Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Ca+2].[Cl-].[Cl-].[Al+3].[Cl-].[Cl-].[C:28]1(C)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCCCCCCCCC>[C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:14]=[CH:13][C:11]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([N:7]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: Nc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCCCCCCC
Agent: [Al+3]
Agent: [Ca+2]
Product: c1ccc(N(c2ccccc2)c2ccc(Nc3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)cc1
Temperature: 0 °C
Yield: 66.9 %

Procedure:
In a 500-ml four-necked flask were charged 68 ml of tridecane (boiling point: 234° C.) as a solvent and 130.2 g (0.50 mol) of 4-diphenylaminoaniline, followed by the addition of 15.4 g (0.138 mol) of anhydrous calcium chloride and 18.5 g (0.138 mol) of anhydrous aluminum chloride under stirring. The resulting mixture was reacted at 210 to 220° C. for 3 hours under a nitrogen atmosphere. After cooling, the reaction mixture was added with 114 ml of toluene, followed by charging in 144 g of ice water. The resulting mixture was stirred and allowed to stand, and then the resulting water layer was separated out. The organic layer was washed successively with 90 ml of a 5% aqueous solution of hydrochloric acid, 60 ml of a 5% aqueous solution of sodium bicarbonate and 60 ml of water. After removal of the organic solvent by distillation under reduced pressure, 72 ml of isopropyl alcohol was added to the residue and the mixture was crystallized overnight at −3 to −8C. The resulting crude crystals were collected by filtration, washed with 27 ml of isopropyl alcohol and then dried, whereby 84.2 g (yield: 66.9%) of the title compound was obtained as pale yellow crystals. As a result of HPLC. analysis (column: YMC-A-312, detection UV: 280 nm, flow rate: 1.0 ml/min, eluent: methanol/tetrahydrofuran=99/1), the compound was found to have a purity of 99.7%.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:12])[CH2:8][CH2:9][C:10]#[CH:11].C(=O)(O)[O-].[Na+]>CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:7]([O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:8][CH2:9][C:10]#[CH:11]
Reactant: C1=COCCC1
Reactant: C#CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: C#CCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
3,4-Dihydro-2H-pyran (5.0 g) was added dropwise to an ice cooled mixture of 4-pentyn-1-ol (5.0 g) and 4-methylbenzenesulfonic acid (0.512 g). The resultant mixture was stirred at room temperature for 4 hours. Solid sodium bicarbonate (1.0 g) was added and the mixture was stirred for 10 minutes, then filtered and washed with diethyl ether. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give 2-(pent-4-ynyloxy)tetrahydropyran (7.72 g) as a clear oil.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(OCc2c(-c3cccnc3)noc2C)nc1
Reactant: CC(C)N
Product: Cc1onc(-c2cccnc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 83 %

Procedure:
As described for example 155, 6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (130 mg, 0.4 mmol), was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (112 mg, 83%) which was obtained as an off white solid. MS: m/e=353.0 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1.O>[C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1ccc2cc(C(=O)NC(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 14.1 %

Procedure:
N-tert-Butyl indole-5-carboxamide was dissolved in dry THF and solution was cooled to −78° C. Butyllithium was added dropwise with continuous stirring. The reaction mixture was stirred at −78° C. for 40 minutes followed by dropwise addition of acetyl chloride. After addition was complete, the reaction mixture was stirred at −78° C. for 30 minutes and then stirred for 1 hour at room temperature. The reaction mixture was diluted with water and organic phase separated. The aqueous phase was saturate with sodium chloride and was extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatrography to afford the title compound as a white solid (14.1% yield), melting point=186.8° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[CH2:25]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1)[CH:26]=[CH2:27].CCN(C(C)C)C(C)C>C1COCC1>[CH2:25]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:31][CH:30]=1)[CH:26]=[CH2:27]
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: C=CCOc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)OC)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.6 %

Procedure:
To a suspension of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (500 mg, 1.38 mmol) in THF (5 mL) was added (4-(allyloxy)phenyl)methanamine (275 mg, 1.38 mmol) and iPr2NEt (0.96 mL, 5.51 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum. The residue was purified via silica gel column (EtOAC/Hexanes=4:1) to give methyl 4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.2 g, 30%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([O:12]C)=[O:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.Cl>O>[C:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc([N+](=O)[O-])c(C(=O)O)s1
Temperature: 75 °C
Yield: 96.6 %

