Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.I[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: Ic1cnccn1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cnccn2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 86-1 (2.2 g, 10 mmol), 2-iodopyrazine 86-2 (2.06 g, 10 mmol), Pd(PPh3)4 (577 mg, 0.5 mmol), toluene (70 mL), ethanol (15 mL) and 2M Na2CO3 (15 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in dichloromethane (200 ml) and treated with 1M HCl aqueous solution (50 mL). The two layers were separated and the aqueous layer was treated with 10% NaOH aqueous solution to adjust the pH to around 13. The resulting suspension was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to give 5-(pyrazin-2-yl)pyridin-2-amine 86-3 as white solid. MS m/z 173.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.12(d, 1H, J=1.6 Hz), 8.73(m, 1H), 8.60(m, 1H), 8.46(d, 1H, J=2.8 Hz), 8.12(dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 6.55(d, 1H, J=8.8 Hz), 6.46(s, 2H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[N:8][C:9]=1[CH3:10].CC1C=CC(S(O[CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])(=O)=O)=CC=1.[Cl-].[NH4+]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:23][CH2:24][C:25]([CH3:27])([OH:28])[CH3:26])=[N:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Cc1nc(O)ccc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1nc(OCCC(C)(C)O)ccc1Br
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
To a suspension of sodium hydride (containing about 40% of a mineral oil, 0.38 g) in N,N-dimethylformamide (10 mL), 5-bromo-2-hydroxy-6-methylpyridine (1.00 g) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (1.51 g) were added under ice-cooling and the resultant reaction mixture was stirred at 60° C. for 2.5 hours. To the mixture, 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (0.50 g) was further added and the resultant reaction mixture was stirred at 60° C. for 1.5 hours. Sodium hydride (containing about 40% of a mineral oil, 40 mg) was further added. To the reaction mixture, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and then dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=50:50 to 33:67) to give the title compound (1.3 g) as a pale yellow oil.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[C:6](\[CH3:17])/[C:7]#[C:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)C.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[CH3:17]/[C:6](/[C:7]#[C:8][C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)=[CH:5]\[CH2:4][OH:3]
Reactant: CCOC(=O)/C=C(\C)C#Cc1cc(Cl)cc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C(C#Cc1cc(Cl)cc(Cl)c1)=C\CO

Procedure:
To a solution of (E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester (130 mg, 0.46 mmol) in THF (0.5 mL) was added dropwise diisobutylaluminium hydride (1.0 M solution in toluene, 2.1 mL, 2.1 mmol) at −20° C. The reaction mixture was stirred for 2 hours at −20° C., whereafter saturated ammonium chloride was added. The mixture was treated with ethyl acetate and decalite and filtered. The filtrate was evaporated to give crude (E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol in 113 mg yield.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][CH:33]=1>C1COCC1>[CH3:29][N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:31][C:32]4[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:36][CH:37]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCC(=O)O)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 15.3 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (45.2 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was redissolved into EtOAc. Hexanes were added to the EtOAc solution causing a precipitate to form. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 15.4% (0.021 g, 0.038 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:50][C:51]([NH2:53])=[O:52]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:20][CH2:21][N:22]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:23][CH2:24]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(CC(N)=O)CC1)C2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 20 mg, 0.033 mmol) and triethylamine (23 uL, 0.165 mmol) in DMF (1.5 mL), is added 2-bromo-acetamide (10 mg, 0.066 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction is filtered and the filtrate is purified by mass-trigger preparative RP LC-MS to afford the title compound 2-[4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidin-1-yl]-acetamide (136) as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, 1H), 8.27 (s, 1H), 8.21 (br, 1H), 7.93 (dd, 1H), 7.73 (m, 1H), 7.40 (dd, 1H), 7.30 (s, 1H), 4.52 (s, 2H), 4.45-4.37 (m, 1H), 4.19-4.15 (br, 2H), 3.87-3.78 (br, 2H), 2.37-2.19 (m, 2H), 2.20-2.15 (m, 1H), 1.40 (d, 6H), 1.25 (d, 6H); ESMS m/z 656.2 (M+H+).
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15])#[N:10]>C(N(CC)CC)C>[C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:7][C:2]1[C:1]([NH:8][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([C:9]#[N:10])[CH:12]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])#[N:10]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)c1

Procedure:
Using a procedure similar to Example 1D, except starting with 1,2-benzenediamine and 3-cyanobenzoyl chloride with triethylamine as base, the title compound was obtained as an off-white solid (18%); IR(KBr): 3362, 2238, 1656, 1552 cm1; NMR(300 MHz, DMSO-d6): 7.33 (m,2H); 7.64 (m, 2H); 7.73 (t, 2H, J=9.5 Hz); 8.05 (d, 2H, J=9.3 Hz); 8.24 (d, 2H, J=9.9 Hz); 8.35 (s, 2H); 10.18 (br s, 2H); MS(FD): 366.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]([N+]([O-])=O)=[CH:9][NH2:10].[CH3:14][S:15][CH:16](SC)[CH2:17][N+:18]([O-:20])=[O:19]>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:16]([S:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19]
Reactant: NC=C(SCc1ccco1)[N+](=O)[O-]
Reactant: CSC(C[N+](=O)[O-])SC
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccco1
Yield: 50.4 %

