Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([CH2:19][CH2:20][C:21]3[O:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:32]N1C(=O)CCC1=O>C1COCC1>[Br:32][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([CH2:19][CH2:20][C:21]4[O:22][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[N:24][N:25]=4)=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCc3nnc(-c4ccccc4)o3)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCc3nnc(-c4ccccc4)o3)nnc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The mixture of 9-pentyl-3-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (53 mg, 0.13 mmol) and N-bromosuccinimide (34 mg, 0.19 mmol) in THF (20 mL) was stirred at 70° C. for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative LCMS to give the desired product. LCMS calculated for C21H22BrN8O2 (M+H): 497.1. found: 497.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29](Cl)=[O:30]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:29]([C:28]4[C:32]([Cl:37])=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=4[Cl:26])=[O:30])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(Cl)cc(Cl)cc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,4,6-trichlorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [OH-].[Li+].[CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)([CH3:5])[CH3:4]>>[CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(Nc2nc3ccccc3n2C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)n1c(Nc2ccc(C(=O)O)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
1 N lithium hydroxide solution (1.2 mL, 1.2 mmol) is added to a solution of methyl 4-(1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzoate (122 mg, 0.395 mmol). The reaction may be stirred at room temperature overnight and concentrated. 1 N hydrochloride solution may be added to the residue and a white precipitate collected by filtration to give 4-(1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzoic acid (66 mg)
Reaction SMILES: [CH3:1][S:2]([CH:4]([C:17]1[CH:21]=[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])[O:19][CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:3].S([O-])(O[O-])(=O)=[O:27].[K+].[K+]>>[CH3:1][S:2]([CH:4]([C:17]1[CH:21]=[C:20]([Si:22]([CH3:23])([CH3:24])[CH3:25])[O:19][CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:27])=[O:3]
Reactant: CCCCCCCCCCCCC(c1coc([Si](C)(C)C)c1)S(C)=O
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Product: CCCCCCCCCCCCC(c1coc([Si](C)(C)C)c1)S(C)(=O)=O

Procedure:
3-(1-methylsulfinyltridecyl)-5-trimethylsilylfuran is oxidized using potassium peroxymonosulfate to give 3-(1-methylsulfonyltridecyl)-5-trimethylsilylfuran. Oxidizing with singlet oxygen by the procedure of Example 1 gives 4-(1-methylsulfonyltridecyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([CH2:31][NH2:32])[OH:30].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[OH:30][CH2:29][CH2:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCO
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCO)ccc21
Yield: 24.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (27 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), ethanolamine (15 mg), DPPA (53 uL), and DIEA (43 uL). LC/MS: m/z 452.9. 1H NMR (DMSO-d6, 400 MHz): δ 8.37 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.81-7.56 (m, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 4.72 (s, 1H), 3.64 (s, 3H), 3.58-3.48 (m, 2H), 3.40-3.32 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:22])([CH3:21])[CH:10]([O:17]C(=O)C)[C:11](=[O:16])[NH:12][CH:13]1[CH2:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:22])([CH3:21])[CH:10]([C:11](=[O:16])[NH:12][CH:13]1[CH2:15][CH2:14]1)[OH:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C(=O)NC1CC1)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C)(C)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of acetic acid 2-tert-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl ester in MeOH (10 mL) was added 10% NaOH (1.5 mL). The reaction mixture was stirred at room temperature for 3 h and then acidified with 1N Hydrochloric acid to pH 7. The reaction mixture was extracted with EtOAc. The organic layer was dried (Na2SO4) concentrated to yield (2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethylethyl)-carbamic acid tert-butyl ester which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:30][N:31](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.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>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH:24]=1
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(Cl)ccc2C(F)(F)F)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4cc(Cl)ccc4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 63 %

Procedure:
A mixture of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-chloro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (0.205 g, 0.42 mmol), zinc cyanide (0.099 g, 0.840 mmol), tetrakis(triphenylphosphine)palladium (0.048 g, 0.042 mmol), and DMF (4 mL) was heated under microwave irradiation at 130° C. for 30 min. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2×80 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes) to give 3-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (0.115 g, 63%): 1H NMR (300 MHz, CDCl3) δ 9.72 (s, 1H), 7.98 (dd, J=9.5, 1.1 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.51 (dd, J=9.5, 1.6 Hz, 1H), 7.41 (s, 1H), 7.31 (dd, J=8.5, 1.3 Hz, 1H), 5.77-5.72 (m, 1H), 5.02-4.96 (m, 1H), 3.40 (m, 2H), 3.04-2.94 (m, 1H), 2.06-1.80 (m, 4H); MS (ESI+) m/z 434 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[CH:10])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][N:16]=[N+:17]=[N-:18])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:19])[CH2:15][N:16]1[CH:10]=[C:9]([C:5]2[C:6]([CH3:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:18]=[N:17]1)[CH3:12]
Reactant: C#Cc1ccc(Cl)nc1C
Reactant: CCOC(=O)CN=[N+]=[N-]
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)nc2C)nn1

