Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:30])[CH2:17][CH2:16][C:15]([CH2:28][NH2:29])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:28][C:15]1([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=2)[CH2:16][CH2:17][C:12]([F:11])([F:30])[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and [4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine. LCMS (MH+): m/z=434.1, tR (minutes, Method F)=3.04
Reaction SMILES: C[C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6]C)=[O:5].F[C:33]1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F.N[C@H](C(N)=O)[C@H](CC)C>>[NH2:6][C:4](=[O:5])[C@@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([F:27])[CH:26]=2)=[N:12]1)=[O:10])[C@@H:2]([CH3:31])[CH2:30][CH3:33]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Agent: CC[C@H](C)[C@H](N)C(N)=O
Product: CC[C@H](C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCN(C)C2)C(N)=O

Procedure:
Compound 50 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with L-isoleucine amide. 1H NMR (CDCl3) δ 7.67 (d, J=8.8 Hz, 1H), 7.49-7.55 (m, 1H), 7.37-7.41 (m, 1H), 7.19-7.24 (m, 1H), 5.95 (s, 1H), 5.63 (s, 1H), 4.30-4.33 (m, 1H), 3.59 (s, 2H), 3.20 (s, 2H), 2.75-2.78 (m, 2H), 2.54 (s, 3H), 2.07-2.10 (m, 1H), 1.60-1.67 (m, 1H), 1.22-1.30 (m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H). LCMS (+ESI) m/z=406.2 [M+H]+.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:12][C:11]=2[CH:21]=1>FC(F)(F)C(O)=O>[OH:6][C:7]1[C:8]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][C:10]2[O:15][CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:12][C:11]=2[CH:21]=1
Reactant: CCOC(=O)C1=COc2ccc(O)cc2O1
Reactant: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=COc2cc(C(C)(C)C)c(O)cc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
Add 0.425 cm3 (4.5 mmol) of tert-butanol to a solution of 0.5 g (2.25 mmol) of ethyl 7-hydroxy-1,4-benzodioxin-2-carboxylate in 3 cm3 of trifluoroacetic acid. The whole is stirred for 24 hours at room temperature and, after concentrating to dryness under reduced pressure, the crude product is then purified by chromatography on a silica column (eluant:petroleum ether/diethyl ether 80:20). Ethyl 7-hydroxy-6-tert-butyl-1,4-benzodioxin-2-carboxylate is obtained in a yield of 78%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][C:11]=1[OH:12])=[O:4].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[O:4]=[C:3]1[CH2:2][O:12][C:11]2[CH:10]=[CH:9][C:8]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:6]=2[NH:5]1
Reactant: CCOC(=O)C(C)c1ccc(O)c(NC(=O)CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C

Procedure:
Ethyl 2-(3-(2-chloroacetamido)-4-hydroxyphenyl)propanoate (100 mg, 0.350 mmol) in acetone (10 mL) was added potassium carbonate (59 mg) at room temperature and refluxed for 3 hours. The reaction mixture was cooled to room temperature and added water (15 mL). The mixture was extracted with EtOAc. The organic layer was dried with MgSO4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=2/1.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11]C(OCC1C=CC=CC=1)=O.O.[NH2:24][NH2:25]>C(O)C>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([NH:24][NH2:25])=[O:2]
Reactant: NN
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)OCc1ccccc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(Cl)ccc1N
Yield: 91.7 %

Procedure:
2-benzyloxycarbonylamino-5-chloro-benzoic acid methyl ester (3 g, 9.4 mmol) was dissolved in 30 mL ethanol. Hydrazine hydrate (1.5 mL, 30.0 mmol) was added and the resultant solution was heated at reflux under a nitrogen atmosphere for two hours, at which LCMS analysis showed complete conversion of the ester as well as the removal of the CBz protecting group. The reaction mixture was subsequently concentrated in vacuo to provide 1.6 g of 2-amino-5-chloro-benzoic acid hydrazide (light brown solid, 92% yield): HPLC retention time=2.21; MS (ES) M+H expected 186.0, found 186.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[Cl-].C[Zn+].[CH2:34](Cl)Cl.O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:34])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: ClCCl
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCCC[C@@H]1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)cn1
Temperature: 50 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (2.50 g, 5.95 mmol) in 30 mL of THF under an atmosphere of nitrogen was added methyl zinc chloride (2 M in THF, 5.95 mL, 11.09 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1:1 complex with DCM (0.146 g, 0.179 mmol). The reaction was heated at 50° C. for 18 h, cooled to rt, and slowly treated with water. A beige solid was removed via filtration and the aqueous layer of the filtrate was extracted 2× with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 400.0 for [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:20]([O:19][C:17]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[O:7][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:23][CH:22]=1)=[CH:15][C:14]2=[O:16])=[O:18])[CH3:21]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)c1cccc2c(=O)cc(-c3ccc(O)cc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c(=O)cc(-c3ccc(OCc4ccc5ccccc5n4)cc3)oc12
Temperature: 100 °C
Yield: 64 %

