Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:12][OH:13].Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:11]2[CH2:12][O:13][C:23](=[O:25])[NH:10]2)=[CH:20][CH:19]=1
Reactant: NC(CO)Cc1ccc(Cl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NC(Cc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Diisopropylethylamine (0.78 ml, 4.5 mmol, 2.25 eq) is added to a solution of 2-amino-3-(4-chlorophenyl)propan-1-ol a93 (0.37 g, 2 mmol, 1 eq) in dichloromethane (75 ml). The mixture is cooled (ice bath) and triphosgene a89 (0.30 g, 1 mmol, 0.5 eq) is added. The mixture is stirred overnight at room temperature, washed with water, with 0.1 N aqueous hydrochloric acid, dried over magnesium sulfate and concentrated in vacuo to give 0.47 g of 4-(4-chlorobenzyl)-1,3-oxazolidin-2-one a94 as a yellow oil. This oil is used in the next step without any further purification.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:20][C@@H:21]([CH3:24])[CH2:22][OH:23])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[OH:23][CH2:22][C@@H:21]([O:20][C:18]1[CH:17]=[C:12]([CH:11]=[C:10]([O:9][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:24]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.3 %

Procedure:
Benzyl bromide (1.89 g, 7.20 mmol) was added to a mixture of methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate (1.55 g, 6.86 mmol) and potassium carbonate (1.89 g, 0.014 mol) in DMF (16 mL) and the reaction stirred at RT for 20 hours. Ethyl acetate (40 mL) was added and the mixture washed with water (40 mL), saturated sodiumbicarbonate solution (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a red oil which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound (1.7 g).
Reaction SMILES: C[C:2]1[C:7]([OH:8])=[CH:6][C:5]2[CH2:9][CH2:10][C@:11]([CH2:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20]/[CH:21]=[C:22](/[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])\[CH3:23])\[CH3:18])([CH3:13])[O:12][C:4]=2[C:3]=1C.CC1C2O[C@@](CC/C=C(/CC/C=C(/CCC=C(C)C)\C)\C)(C)CCC=2C=C(O)C=1>>[CH3:28][C:27]([CH3:29])=[CH:26][CH2:25][CH2:24]/[C:22](/[CH3:23])=[CH:21]/[CH2:20][CH2:19]/[C:17](/[CH3:18])=[CH:16]/[CH2:15][CH2:14][C:11]1([CH3:13])[O:12][C:4]2[CH:3]=[CH:2][C:7]([OH:8])=[CH:6][C:5]=2[CH2:9][CH2:10]1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC[C@]1(C)CCc2cc(O)c(C)c(C)c2O1
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC[C@]1(C)CCc2cc(O)cc(C)c2O1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC1(C)CCc2cc(O)ccc2O1

Procedure:
Both γ-tocotrienol, referred to herein as Compound 1, and δ-tocotrienol, referred to herein as Compound 2, were isolated from a tocotrienol-rich fraction of palm oil using normal phase vacuum liquid chromatography. Compounds 3-29 and 35-44 which are 3,4-dihydro-1,3-oxazines, Compounds 30-31 which are Mannich bases, and Compounds 32-34 which are hydroxymethyl tocotrienol analogs were prepared as semi synthetic derivatives of Compounds 1 and 2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12](Cl)=[CH:11][C:10]=2[CH3:16])=[CH:5][CH:4]=1)#[N:2].[C:17]([O:21][CH3:22])(=[O:20])[NH:18][NH2:19]>C(O)CCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:19][NH:18][C:17]([O:21][CH3:22])=[O:20])=[CH:11][C:10]=2[CH3:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1ccc(C#N)cc1
Solvent: CCCCO
Product: COC(=O)NNc1cc(C)c(-c2ccc(C#N)cc2)nn1