Procedure:
The title compound was prepared as described in Example 413, Step 2 using 6-chloro-3-ethynyl-2-methylpyridine (250 mg, 1.65 mmol) and ethylazidoacetate (0.93 ml, 1.65 mmol) as starting materials
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1>FC(F)(F)CO>[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Reactant: CN1CCNCC1
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
1-Methylpiperazine (0.50 mL, 4.51 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 87, 750 mg, 1.75 mmol) in 2,2,2-trifluoroethanol (15 mL) and the mixture was heated in a microwave at 120° C. for 1 h and then 140° C. for 0.5 h. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). This organic solution was washed with sat. NaHCO3 (100 mL), water (2×100 mL) and then brine (100 mL). The solution was then dried (MgSO4) and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% CH3OH in CH2Cl2 gave the title compound (772 mg, 87%) as a orange solid; 1H NMR: (CDCl3) 2.37 (3H, s), 2.59-2.65 (4H, m), 3.07-3.14 (4H, m), 3.90 (3H, s), 3.99 (3H, s), 6.63 (1H, s), 7.25-7.3 (1H, m) partially obscured by chloroform peak, 7.31-7.36 (1H, m), 7.39 (1H, d), 7.56 (1H, s), 8.22 (1H, s), 8.39 (1H, s), 8.47 (1H, d), 9.18 (1H, s); m/z: ES+ MH+ 508.19.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][CH:15]1[CH2:20][O:19][CH2:18][CH:17]([CH3:21])[NH:16]1.O>C(#N)C>[CH3:14][CH:15]1[N:16]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:17]([CH3:21])[CH2:18][O:19][CH2:20]1
Reactant: CC1COCC(C)N1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN1C(C)COCC1C
Temperature: 60 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (0.311 g, 2.25 mmol) and ethyl bromoacetate (0.319 g, 1.91 mmol) was added to the solution of 3,5-dimethylmorpholine (0.2 g, 1.73 mmol) in acetonitrile (4 mL) at room temperature. The reaction mixture was stirred at 60° C. for 12 h. The reaction mixture was transferred into iced-water and extracted with ethyl acetate (20 mL×3). The combined organic layers was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification (Crude Yield: 54%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[NH2:15][C:11]1[CH:10]=[C:9]([C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cccc(C(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.1 %

Procedure:
To a solution of morpholino(3-nitrophenyl)methanone (2 g, 8.47 mmol) in Ethyl acetate (40 ml) was added tin(II) chloride dehydrate (7.64 g, 33.9 mmol). Resulting reaction mixture was stirred at RT for 17 h. The reaction mixture was neutralized with NaOH (2N), the mixture was filtered and the filtrate was extracted with Ethyl acetate (250 ml×2). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum to give the title product (1.4 g).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:20])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>N1C=CC=CC=1>[C:1]([NH:5][CH2:6][CH:7]([O:20][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1)[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1cccc2c1CC(=O)N2
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NCC(COc1cccc2c1CC(=O)N2)OC(=O)c1cccnc1
Reaction time: 96 h

Procedure:
1 g of 4-(3-tert-butylamino-2-hydroxypropoxy)oxindole, 20 cc of chloroform, 10 cc of pyridine and 0.713 g of nicotinoyl chloride are allowed to stand at room temperature for 4 days, the mixture is then concentrated by evaporation as carefully as possible at reduced pressure and the residue is taken up in water. The reaction mixture is rendered alkaline with a 10% ammonia solution, is extracted with methylene chloride, and subsequently an excess of 2 N hydrochloric acid in ethanol is added. The solvent and excess hydrochloric acid are carefully removed by evaporation at reduced pressure and the dihydrochloride of the title compound is crystallized from ethanol, needle druses. M.P. 215°-218° .
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30](Cl)=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[Br:40]C1C=CC([C@@H](O)C(F)(F)F)=C(C2C=CC=CC=2)C=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Br:40])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: O[C@H](c1ccc(Br)cc1-c1ccccc1)C(F)(F)F
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol (Intermediate 38).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH2:12][C:13]1=[O:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Product: CC(=O)N1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21