Procedure:
4'-Hydroxy-8-ethoxycarbonylflavone (1 eq.) and 2-chloromethylquinoline (1.1 eq.) were dissolved in DMF, followed by the addition of potassium carbonate (1.2 eq.). The resulting mixture was stirred at 100° C. and, subsequent to the completion of the reaction, was charged into water. The water layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from DMF-ethanol, whereby the title compound represented by the following formula was obtained (yield: 64%). ##STR21##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:18]([O:22][C:23]([N:25]1[CH2:28][CH:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2COc3ccc(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A solution of 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #2, Step E; 5 g, 21.6 mmol) and 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (7.37 g, 43.1 mmol) in MeOH (90 mL) and HOAc (10 mL) was stirred at rt for 2 h. Sodium cyanoborohydride (2.7 g, 43.1 mmol) was added in portions and the resulting dark solution was stirred at rt for 2 h. The solvent was removed in vacuo and the residue was washed with aqueous Na2CO3 (100 mL) and extracted with EtOAc (4×100 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (4.48 g, 54%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.28 (brs, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.15 (s, 1H), 6.13 (d, J=8.4 Hz, 1H), 4.70 (m, 1H), 4.58 (d, J=13.2 Hz, 2H), 4.30 (m, 2H), 4.17 (m, 1H), 4.01 (m, 1H), 3.75 (m, 2H), 1.51 (d, J=6.8 Hz, 3H), 1.47 (s, 9H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].Cl.[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18]Cl)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:15])[CH3:14]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A suspension of 2.94 g of isatin, 4.20 g of 2-diisopropylaminoethyl chloride hydrochloride, and 3.17 g of anhydrous potassium carbonate in 50 ml of toluene was stirred for 4 hours at 90° C. After cooling, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 4.93 g of 1-(2-diisopropylaminoethyl)isatin. The chemical properties of this product are identical with those of the product obtained by Reference Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.B.[O:24]1CCCC1.[OH-].[Na+].OO>O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][OH:24])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: C1CCOC1
Reactant: C=Cc1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 40 °C
Yield: 35.1 %

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-vinyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (1.40 g, 4.45 mmol) was dissolved tetrahydrofuran (20 mL) and treated with borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 8.9 mL, 8.9 mmol). After 2 hours the mixture was treated dropwise with water (5 mL). Then 15% aqueous sodium hydroxide (5 mL) and 30% aqueous hydrogen peroxide was added and the mixture was warmed to 40° C. for 2 hours. The cooled solution was extracted with dichloromethane (3×20 mL) and ethyl acetate (3×50 mL). The combined organics were washed with brine, dried over sodium sulfate, concentrated and the mixture of regioisomers were separated by flash chromatography (1:1 hexanes/ethyl acetate to ethyl acetate gradient) to give 2-chloro-5,11-dihydro-11-ethyl-8-(β-hydroxy)ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.52 g, 35%), m.p. 57°-59° C., and 2-chloro-5,11-dihydro-11-ethyl-8-(α-hydroxy)ethyyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.15 g, 10%), m.p. 65°-67° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[NH:10][N:9]=[C:8]([C:11]([O-:13])=[O:12])[C:7]=1[CH3:14])[CH3:4]>C(O)C.C1COCC1>[CH2:3]([O:5][C:6]1[NH:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[C:7]=1[CH3:14])[CH3:4]
Reactant: CCOc1[nH]nc(C(=O)[O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1[nH]nc(C(=O)O)c1C
Yield: 62.6 %