Procedure:
A mixture of 18.0 g. of 6-(p-cyanophenyl)-5-methyl-3-chloropyridazine, 13.3 g. of methyl carbazate and 200 ml. of n-butanol is refluxed for 3 hours. The solvent is removed to give an oil which crystallizes on addition of water to give 11.9 g. of product. Recrystallization from methanol-ether gives white crystals, m.p. 191°-192° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A solution of 22.2 g of 2-bromopyridine in 100 ml of THF is cooled to −70° C., 87.8 ml of n-butyllithium are added dropwise and the mixture is stirred for 30 minutes. A solution of 25.6 g of 1-benzyl-4-piperidinone in 100 ml of THF is then added dropwise at −60° C., and the mixture is stirred overnight while allowing the temperature to rise to rt. The reaction mixture is poured into water and extracted with ether, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H gel, eluting with DCM and then with a DCM/MeOH mixture gradient of from (99/1; v/v) to (90/10; v/v). 21.5 g of the expected product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12]C)[CH:11]=1)[N:8]=[C:7]([Cl:14])[N:6]=[CH:5]2.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([Cl:14])[N:6]=[CH:5]2
Reactant: COc1cc(Br)cc2cnc(Cl)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(Br)cc2cnc(Cl)nc12
Temperature: 20 °C
Reaction time: 48 h

Procedure:
6-bromo-2-chloro-8-methoxy-quinazoline (1.24 g, 4.52 mmol) is taken up in 7 mL DCM, combined with boron tribromide (12.95 mL, 12.95 mmol) and stirred for 2 d at 20° C. Then the mixture is diluted with ice water, the precipitate formed is filtered off, dried and 6-bromo-2-chloro-quinazolin-8-ol (HPLC-MS: tRet.=1.77 min; method FSUN) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([OH:18])[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[Cl:19][C:15]1[CH:14]=[C:13]([F:20])[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([C:7]([F:8])([F:10])[F:9])[N:5]([CH3:11])[N:4]=2)=[CH:17][C:16]=1[O:18][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
At 25° C., 13.16 g (0.04 mole) 4-chloro-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 6.1 g (0.044 mole) K2CO3, and 4.8 mL (0.044 mole) ethyl bromoacetate were slurried in 25 mL acetone. The reaction mixture was stirred at 25° C. for 16 hours. The reaction solution was poured into 150 mL ice water, filtered, washed with water and air dried. The residue was recrystallized from hexane to give 16.6 g (100%) of (2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)acetic acid, ethyl ester as a white solid, mp 130°-131° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[C:26]([F:37])[CH:25]=3)[CH:15]=2)=[C:9]([CH3:38])[CH:8]=1)[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([F:37])[CH:25]=3)[CH:15]=2)=[C:9]([CH3:38])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cc(COc3ccc(CCC(=O)OCC)c(F)c3)ccc2OC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCOc1cc(C)c(-c2cc(COc3ccc(CCC(=O)O)c(F)c3)ccc2OC)c(C)c1
Yield: 19.9 %

Procedure:
To a mixture of ethyl 3-(4-{[4′-(2-ethoxyethoxy)-6-methoxy-2′,6′-dimethylbiphenyl-3-yl]methoxy}-2-fluorophenyl)propanoate (0.45 g, 0.86 mmol), methanol (4.5 mL) and tetrahydrofuran (9 mL) was added 1 N aqueous sodium hydroxide solution (1.7 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was neutralized with 1 N hydrochloric acid and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/2) to give the title compound (85 mg, yield 20%) as a colorless oil.
Reaction SMILES: [N:1]1([C:5]2[N:9]=[C:8]([CH:10]=[CH:11][C:12]3[N:22]=[C:15]4[N:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH2:4][CH2:3][CH2:2]1>[Pd].CO>[N:1]1([C:5]2[N:9]=[C:8]([CH2:10][CH2:11][C:12]3[N:22]=[C:15]4[N:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=Cc3nc(N4CCC4)nn3C)nc2n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)n2nc(CCc3nc(N4CCC4)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.8 %

