Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:12]=2[S:13][C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:19])[F:20])=[CH:11][C:12]=2[S:13]([C:14]([F:16])([F:17])[F:15])=[O:27])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=S(c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
A solution of 2-(p-chlorophenyl)-5-(trifluoromethyl)-3-[(trifluoromethyl)thio]pyrrole (5.5 g, 15.9 mmol) in chloroform is cooled to 0° C., treated with 3-chloroperoxybenzoic acid (5.49 g, 60%, 19.1 mmol), stirred for several hours and filtered to remove solids. The solids are dissolved into ether and the organic solution is washed with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. Recrystallization of the solid from ether gives the title product as a white solid (mp 198°-200° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][C:6]([CH3:12])=[CH:7][C:8](=[O:11])[C:9]=1[OH:10])[CH3:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:1][CH:2]([C:4]1[O:5][C:6]([CH3:12])=[CH:7][C:8](=[O:11])[C:9]=1[O:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:3]
Reactant: BrCc1ccccc1
Reactant: Cc1cc(=O)c(O)c(C(C)O)o1
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(C)O)o1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1 )-one, using 8.5 g (50 mmol, 1 eq.) of 2(1-hydroxyethyl)-3-hydroxy-6-methyl-pyran-4(1H)-one and 9.5 g benzyl bromide (55 mmol, 1.1 eq.) to yield the pure product 10.1 g (77.7%) after recrystallisation from CH2Cl2/Pet. ether 40/60, as a white crystalline solid. m.p 91-92° C.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([O:15]C(=O)C)[CH:12]=[C:11]2[C:6]=1[C:7](=[O:29])[C:8]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[C:9]([CH2:19]Br)[O:10]2)(=O)C.[CH3:30][NH:31][CH3:32].[ClH:33]>C(Cl)(Cl)Cl>[ClH:33].[CH3:30][N:31]([CH2:19][C:9]1[O:10][C:11]2[C:6]([C:7](=[O:29])[C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[C:5]([OH:4])[CH:14]=[C:13]([OH:15])[CH:12]=2)[CH3:32]
Reactant: COc1ccc(-c2c(CBr)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Reactant: CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(CN(C)C)oc3cc(O)cc(O)c3c2=O)cc1
Reaction time: 1 h

Procedure:
To a solution of 5,7-diacetoxy-4'-methoxy-2-bromomethylisoflavone (500 mg) in 5 ml chloroform, was added 240 mg of 50% aqueous solution of dimethylamine at room temperature with stirring. After one hour, the solid which separated out was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:chloroform). To the liquid thus obtained was added ethanolic solution of hydrogen chloride, the solvent was distilled off, and the solid which separated out was recrystallized from ethanol, giving 150 mg of 2-(dimethylaminomethyl)-5,7-dihydroxy-4'-methoxyisoflavone hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14]([NH:15][CH:16]=[O:17])[C:3]=12.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14]([N:15]([CH3:20])[CH:16]=[O:17])[C:3]=12
Reactant: Cc1c2n(c3ccccc13)CCCC2NC=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2n(c3ccccc13)CCCC2N(C)C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of N-(6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-yl)formamide (7.4 g, 32.4 mmol) in dimethylformamide (90 mL) was added dropwise at 25° C. to a suspension of sodium hydride (1.78 g, 37 mmol, ~50% suspension in mineral oil) in the same solvent (90 mL). The reaction mixture was stirred at 25° C. for 2 hours under exclusion of moisture. Methyl iodide (5.1 g, 35.6 mmol) was added and the mixture stirred at 25° C. overnight. The solvent was evaporated in vacuo and the residue partitioned between water (100 mL) and chloroform (150 mL). The organic layer was separated, dried over MgSO4, filtered, and evaporated to afford 7.85 g (100%) of the title compound as an amber oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:17])([CH3:16])[C:9](=[O:15])[N:10]=2)[C:5]=1[OH:18])[CH:2]=[CH2:3].[Br:19]N1C(=O)CCC1=O>>[Br:19][CH2:3][CH:2]1[O:18][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH2:1]1)[NH:10][C:9](=[O:15])[C:8]([CH3:17])([CH3:16])[CH2:7]3
Reactant: C=CCc1cc(C)c2c(c1O)=CC(C)(C)C(=O)N=2
Reactant: O=C1CCC(=O)N1Br
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(CBr)C2
Yield: 181.5 %