Procedure:
2 M solution of sodium hydroxide (98 ml, 197 mmol) was added to a solution of 5-ethoxy-4-methyl-1H-pyrazole-3-carboxylate (7.8 g, 39.4 mmol) in ethanol (70 ml) and THF (30 ml). The reaction mixture was refluxed for 3 h and then the solvents were evaporated and water (200 ml) was added to the residue. It was acidified to pH 1 with conc. HCl and extracted three times with EtOAc. The precipitate formed in the extraction was filtered and washed with EtOAc and the filtrate evaporated to dryness affording 4.2 g (62%) of the title compound. LC-MS: [M+1]=171.17.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.BrC1C=CC(O[C@@H]2CCC[C@@H]2N)=CC=1[F:35]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:19][C:20]=1[F:35]
Reactant: N[C@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1

Procedure:
The title compound of Step 7 was prepared according to the general procedure for the synthesis of cis-N-[2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that (1S,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentanamine was used instead of cis-2-(4-bromophenoxy)cyclopentanamine, and the chromatographic purification was carried out with a gradient of 0% to 10% methanol in dichloromethane, to provide the title compound as an off-white solid. Yield: 4.15 g, 10.9 mmol, 54% from (1R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl acetate (5 steps). 1H NMR (500 MHz, CDCl3) δ 1.36 (d, J=6.7 Hz, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.62-1.69 (m, 1H), 1.77-1.90 (m, 3H), 1.92-2.00 (m, 1H), 2.10-2.15 (m, 1H), 3.14 (septet, J=6.8 Hz, 1H), 3.86 (m, 1H), 4.56-4.60 (m, 2H), 6.61 (ddd, J=8.9, 2.8, 1.1 Hz, 1H), 6.70 (dd, J=10.3, 2.8 Hz, 1H), 7.43 (dd, J=8.8, 8.1 Hz, 1H). The absolute configuration of N-[(1S,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl]propane-2-sulfonamide was assigned by analogy to the stereochemistry of compounds in Example 7 and Preparation 6.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]=[CH:5][C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:8][C:7]=1[CH2:19][CH2:20][CH3:21].[Li+].[OH-]>C1COCC1.CO>[CH2:12]([C:11]1[CH:10]=[C:9]([C:15]([F:16])([F:18])[F:17])[CH:8]=[C:7]([CH2:19][CH2:20][CH3:21])[C:6]=1[CH:5]=[CH:4][C:3]([OH:22])=[O:2])[CH2:13][CH3:14]
Reactant: CCCc1cc(C(F)(F)F)cc(CCC)c1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1cc(C(F)(F)F)cc(CCC)c1C=CC(=O)O
Yield: 76.3 %

Procedure:
3-(2,6-Dipropyl-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (343 mg) was reacted with 1N LiOH (5 ml) in THF (10 ml) and CH3OH (5 ml) for 1 hr. The reaction mixture was concentrated in vacuo. Water (30 ml) was added to the resulting residue, which was neutralized with 1N HCl solution. The mixture was extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over MgSO4. The filterate was concentrated in vacuo to yield title compound (250 mg, 82%).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1>CN(C=O)C.C(Cl)Cl>[O:21]1[CH2:22][CH2:23][CH:19]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:20]1
Reactant: IC1CCOC1
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(SC2CCOC2)cc1
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a suspension of methyl 4-sulfanylbenzoate (0.85 g, 5.05 mmol), potassium carbonate (1.39 g, 10.1 mmol) in DMF (10 mL) at room temperature was added 3-iodotetrahydrofuran (1.00 g, 5.05 mmol). The resulting suspension was stirred for 16 hours. The reaction mixture was diluted with DCM (25 mL), filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM (25 mL) and washed with water (3×15 mL) and saturated aqueous brine solution (1×15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 4-tetrahydrofuran-3-ylsulfanylbenzoate (1.03 g, 86%) as a yellow solid. ESI-MS m/z calc. 238.1. found 239.3 (M+1)+; Retention time: 1.47 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.91-7.83 (m, 2H), 7.48-7.39 (m, 2H), 4.16-4.08 (m, 2H), 3.91-3.72 (m, 5H), 3.55 (q, J=7.6 Hz, 1H), 2.49-2.35 (m, 1H), 1.86-1.74 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:21].[ClH:21].[Cl:21][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccnc(Cl)n2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1nccc(NC2CCNCC2)n1