Procedure:
A mixture of 2-(2-(3-(azetidin-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (15 mg, 48.3 μmol, Eq: 1.00) and palladium on carbon 10% (5.14 mg, 4.83 μmol, Eq: 0.1) in methanol (15 ml) was stirred for 6 hours at 25° C. under hydrogen atmosphere. The catalyst was filtered off, evaporation of the solvent afforded 2-[2-(5-azetidin-1-yl-2-methyl-2H-[1,2,4]triazol-3-yl)-ethyl]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (14.3 mg/94.7%) as a light yellow solid. MS: m/z=313.4 (M+H+).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([CH3:29])[C:21]=1[S:22]([CH2:25][N+:26]([O-:28])=[O:27])(=[O:24])=[O:23])[NH2:18]>C(Cl)Cl>[CH3:29][C:20]1[CH:19]=[C:17]([NH:18][C:11]([NH:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=2)(=[O:8])=[O:9])=[O:12])[CH:16]=[C:15]([CH3:14])[C:21]=1[S:22]([CH2:25][N+:26]([O-:28])=[O:27])(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c2)cc1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
A solution of 1.55 ml (10.2 mmol) of p-toluenesulphonyl isocyanate in 15.5 ml of anhydrous methylene chloride is added dropwise to a suspension, maintained under a nitrogen atmosphere, of 2.6 g (10.6 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 52 ml of anhydrous methylene chloride. The temperature of the reaction medium rises spontaneously by 2° C. Stirring of the solution obtained is continued for 30 minutes at room temperature. The reaction medium is then concentrated to dryness under reduced pressure; the residue is purified by chromatography on a column of silica (eluent: methylene chloride and then a 9/1 methylene chloride/methanol mixture) and crystallization from methylene chloride, to give 2.5 g (57%) of 1-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-3-[(4-methylphenyl)sulphonyl]urea.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.[Li]CCCC.Cl>C1COCC1>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([B:13]([OH:18])[OH:14])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(B(O)O)cc1
Temperature: 0 °C
Yield: 104.6 %

Procedure:
To a solution of 4-bromo-N-methyl-benzene sulfonamide (24.9 g, 0.1 mol) and B(OiPr)3 (28.2 g, 0.15 mol) in THF (200 mL) was added n-BuLi (100 mL, 0.25 mol) at −70° C. The mixture was slowly warmed to 0° C., then 10% HCl solution was added until pH 3-4. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and evaporated under reduced pressure to give 4-(N-methylsulfamoyl)phenylboronic acid (22.5 g, 96%), which was used in the next step without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 8.29 (s, 2H), 7.92 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 2.36 (d, J=5.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C@H:3]1[CH:8]=[CH:7][CH2:6][C@H:5]([CH3:9])[C@H:4]1[C:10](=[O:12])[CH3:11])[CH3:2].[CH3:13][CH2:14][O-].[Na+].[Li+].CC([N-]C(C)C)C.C(C)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)C.C1CCCCC1.O.C1COCC1>[CH2:1]([C@H:3]1[CH:8]=[CH:7][CH2:6][C@H:5]([CH3:9])[C@@H:4]1[C:10](=[O:12])/[CH:11]=[CH:13]/[CH3:14])[CH3:2]
Reactant: CC[C@H]1C=CC[C@H](C)[C@H]1C(C)=O
Reactant: CC[O-]
Agent: CC(C)[N-]C(C)C
Agent: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C/C=C/C(=O)[C@@H]1[C@@H](CC)C=CC[C@@H]1C

Procedure:
A crude 80:20 mixture of 1-(rel-(1S,2S,6S)-/1-(rel-(1R,2S,6S)-2-ethyl-6-methylcyclohex-3-enyl)ethan-1-one (2.6 g) was prepared as described in Example 2 by EtONa catalyzed epimerization of 1-(rel-(1R,2S,6S)-2-ethyl-6-methylcyclohex-3-enyl)ethan-1-one (3.15 g, 18.9 mmol, Example 3) in ethanol (30 ml) at reflux (25 h). Aldolisation (LDA, AcH, THF) and water-elimination (PTSA.H2O, cyclohexane, reflux, 45 min.) gave a 83:17 mixture of 1-(rel-(1S,2S,6S)-/1-(rel-(1R,2S,6S)-2-ethyl-6-methylcyclohex-3-enyl)ethan-1-one (1.27 g, 2 steps: 42%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH:29]1([C:32]2[NH:36][N:35]=[C:34]([NH2:37])[CH:33]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH2:25][CH2:26]2)=[N:7][C:2]([NH:37][C:34]2[CH:33]=[C:32]([CH:29]3[CH2:31][CH2:30]3)[NH:36][N:35]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2)CC1
Yield: 59.4 %

