which was obtained as a light yellow solid. MS: m/e=388.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=1.C1(C)C=CC=CC=1.CC(C)([O-])C.[K+]>O>[CH:16]1([C:14]2[N:13]([CH3:19])[C:12]3[CH:20]=[C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:27]5[N:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[S:25][CH:26]=5)=[CH:3][C:4]4=[O:21])[CH:9]=[CH:10][C:11]=3[N:15]=2)[CH2:18][CH2:17]1
Reactant: OCc1csc(C(F)(F)F)n1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)cc21
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a mixture of 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (2-(trifluoromethyl)thiazol-4-yl)methanol (80 mg) and toluene (5 ml) was added potassium tert-butoxide (98 mg) at 100° C., and the mixture was stirred at the same temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (29.0 mg) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9].[I:14][C:15]1[C:23]([I:24])=[C:22]([C:25]([O-:27])=[O:26])[C:21]([I:28])=[C:20]([I:29])[C:16]=1[C:17]([O-:19])=[O:18]>CN(C=O)C>[I:14][C:15]1[C:23]([I:24])=[C:22]([C:25]([O:27][CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9])=[O:26])[C:21]([I:28])=[C:20]([I:29])[C:16]=1[C:17]([O:19][CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9])=[O:18]
Reactant: O=C([O-])c1c(I)c(I)c(C(=O)[O-])c(I)c1I
Reactant: CCCCC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCC(C)OC(=O)c1c(I)c(I)c(C(=O)OC(C)CCCC)c(I)c1I
Temperature: 76 °C
Reaction time: 22 h
Yield: 31 %

Procedure:
Cesium carbonate (1.63 g, 5.0 mmol) and 2-bromohexane (2.0 ml, 16 mmol) were added to a flask containing a stirred mixture of 2,3,5,6-tetraiodoterephthalate acid (1.4 g, 2.0 mmol) and dry DMF (20 ml). The reaction flask was immersed in an oil bath which was warmed to 76° C. over a period of 0.5 hr. After stirring under an atmosphere of N2 for 22 hrs, the reaction was allowed to cool, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up into EtOAc (200 ml), washed with saturated aqueous sodium bicarbonate (2×50 ml), water (50 ml) and brine (50 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:19; Et2O:hexanes) provided bis (2-hexyl) 2,3,5,6-tetraiodoterephthalate (0.52 g, 44%) as a light yellow solid. Mp 114°-115° C.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[O:15][CH3:16].[CH2:17](N(C(C)C)C(C)C)C.C=O>ClCCl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH3:17])[CH2:13][CH2:14]2)=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: COc1cc(N2CCNCC2)ccc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: [Na]
Solvent: ClCCl
Product: COc1cc(N2CCN(C)CC2)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyhydroborate (25.9 mg) was added to 1-(4-bromo-3-methoxy-phenyl)piperazine (30 mg), N-ethyl-N-isopropyl-propan-2-amine (0.030 ml) and 37% aqueous formaldehyde (8.01 μl) dissolved in dichloromethane (1 ml). The resulting mixture was stirred at 25° C. for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (5 ml) and extracted with ethyl acetate (2×10 ml). The combined organic phases were dried over magnesium sulfate and concentrated to afford the crude 1-(4-bromo-3-methoxy-phenyl)-4-methyl-piperazine (25.00 mg). NMR Spectrum: (CDCl3) 2.38 (s, 3H), 2.60 (bs, 4H), 3.17-3.28 (m, 4H), 3.88 (s, 3H), 6.41 (dd, 1H), 6.47 (d, 1H), 7.36 (d, 1H); Mass spectrum: M+H+ 286
Reaction SMILES: C(Cl)Cl.[NH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1.[Br:16][CH2:17][C:18](Br)=[O:19].[Cl-].[NH4+]>C(N(CC)CC)C>[Br:16][CH2:17][C:18]([NH:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: NC1CCCOc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)NC1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a 5 ml methylene chloride solution of 150 mg of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine (Japanese Unexamined Patent Publication (Kokai) No. 4-178381) and 0.15 ml of triethylamine was added dropwise, under ice cooling, 0.08 ml of bromoacetyl bromide. This was then stirred at room temperature for 1 hour. To the reaction was added 5 ml of a saturated aqueous solution of ammonium chloride, then extraction was performed with methylene chloride. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=25:1) to obtain the above-referenced compound (8) in an amount of 165 mg (yield of 65%).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH3:22])[CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CI.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH3:22])[CH:9]=[CH:10][C:11]=2[N:13]([CH3:30])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-4-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (7.8 g), methyl iodide (1.7 ml), potassium carbonate (2.9 g) and N,N-dimethylformamide (14 ml) was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with diethyl ether-hexane to give the title compound (6.85 g, yield 85%) as colorless needle crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10]N)[CH:6]=[C:7]([Cl:9])[CH:8]=1.ClC1C=[C:20]2[C:16]([C:17](C)(C)CN2)=[CH:15]C=1>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]2[C:4]=1[C:16]([CH3:20])([CH3:17])[CH2:15][NH:10]2
Reactant: NNc1cc(Cl)cc(Cl)c1
Reactant: CC1(C)CNc2cc(Cl)ccc21
Agent: Cl
Product: CC1(C)CNc2cc(Cl)cc(Cl)c21

Procedure:
Prepared from 3,5-dichlorophenylhydrazine hydrochloride in an analogous manner to that described for 6-chloro-3,3-dimethyl-2,3-dihydro-1H-indole (Preparation 25). MS: [M+H]+=216.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford desired N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)benzamide (0.02 g, 20%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br[CH2:24][C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]>C(#N)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH2:24][C:25](=[O:26])[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:21])=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(CBr)c1cccnc1
Solvent: CC#N
Product: O=C(Cc1ccc(OCc2ccc3ccccc3n2)cc1)OCC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.6 %

Procedure:
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (2.0 g, 0.006 mol) in acetonitrile (200 mL) were added TEA (1.74 mL, 0.01 mol), and 2-bromo-1-(pyridin-3-yl)ethanone (3.42 g, 0.017 mol) under an inert atmosphere. The reaction mixture was then stirred at RT for 16 h, concentrated in vacuo and the residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2-oxo-2-(pyridin-3-yl)ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (1.5 g, 54%) as a solid.