Procedure:
A solution of 2-[(2-furanylmethyl)thio]-2-nitroethenamine (3.14 g.) and 1,1-bis-(methylthio)-2-nitroethane (13.2 g.) in dioxan (100 ml.) was heated at 100° for 11/2 hours. The solution was evaporated in vacuo and the residue suspended in warm ethyl acetate (70 ml.). The cooled suspension was filtered and the filtrate evaporated in vacuo. The oily residue was suspended in ether and the solid which separated was filtered and crystallised from ethanol to give the title compound (2.17 g.), m.p. 68°-70°.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:15](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1>C(O)C>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:15](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1
Reactant: CNC
Reactant: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Solvent: CCO
Product: CN(C)CCOc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Reaction time: 84 h
Yield: 86.2 %

Procedure:
10 ml of a 40% aqueous solution of dimethylamine are added to a solution of 5.37 g (12 mmoles) of (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, prepared as described in Example 7, in 10 ml of ethanol. The mixture is allowed to stand for 3-4 days, then evaporated, the residue is diluted with 50 ml of benzene, the resulting solution is washed with water until neutral, dried and evaporated. The residue is crystallized from hexane. 4.26 g (86.2%) of (E)-1-[4-(2-dimethylaminoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene are obtained; m.p.: 90°-91° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:18]=[C:19]([C:32]2[N:37]=[C:36]([CH3:38])[N:35]=[C:34]([N:39]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)[CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[N:33]=2)[C:20]([NH:23][C:24]2[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.O1CCOCC1>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:39]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)[C:34]2[N:33]=[C:32]([C:19]3[C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)=[N:21][CH:22]=[C:17]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:18]=3)[N:37]=[C:36]([CH3:38])[N:35]=2)=[CH:46][CH:45]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4cnn(C)c4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 140 °C
Yield: 133.7 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41.5 mg, 0.199 mmol) (Aldrich), 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (97 mg, 0.166 mmol), Pd2dba3 (6.08 mg, 6.64 μmol) (Strem Chemicals), and 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (6.33 mg, 0.013 mmol) (Strem Chemicals) was purged with argon, treated with dioxane (2 mL) and 1 M aqueous sodium carbonate (0.415 mL, 0.415 mmol), and heated in a microwave at 140° C. for 30 min. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (30 mL), washed with brine and dried over MgSO4, filtered and concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (140 mg, 0.222 mmol) which was used in the next step without further purification. m/z (ESI, +ve ion) 630.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.60 (1H, s); 8.83 (1H, d, J=2.5 Hz); 8.41 (1H, d, J=2.5 Hz); 8.27 (1H, d, J=2.7 Hz); 7.89 (1H, dd, J=8.8, 2.7 Hz); 7.68 (1H, s); 7.52 (1H, s); 7.21 (4H, dd, J=13.5, 8.6 Hz); 6.86 (4H, dd, J=13.1, 8.6 Hz); 6.71 (1H, d, J=9.0 Hz); 4.88 (2H, s); 4.82 (2H, s); 3.93 (3H, s); 3.93 (3H, s); 3.81 (3H, s); 3.78 (3H, s); 2.59 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[CH2:7][O:8][C:4]=2[C:3]=1[O:12][CH3:13]>[Pd].C(O)(=O)C>[CH3:13][O:12][C:3]1[C:4]2[O:8][CH2:7][CH2:6][C:5]=2[CH:10]=[CH:11][C:2]=1[OH:1]
Reactant: COc1c(O)ccc2c1OCC2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1c(O)ccc2c1OCC2

Procedure:
A solution of 6-hydroxy-7-methoxy-3(2H)-benzofuranone, 233 mg. (1.29 mmole) in 5 ml. of acetic acid was hydrogenated for 4 hours at room temperature under 53 psi of H2 using 50 mg. of 10% Pd/C as catalyst. The mixture was then filtered, concentrated in vacuo to a residue which was chromatographed over silica gel (E. Merck 60) eluting with CHCl3 to yield, after evaporation, a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:14]=[C:13](Cl)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]1([CH:35]=[CH:34][CH:33]=[C:31]([OH:32])[CH:30]=1)[OH:29].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:14]=[C:13]([C:33]3[CH:34]=[CH:35][C:28]([OH:29])=[CH:30][C:31]=3[OH:32])[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc(Cl)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Oc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Temperature: 85 °C
Yield: 97.2 %