Procedure:
A solution of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (506 mg, 1.22 mmol), 5-cyclopropyl-1H-pyrazol-3-amine hydrochloride (272 mg, 1.70 mmol), cesium carbonate (1.176 g, 3.609 mmol), [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (147.6 mg, 0.2370 mmol) and diacetoxypalladium (53.8 mg, 0.240 mmol) in anhydrous dioxane (10 mL) stirred in a sealed tube under the microwave radiation at 150° C. for 2 h. Then the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a light yellow solid (364 mg, 59.5%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)Cl.O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CC(O)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CC(O)CCN1C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a cold (5° C.) solution of methyl 4-hydroxypiperidine-2-carboxylate, 13a, (5.17 g, 32.48 mmol) and triethylamine (6.00 mL, 43.05 mmol) in CH2Cl2 (135 mL) was added dropwise benzyl chloroformate (6.20 mL, 43.43 mmol) over 10 min. The resulting solution was stirred at 5° C. for 1 hour and then allowed to warm to room temperature. The reaction mixture was diluted with water and the layers were separated. The aqueous was re-extracted with CH2Cl2 and the combined organics were dried over MgSO4, filtered and evaporated to dryness. The crude was passed through a plug of silica gel, eluting with 30-80% EtOAc/Hexanes to afford the desired product, 13b.
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5].CC/C=C/C=C\CCCCCCCCOC(C)=O.[H][H]>CO>[Cl:1][C:2]1[C:18]([NH2:19])=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5]
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c([N+](=O)[O-])c1Cl
Reactant: [H][H]
Agent: CC/C=C/C=C\CCCCCCCCOC(C)=O
Solvent: CO
Product: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c(N)c1Cl
Reaction time: 6 h

Procedure:
182.4 g (0.500 mol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N′-isopropyl-N′-methylsulfamide in 391 g of methanol were admixed with 1.33 g (0.005 mol %) of 1% Pt-2% V/C and hydrogenated with 5 bar of hydrogen with stirring at 60° C. After 6 h the solution was depressurized, the reaction mixture was filtered and the solvent was removed by distillation. This gave 157.1 g (97%) of the title compound in the form of a solid (m.p.: 147-149° C.).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].CC(C)([O-])C.[K+].CO[C:20](=O)[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O1CCCC1.O>[OH:8][C:7]1[C:2]2[O:1][C:20](=[CH:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH2:10][C:9](=[O:11])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cccc(O)c1O
Reactant: COC(=O)CN1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC(=CN2CCOCC2)Oc2c(O)cccc21
Temperature: 25 °C
Yield: 68.7 %