Procedure:
Using 6-allyl-5-hydroxy-3,3,8-trimethylcarbostyril (1.36 g, 3.28 mmol) and N-bromosuccinimide (1.12 g, 6.28 mmol), the procedure of Example 277 was followed (reaction, post-treatment, and recrystallization from chloroform-ether-n-hexane). 1.93 g of the title compound was obtained as colorless needles (94.9%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]([F:15])([F:14])[F:13])#[N:2].[Br:16]Br>C(O)(=O)C>[Br:16][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([C:12]([F:15])([F:13])[F:14])=[C:3]2[C:1]#[N:2]
Reactant: N#Cc1c(C(F)(F)F)[nH]c2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: N#Cc1c(C(F)(F)F)[nH]c2ccc(Br)cc12
Yield: 65 %

Procedure:
A solution of 3-cyano-2-(trifluoromethyl)indole (1.05 g, 5.0 mmole) in acetic acid is treated with Br2 (0.6 mL, 6.0 mmole) at room temperature, and stirred until reaction is complete by TLC. The reaction mixture is worked up as described in Example 22 to afford the title product as a white solid after chromatography (silica gel and 4:1 hexanes:ethyl acetate) and crystallization, 0.95 g (65% yield), mp 188°-191.5° C., identified by IR, 1HNMR, 19FNMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5](=[O:7])[N:6]=1.[CH:8]([C:10]1[CH:28]=[CH:27][C:13]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])=[C:12]([O:29][CH3:30])[CH:11]=1)=O>>[NH2:1][C:2]1[S:3][C:4](=[CH:8][C:10]2[CH:28]=[CH:27][C:13]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[C:23]([F:24])([F:25])[F:26])=[C:12]([O:29][CH3:30])[CH:11]=2)[C:5](=[O:7])[N:6]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Reactant: NC1=NC(=O)CS1
Product: COc1cc(C=C2SC(N)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
4-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile was prepared using 2-amino-thiazol-4-one and 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile according to General Procedure B. 1H NMR (400 Hz, DMSO-d6) δ 8.96 (bs, NH), 8.74 (bs, NH), 8.32 (d, 1H), 7.99 (dd, 1H), 7.65 (d, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 7.24 (d, 1H), 6.89 (d, 1H), 3.88 (s, 3H); LC/MS (m/z) [M+1]+420.0 (C19H13F3N3O3S, 420.38).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:15]1([C@@:20]([OH:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1.[C:31]([O:35][C:36]([N:38]1[CH2:42][CH2:41][C@@H:40](O)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:31]([O:35][C:36]([N:38]1[CH2:42][CH2:41][C@@H:40]([O:22][C:21](=[O:23])[C@:20]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, diisopropyl azodicarboxylate (980 μl, 5 mmol) was slowly added to a mixture of (R)-cyclopentylhydroxyphenylacetic acid (1.1 g, 5 mmol), (R)-3-hydroxypyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 5.5 mmol), and triphenylphosphine (1.3 g, 5 mmol) in 10 ml of THF. The reaction mixture was then stirred at room temperature overnight.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]3[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[ClH:29]>O1CCOCC1>[ClH:29].[C:1]1([N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]3[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(c3ccccc3)C2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(c3ccccc3)C2)nc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (47 mg) in dioxane (1.4 mL) was added 1N sodium hydroxide (0.42 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O (7 mL) and acidified with 1N hydrochloric acid (to pH 4). A resulting precipitate was collected by filtration, and washed with water to give (2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid hydrochloride (39 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:14][N:8]3[NH:7][CH2:6][CH2:5]2)[CH:11]=1.[CH3:22]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:20])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:22])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)CCN2C
Temperature: 120 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To 1.69 g (5.5 mmol) of the compound (132) obtained in Example 24, 10 ml (109 mmol) of dimethylsulfate was added, and the solution was heated at 120° C. for 4.5 hours. After air-cooling, the solution was added to 90 ml of ice/water to which 15 g (109 mmol) of anhydrous potassium carbonate was added, and the solution was stirred for 1 hour. The solution was extracted with 200 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 60 g, eluent solvent; chloroform methanol=100:1) to obtain 600 mg of the subject compound (133) in a 36% yield.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:12]([OH:14])=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:15](O)[CH3:16]>>[ClH:1].[CH2:15]([O:13][C:12](=[O:14])[C@H:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:2])[CH3:16]
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hydrogen chloride gas is bubbled through a solution of (L)-homophenylalanine (5.13 g, 28.7 mmol) in 100 mL of ethanol for 5 minutes. The mixture is stirred at room temperature for 16 hours. The mixture is concentrated in vacuo to yield L-homophenylalanine ethyl ester hydrochloride as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:8]1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1ccccc1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)c3ccccc3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: Cc1cc(C)cc(N=C=O)c1
Product: Cc1cc(C)cc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)c1