Procedure:
A solution of 4-(2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.2 g, 10.23 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (70 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 213.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH3:22])[CH3:21]
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
p-Hydroxytoluene (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]([CH3:30])[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:13].[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C1COCC1>[CH3:10][N:11]([CH3:30])[C:12]([CH:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:31](=[O:34])[CH:32]=[CH2:33])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:18][CH2:19]1)=[O:13]
Reactant: C=CC(=O)Cl
Reactant: CN(C)C(=O)C1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(C(=O)N(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
Diisopropylethylamine (0.1 ml, 0.7 mmol) was added in one portion to a stirred solution of 1-(4-amino-benzenesulfonyl)-piperidine-4-carboxylic acid dimethylamide (0.15 g, 0.49 mmol) in THF (3 ml) at room temperature. To this mixture was added acryloyl chloride (0.05 ml, 0.58 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue was purified by column chromatography (elution: 40% heptane, 60% ethyl acetate) to give the title compound (0.03 g, 15% yield) as a white solid.
Reaction SMILES: [H-].[K+].[CH:3]([O:6][P:7]([CH2:13][P:14]([O:20][CH:21]([CH3:23])C)(=[O:19])[O:15][CH:16]([CH3:18])C)(=[O:12])[O:8][CH:9]([CH3:11])C)([CH3:5])C.Cl[CH2:25][C:26]1[C:31]([CH2:32]Cl)=[CH:30][CH:29]=[CH:28][N:27]=1>CS(C)=O>[CH2:21]([O:20][P:14]([C:13]1([P:7]([O:6][CH2:3][CH3:5])(=[O:12])[O:8][CH2:9][CH3:11])[CH:25]=[C:26]2[C:31]([CH:30]=[CH:29][CH2:28][NH:27]2)=[CH:32]1)(=[O:19])[O:15][CH2:16][CH3:18])[CH3:23]
Reactant: ClCc1cccnc1CCl
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=CCNC2=C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice bath chilled solution of 35% potassium hydride in mineral oil (5.2 g; 0.045 moles) stirring under argon in 70 ml of DMSO (dry) is added a solution of tetraisopropylmethanediphosphonate (7.82 g; 0.023 moles) in 30 ml of DMSO. On completion of a dropwise addition, the resulting solution is stirred at room temperature for one hour. A solution of 2,3-bis(chloromethyl)pyridine (4.0 g; 0.023 mole) (crude product as isolated by K. Tsuda et.al., Chem Pharm Bull., 1, (1953), 142) in 15 ml of DMSO is slowly added and the reaction mixture is then heated at 90° C. for 1 hour. After cooling, the DMSO is removed under vacuum. 2.1 g (21%) of the desired product is purified via flash chromatography using a 5-15% ethanol in methylene chloride gradient on silica gel.
Reaction SMILES: C(OC(=O)[C:7]([C:30]#[N:31])=[C:8]([NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[NH:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])(C)(C)C>C(Cl)Cl>[F:23][C:22]([F:24])([F:25])[C:20]1[CH:21]=[C:16]([NH:15][C:8]([NH:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:7][C:30]#[N:31])[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=1
Reactant: CC(C)CCNC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)CCNC(=CC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 29.5 %

Procedure:
To a solution of 3-[3,5-bis(trifluoromethyl)phenylamino]-2-cyano-3-(3-methylbutylamino)acrylic acid tert-butyl ester (194 mg, 0.417 mmol) in DCM (2 mL) trifluoroacetic acid (2 mL) was added. After 30 min at room temperature the solution was concentrated, the residue was redissolved in carbon tetrachloride (10 mL) and reconcentrated. The product was purified by flash chromatography (6 g silica gel, gradient of heptane/ethyl acetate). 45 mg (30%) of the title compound was obtained as an oil. LCMS: MH+ =366. This compound was identical by LCMS to the product obtained from solid-phase synthesis.