Procedure:
2',3'-Dihydroxy-acetophenone (7.5 g, 49 mmole) is dissolved in 303 ml dry tetrahydrofuran in a flame dried 1,000 ml three neck round bottom flask under nitrogen. The solution is treated rapidly dropwise with potassium t-butoxide (1.0 M/THF) (197 ml, 197 mmole) and is mechanically stirred vigorously as methyl-2-(4-morpholinyl)-acetate (10.2 g, 64 mmole) is added neat. The reaction mixture is heated at reflux for 48 h, is treated with a second lot of methyl-2-(4-morpholinyl)-acetate (7 g, 44 mmole), and is stirred an additional 24h at reflux. The reaction is cooled to room temperature, is diluted with 200 ml water, and the tetrahydrofuran is removed in vacuo. The pH of the aqueous residue is adjusted to 6.8 with 10% hydrochloric acid and the mixture is extracted with 5×100 ml dichloromethane. The combined organics are dried over magnesium sulfate and are concentrated in vacuo to a brown solid. The solid is washed with 200 ml diethyl ether and is dried to afford 8.8 g of a tan solid. The solid is recrystallized twice from ethyl acetate to provide 7.5 g (60%) of the title compound as an off-white solid, mp. 202.5° C.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].[C:6]([N:10]=[N:11][C:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7].O>CCCCC>[C:6]([N:10]=[N:11][C:12]1([NH:18][C:19]([O:3][CH2:1][CH3:2])=[S:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CCO
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCC
Product: CCOC(=S)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 50 ml of ethanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 11.2 grams (0.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane was added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours and then allowed to stand overnight. The next morning the reaction mixture was poured into 200 ml water and the product extracted with 50 ml pentane. The pentane extract was washed twice with water, once with 10% NaHCO3, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave a mushy solid. The solid was slurried in a small amount of cold pentane and filtered. The solids were air dried and weighed 7.1 grams (52% crude yield) and melted at 57°-62° C. The product had a strong broad band at 1515 cm-1 and a sharp NH band at 3300 cm-1 in its infrared spectrum.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[O:4].C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1.C([SiH](CCCCCC)CCCCCC)CCCCC.CN(C)[CH:56]=[O:57]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]([CH3:18])[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([CH:56]=[O:57])=[CH:10][CH:9]=2)=[O:4]
Reactant: COc1c(C(=O)N(C)C)cnc2ccc(I)cc12
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[SiH](CCCCCC)CCCCCC
Product: COc1c(C(=O)N(C)C)cnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-iodo-4-methoxy-quinoline-3-carboxylic acid dimethylamide (example 10b) (1.27 g, 3.57 mmol), trethylamine (1.23 mL, 8.93 mmol), diphenylpropylphosphine (dpp, 81 uL, 0.36 mmol) and palladium(II) acetate (80 mg, 0.36 mmol) in dry N,N-dimethylformamide (20 mL) in pressure tube was stirred under carbon monoxide at 75 psi at room temperature for 10 min. After addition of trihexylsilane (2.54 mL, 7.14 mmol), the mixture was then stirred under carbon monoxide at 75 psi at 80° C. for 3 h. The reaction was allowed to cool to 25° C. and then extracted with methylene chloride (2×100 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3×50 mL) and water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-40% ethyl acetate in hexanes in 30 min) afforded 6-formyl-4-methoxy-quinoline-3-carboxylic acid dimethylamide as a white solid. LC-MS m/e 259 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18]C)=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+].CC(OC)(C)C>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1
Reactant: CCC(C)n1cc(C)c2c(C(=O)OC)cc(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)n1cc(C)c2c(C(=O)O)cc(Br)cc21
Reaction time: 0.08 h

Procedure:
Methyl 6-bromo-1-(sec-butyl)-3-methyl-1H-indole-4-carboxylate (3.24 g, 9.99 mmol) was dissolved in methanol (30 mL) and tetrahydrofuran (THF) (7 mL). The contents were stirred for 5 min., and then aq. 3N NaOH (19.99 mL, 60.0 mmol) was added via addition funnel over 3 min. The contents rapidly became a yellow suspension and were stirred at room temperature for 65 h. The volatiles were removed in vacuo and the residue dissolved in water (60 mL). The contents were washed with ether (1×50 mL). The aq layer was cooled in an ice bath and adjusted to pH 3-4 with 1M HCl, from which an oily residue precipitated. The contents were extracted with EtOAc (2×60 mL). The combined organic layers were dried over magnesium sulfate, filtered through celite, and concentrated in vacuo. The residue obtained was treated with TBME, concentrated in vacuo, and then dried under hi vacuum to afford a yellow foam as 3.08 g (93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 (t, J=7.33 Hz, 3H), 1.39 (d, J=6.82 Hz, 3H), 1.71-1.86 (m, 2H), 2.30 (s, 3H), 4.48-4.62 (m, 1H), 7.40-7.49 (m, 2H), 7.96 (d, J=1.77 Hz, 1H), 12.99 (s, 1H); LCMS=310.0/312.0 (MH+).