Procedure:
61 mg of pale yellow solid 3-{4-[3-(3,5-dimethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3,5-dimethylphenyl isocyanate.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl[CH2:8][O:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[C:1]([O:6][CH2:8][O:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: ClCOC1Cc2ccccc2C1
Reactant: C=C(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCOC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Into a mixture of 103 g of methacrylic acid, 183 g of chloromethyl(2-indanyl)ether, and 1500 g of toluene was added 111 g of triethylamine under ice-cooling with agitation, and then the reaction mixture was agitated at room temperature for 16 hours. After a usual aqueous work-up, the solvent was removed by distillation to obtain a crude product. It was purified by a column chromatography to obtain 209 g of an objective product, (indane-2-yloxy)methyl methacrylate (yield 90%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]([NH2:25])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].CCN(CC)CC>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:25][C:19]4[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([Br:16])[CH:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ccc(N)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reaction time: 16 h

Procedure:
To a Solution of the Crude 1-Benzo[1,3]Dioxol-5-yl-Cyclopropanecarbonyl Chloride (3.0 mmol) in CH2Cl2 (30 mL) at ambient temperature was added a solution of 3-bromo-4-methoxybenzenamine (3.3 mmol), Et3N (15 mmol), and CH2Cl2 (90 mL) dropwise. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 (500 mL). The solution was washed with 1N HCl (2×250 mL), sat. aq. NaHCO3 (2×250 mL), then brine (250 mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuo to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methoxyphenyl)cyclopropanecarboxamide (B-10) with suitable purity to be used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20]C)[CH:15]=[O:16])([O:3]C)=[O:2].O>C(O)(=O)C.Br>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=[O:16])([OH:3])=[O:2]
Reactant: COC(=O)c1ccccc1Sc1cc(C=O)ccc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(O)c(Sc2ccccc2C(=O)O)c1

Procedure:
Heat 126 g of the aldehyde of Step C in a mixture of 1500 ml of glacial acetic acid and 1500 ml of 48% hydrogen bromide in an oil bath at 150° C. with mechanical stirring until no trace of nondemethylated product remains (4-5 days). Cool the reaction mixture and pour into 7 liters of water. Separate the precipitate, wash well with water and dry in vacuo at 70° C. to constant weight. (Yield: 108.2 g).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].[F:8][C:9]([F:17])([F:16])[C:10]([C:12]([F:15])([F:14])[F:13])=[O:11].[OH-].[K+]>>[F:8][C:9]([F:17])([F:16])[C:10]([OH:11])([C:12]([F:15])([F:14])[F:13])[CH2:4]/[CH:3]=[CH:2]/[C:1]([O:6][CH3:7])=[O:5]
Reactant: C=CCC(=O)OC
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: COC(=O)/C=C/CC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a nitrogen-flushed, 150 mL steel reaction vessel with teflon-coated magnetic stirbar was added 30.0 g methyl 3-buteneoate (300 mmol, 1 eq.). Hexafluoroacetone (55.8 g, 336 mmol, 1.1 eq.) was condensed into the vessel at −78° C. The reaction vessel was sealed under 1 atmosphere of nitrogen and warmed to room temperature slowly. The reaction was heated at 160° C. for 16 hours after which the pressure had decreased dramatically. The vessel was cooled in an ice bath and the excess hexafluoroacetone was carefully vented through a saturated potassium hydroxide solution. The crude reaction mixture was vacuum distilled using a 6-inch, vacuum-jacketed vigereaux column with a short-path distillation head. The product was isolated at 75-80° C. (6 Torr) as a colorless liquid. A second distillation of the prefraction resulted in a total isolated yield of 55.4 g (69%) of E-methyl 6,6,6-trifluoro-5-hydroxy-5-(trifluoromethyl)hex-2-enoate (I).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[Li])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([N:22]([CH2:39][CH3:40])[C:23]([C:25]1[C:26]([O:37][CH3:38])=[N:27][CH:28]=[CH:29][C:30]=1[C:31](N(OC)C)=[O:32])=[O:24])[CH3:21]>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:31]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([O:37][CH3:38])[C:25]=2[C:23]([N:22]([CH2:20][CH3:21])[CH2:39][CH3:40])=[O:24])=[O:32])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1cc2cnccc2n1S(=O)(=O)c1ccccc1
Reactant: CCN(CC)C(=O)c1c(C(=O)N(C)OC)ccnc1OC
Product: CCN(CC)C(=O)c1c(C(=O)c2cc3cnccc3n2S(=O)(=O)c2ccccc2)ccnc1OC