Procedure:
To a 2-neck flask equipped with a reflux condenser, an argon inlet, a magnetic stirring bar and a glass stopper was introduced 3.79 g of 2,4-bis(4-tert-butylphenyl)-6-chloro-1,3,5-triazine of example 1. To it was added 30 mL of chlorobenzene, 1.21 g of resorcinol and 2 g of aluminum chloride at room temperature. The reaction mixture was heated at 85° C. for 6 hr. The heating was discontinued and the reaction was allowed to cool to room temperature. To it was then added 5% ice-cold aq. HCl, and the mixture concentrated under reduced pressure. The residue was washed with water and dried to give 4.4 g of a product characterized to be 2,4-bis(4-tert-butylphenyl)-6-(2,4-dibydroxyphenyl)-1,3,5-triazine.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:9][CH:8]=1)C.[CH3:29][NH:30][CH3:31]>>[CH2:21]([O:20][C:18](=[O:19])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4](=[O:3])[N:30]([CH3:31])[CH3:29])=[CH:8][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: CNC
Product: CN(C)C(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 55 °C
Yield: 52 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid ethyl ester 23 (0.50 g, 1.3 mmol) and dimethylamine (2.0 M in THF, 10 mL, 20 mmol) in a sealed tube was heated at 55° C. for 48 h. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/CH2Cl2, 1:4, 1:3, v/v) to provide [4-(4-dimethylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester 28 (0.26 g, 52% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.55 (m, 4H), 2.55 (m, 2H), 2.90 (s, 3H), 3.05 (s, 3H), 3.20 (m, 2H), 4.65 (s, 2H), 5.08 (s, 2H), 6.80 (d, 2H), 7.05 (d, 2H), 7.35 (m, 5H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (536 mg, 80%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: COc1ccc2c(c1)C(C)NCC2
Reactant: Cc1nc(Cl)nc(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(C)N(c1nc(Cl)nc(C)c1C)CC2
Yield: 67.8 %

Procedure:
After 1-methyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline (0.9 g, 5.1 mmol) and triethylamine(0.7 ml, 5.1 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine (0.8 g, 4.64 mmol) in dimethylformamide, 1.0 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 70.3%)
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(Cl)c(Cl)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3,4-dichlorophenylboronic acid. The title compound was obtained in 81% yield as yellow foam. MS (m/e): 550.2 (MH+, 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][OH:11])=[N:2]1>COCCOC.[O-2].[O-2].[Mn+4]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[N:2]1
Reactant: OCc1n[nH]c2ccccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: COCCOC
Product: O=Cc1n[nH]c2ccccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A solution of 2.27 g of (1H-indazol-3-yl)methanol in 220 ml of 1,2-dimethoxyethane is added to 13.32 g of manganese dioxide. After one hour at a temperature in the region of 20° C., the reaction mixture is refluxed for 15 minutes. After cooling to a temperature in the region of 20° C., the reaction medium is filtered through a sinter funnel packed with Celite. The collected filtrate is concentrated under reduced pressure at a temperature in the region of 40° C. 2.02 g of 1H-indazole-3-carboxaldehyde are thus obtained in the form of a yellow powder, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:4][CH:5]1[N:8](C(C(OCC2C=CC=CC=2)=O)=C(C)C)[C:7](=[O:23])[C:6]1([O:34][CH3:35])[NH:24][C:25](=[O:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:3])[CH3:2].P([O-])([O-])([O-])=O.[O-][Mn](=O)(=O)=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O.CCOC(C)=O>[C:1]([O:4][CH:5]1[NH:8][C:7](=[O:23])[C:6]1([O:34][CH3:35])[NH:24][C:25](=[O:33])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:3])[CH3:2]
Reactant: COC1(NC(=O)Cc2ccccc2)C(=O)N(C(C(=O)OCc2ccccc2)=C(C)C)C1OC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC1(NC(=O)Cc2ccccc2)C(=O)NC1OC(C)=O
Reaction time: 0.13 h

Procedure:
To a stirred solution of 240 mg (0.5 mmol) of azetidinone prepared in Example 1 in 8 ml of 8:1 acetone-water and 2 drops of pH 7 0.1 N phosphate buffer at 25° C. is added 79 mg (0.5 mmol) of solid KMnO4. The mixture is stirred under N2 at 25° for 8 minutes and an additional 79 mg (0.5 mmol) of KMnO4 is then added. The mixture is stirred further for 45 minutes and diluted with EtOAc. The mixture is treated with sufficient aqueous sodium thiosulfate to destroy any remaining permanganate. The mixture is then filtered through celite and washed thoroughly with ethyl acetate. The filtrate is partitioned between EtOAc/brine and the organic phase is separated, dried (MgSO4), filtered and evaporated. Purification of the residue by plate layer chromatography affords 4-acetoxy-3-methoxy-3-phenylacetamido-azetidin-2-one (1). ##STR39##
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28](C3SC=CC=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].S(Cl)(=O)(=O)[NH2:38]>>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([NH2:38])(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Agent: Cl
Product: N#Cc1ccc2c(c1)CN(S(N)(=O)=O)[C@H](Cc1ccccc1)CN2

Procedure:
The title compound was prepared from Compound A of Example 23 and sulfamyl chloride following the procedure of Compound B of Example 37.