Procedure:
Prepared from 5-benzoyl-2-indolinone and acetic anhydride
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)C>[N:12]1([C:6]2[CH:11]=[CH:10][C:9]([S:2]([OH:5])(=[O:3])=[O:1])=[CH:8][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: c1ccc(N2CCCC2)cc1
Reactant: O=S(=O)(O)O
Solvent: CCOCC
Product: O=S(=O)(O)c1ccc(N2CCCC2)cc1
Temperature: 170 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
A solution of H2SO4 (6.8 g, 68.00 mmol) in diethylether (80 mL) was added to 1-phenylpyrrolidine (10 g, 68.03 mmol) in diethylether (20 mL) at 0° C. The diethylether was decanted, and the resulting solution was stirred for 3 hours at 170° C., then concentrated in vacuo to afford 7.3 g (43%) of 4-(pyrrolidin-1-yl)benzenesulfonic acid as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]=[CH2:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: CCO
Product: CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g), bis(tricyclohexylphosphine)palladium(II)dichloride (332 mg), tripotassium phosphate (11 g) and vinylboronic acid pinacol ester (3 g) were added toluene (27 mL) and water (1.4 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g). The obtained 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g) was dissolved in ethanol (20 mL), 5% palladium carbon-ethylenediamine complex (600 mg) was added, and the mixture was stirred at room temperature for 8 hr under hydrogen atmosphere. The mixture was filtered through celite, and the solvent was evaporated from the filtrate to give 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg). The obtained 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg) was dissolved in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1.5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (7 ml), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (441 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:33])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=2.C(OCC)(=O)C.[CH3:40][N:41](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:33])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:17]=[C:16]([C:40]#[N:41])[CH:15]=2
Reactant: CN(C)C=O
Reactant: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(C#N)ccc12
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
Trifluoro-methanesulfonic acid 3-(2,4-dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromen-7-yl ester (862 mg, 1.766 mol), Zn (CN)2 (310 mg) and Pd(PPh3)4 (204 mg) were dissolved in DMF (12 mL) at room temperature in a sealed tube. After 10 min, the reaction mixture was heated to 150° C. for 4 h. The reaction mixture was cooled to room temperature and ethyl acetate (200 mL) was added. The reaction mixture was then poured into a separation funnel, washed with water (2×100 ml) and brine (2×100 ml). The organic layer was dried over sodium sulfate and concentrated. The product was purified on silica gel eluted with 30-50% ethyl acetate in hexanes to yield 3-(2,4-Dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromene-7-carbonitrile as a slightly yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1)[CH3:2].F[B-](F)(F)F.[CH2:32]([O+](CC)CC)[CH3:33]>O1CCOCC1>[CH2:32]([O:10][C:8]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:6]2[S:26][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[N:9]=1)[CH3:33]
Reactant: CCc1cc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCOc1nc2cc(CC)sc2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a mixture of 4′-[(5-ethyl-2-oxo-1,2-dihydro-3H-thieno[2,3-d]imidazol-3-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and 1,4-dioxane was added triethyloxonium tetrafluoroborate (1M methylene chloride solution, 4.2 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was extracted with chloroform and water. The obtained chloroform layer was successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.48 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[O:12])=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)(=[O:36])=[O:12])=[CH:9][CH:10]=1
Reactant: COC(=O)C(=O)c1ccc(S(=O)CCOc2ccc3ccccc3c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(S(=O)(=O)CCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of rac.-4-[[2-(2-naphthalenyloxy)ethyl]sulfinyl]-alpha-oxobenzeneacetic acid methyl ester (1 g) in dichloromethane (50 mL) was treated with 85% metachloroperbenzoic acid (0.81 g) and stirred at room temperature for one hour. The mixture was washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered, passed through silica gel (5 g) and the product eluted with dichloromethane. Crysallization from dichloromethane-hexane gave 0.61 g of 4-[[2-(2-naphthalenyloxy)ethyl]sulfonyl]-alpha-oxobenzeneacetic acid methyl ester, mp 110°-111° C.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=[N:7][CH:8]=[CH:9][CH:10]=1>C(O)=O.O>[O:17]=[C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:6]1[C:5]([CH2:4][CH:3]=[O:2])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COC=Cc1cccnc1N1CCCCC1=O
Solvent: O=CO
Solvent: O
Product: O=CCc1cccnc1N1CCCCC1=O
Temperature: 50 °C

Procedure:
1-[3-(2-Methoxyethenyl)pyridin-2-yl]piperidin-2-one a4-2 (0.340 g, 1.464 mmol, 1 eq) is dissolved in a mixture of formic acid and water (10 ml/0.5 ml). The reaction mixture is heated at 50° C. overnight. The solvent is removed under reduced pressure to afford crude [2-(2-oxopiperidin-1-yl)pyridin-3-yl]acetaldehyde a4-3 which is used in the next step without any further purification.