Procedure:
This compound was prepared according to the method described in Example 14c starting from 1-benzenesulfonyl 2-lithio 5-aza indole and 3-diethylaminocarbonyl 2-methoxy 4-(N-methoxy N-methylaminocarbonyl) pyridine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH:34]2[CH3:40].C([O-])(O)=O.[Na+]>>[CH3:40][CH:34]1[C:33]2[C:37](=[C:29]([NH:28][C:2]3[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:26][CH:27]=4)[N:3]=3)[CH:30]=[CH:31][CH:32]=2)[C:36](=[O:38])[N:35]1[CH3:39]
Reactant: CC1c2cccc(N)c2C(=O)N1C
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4C)n2)cc1)OCC
Yield: 66.5 %

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (179.0 mg, 0.4224 mmol) and 7-amino-2,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 157A, 83.7 mg, 0.475 mmol). The reaction mixture was poured into a separatory funnel containing saturated NaHCO3 and was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified using a Teledyne/ISCO Combiflash system, eluting first with 40-100% EtOAc:Heptane and then 0-15% MeOH:CH2Cl2. The product was purified again by MDP (under basic conditions; ammonium bicarbonate buffer (pH 9)) to afford the title product as an off-white solid (158.3 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (br s, 1H), 9.93 (s, 1H), 8.71 (br s, 1H), 8.48 (s, 1H), 7.38-7.80 (m, 3H), 7.15-7.33 (m, 3H), 4.59 (q, J=6.6 Hz, 1H), 3.90-4.02 (m, 4H), 3.22 (d, J=21.5 Hz, 2H), 3.01 (s, 3H), 1.43 (d, J=6.6 Hz, 3H), 1.18 (t, J=6.9 Hz, 6H). MS (ES+): m/z 564.17 (100) [MH+]. HPLC: tR=1.56 min (TOF, polar—3 min).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](O)=[O:12].C1COCC1.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12]
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
A mixture of 4-oxochromene-2-carboxylic acid (20.0 g, 105 mmol) and Pd/C (3.0 g, w/w=10%) in AcOH (200 mL) was placed in Parr hydrogenation apparatus under H2 (50 psi) and stirred for 25 h at rt. It was then filtered and concentrated. The residue was suspended in water (300 mL), stirred for 10 min, filtered and dried to give 3,4-dihydro-2H-chromene-2-carboxylic acid (13.5 g, 72%) as a white solid. BH3 (57 mL, 114 mmol, 2.0 M in THF) was added slowly to a solution of this carboxylic acid in THF (120 mL) at 0° C. The reaction mixture was then warmed to rt and stirred for 5 h at this temperature. THF/H2O (30 mL, 1:1) was added drop wise while keeping the temperature between 0-5° C. and stirred for 20 min. K2CO3 (26.0 g, 189 mmol) was added and the reaction was vigorously stirred for 30 min. The THF layer was separated and concentrated to give the title compound (11.0 g, 89%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.10-7.03 (m, 2H), 6.86-6.81 (m, 2H), 4.14-4.08 (m, 1H), 3.85-3.68 (m, 2H), 2.92-2.84 (m, 1H), 2.80-2.73 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.79 (m, 1H). LCMS: 165 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:22])[N:4]=1.CN1C=CN=C1.[F:29][CH:30]([F:35])[S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[F:29][CH:30]([F:35])[S:31]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:22])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: COc1nc(OC)nc(C2C(=O)Nc3c(OC)cccc32)n1
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3c(OC)cccc32)n1
Temperature: -15 °C
Reaction time: 48 h

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-methoxy-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.47 g) are introduced as initial charge in 8 ml of dichloromethane and cooled to −15° C. with nitrogen. With stirring, difluoromethanesulfonyl chloride (0.62 g) is added dropwise in two portions and the mixture is heated to 10° C. in 2.5 hours. It is cooled to 0° C., 1-methyl-1H-imidazole (0.24 g) and difluoromethanesulfonyl chloride (0.35 g) are added, and the mixture is warmed to room temperature over the course of 3 hours, after-stirred for 4 hours and left to stand for 48 hours. For work-up, water is added and the mixture is stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 91% (0.52 g, 39% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[CH2:25]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[NH2:30])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:32])[CH:29]([NH:30][C:19]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)=[O:21])[CH3:31])[CH3:26]
Reactant: CCOC(=O)C(C)N
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: CCOC(=O)C(C)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 17 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using DL-alanine ethylester hydrochloride instead of 3-methoxypropylamine, to the title compound (23 mg, 17%) which was obtained as a light yellow gum. MS: m/e=410.1 [M+H]+.