Procedure:
LiOH monohydrate (0.122 g, 2.90 mmol) was dissolved in 1 mL water and added to methyl 5-tert-butyl-3-nitrothiophene-2-carboxylate (0.235 g, 0.966 mmol) in 3 ml of a 3:1 mixture of THF:MeOH. The resulting mixture was heated at 75° C. for 5 hours. The reaction was cooled down to room temperature, acidified with 1N HCl, extracted with ethyl acetate, and the crude product was recrystallized from dichloromethane:hexane to afford 0.214 g of 5-tert-butyl-3-nitrothiophene-2-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:40][CH:39]=1)[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=2)[NH:16][C:15]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:89]1[CH2:94][CH2:93][O:92][CH2:91][CH2:90]1>C(Cl)Cl.CO.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:89]3[CH2:94][CH2:93][O:92][CH2:91][CH2:90]3)=[O:25])[CH:21]=2)[NH:16][C:15]=1[C:26]1[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)[CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][S:45]([CH3:48])(=[O:46])=[O:47])=[CH:40][CH:39]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OCc2ccccc2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 33.4 mg (0.050 mmol) of [3-[2-[benzyloxycarbonyl-[4-[4-(methanesulfonylamino)phenyl]butyl]amino]-ethyl]-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid, 26.0 mg (0.050 mmol) of PyBOP reagent, 0.010 mL (7.3 mg, 0.072 mmol) of triethylamine, 0.0065 mL (6.5 mg, 0.075 mmol) of morpholine, and 0.0400 mL of dry methylene chloride was stirred under nitrogen at room temperature in a stoppered flask. After 5.5 hours, the solution was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the crude product by preparative tlc on 2 1000-micron silica gel GF plates (developed in 93:7 CH2Cl2) afforded a quantitative yield amorphous, white solid; homogeneous by TLC in 95:5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=737.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[CH:21]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[O:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]([C:5]([OH:7])=[O:6])=[CH:9][C:10]=1[CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(C)c(Oc2ccc(OC)c(C(C)C)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Oc2c(C)cc(C(=O)O)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a solution of methyl 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzoate (8.53 g, 16.7 mmol, intermediate for the synthesis of Example 19-3) in methanol (60.0 mL) at 0° C. was added a solution of 1 N NaOH (28.15 mL, 28.15 mmol). The reaction mixture was stirred at room temperature for 16 h and acidified with cold concentrated HCl. The reaction mixture was extracted with ethyl acetate (10.0 mL) and the organic layer was dried over MgSO4. The solvent was removed under reduced pressure to afford 4-(3′-iso-propyl-4′-methoxyphenoxy)-3,5-dimethylbenzoic acid as a pink solid (1.38 g, 78%): 1H NMR (300 MHz, DMSO-d6): δ 12.88 (s, 1 H), 7.76 (s, 2 H), 6.85 (m, 1 H), 6.75 (m, 1 H), 6.34 (m, 1 H), 3.73 (s, 3 H), 3.20 (m, 1 H), 2.11 (s, 6 H), 1.12 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (17:3); Rf=0.00.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[OH:26].C(N(CC)CC)C.Cl.C(N(CC)CC)C>O1CCCC1>[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[O:26][C:9](=[O:10])[CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)CC(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OC(=O)CC(c1ccccc1)c1ccccc1
Yield: 91.2 %

Procedure:
Forty-six and thirty-seven hundredths grams (a 10% excess) of 3,3-diphenylpropionic acid chloride in 120 ml tetrahydrofuran are placed into a 500 ml round-bottom flask which is equipped with a mechanical agitator. Eighteen and three-tenths grams 2,6-dimethylphenol with 16.7 grams triethylamine in 150 ml tetrahydrofuran are added, dropwise, to this solution while stirring. The mixture is stirred for 12 hours at room temperature. The precipitated triethylamine-hydrochloride is sucked off and the tetrahydrofuran is evaporated in vacuo. The residue is taken up in ether and washed three times with water. The solvent is dried with sodium sulfate and then evaporated in vacuo. There remain 45.0 grams 3,3-diphenylpropionic acid-2,6-dimethylphenyl ester [91.2% yield]. Forty-five grams of this ester are dissolved in a 500 ml flask in 200 ml nitrobenzene. Eighteen and two-tenths grams aluminum chloride are added and the substance is stirred, excluding any humidity, with a KPG agitator. The mixture is heated to 100° C. and the components are left to react at this temperature for 1 day. The nitrobenzene is distilled off in vacuo, the residue is taken up with ether and crushed ice is added. Subsequently, the ether phase is washed well with water, dried with sodium sulfate and the ether is evaporated except for a small amount. Thirty-two grams [71.3%] 4-hydroxy-3,5-dimethyl-β,β-diphenylpropiophenone crystallize out. Ten grams of this compound are dissolved in 80 ml dry acetone for the etherification and 25 grams water-free potash (100% excess) are added. Twelve and twenty-five hundredths grams (200% excess) diethylamine-ethylchloride, dissolved in 150 ml acetone, are added dropwise, with the exclusion of humidity, to this solution. The solution is boiled under reflux for 1 day. The potash is filtered off, the acetone evaporated in vacuo and the residue taken up in ether. The ether solution is washed in water and dried with sodium sulfate. The hydrochloride salt is precipitated with ethereal hydrochloric acid. After recrystallization from a methanol/ether solution, 9.55 grams [67.8%] 4-[2-(N,N-diethylamino)-ethoxy] -3,5-dimethyl-β,β-diphenylpropiophenone hydrochloride (Melting point of 95°-97° C.) and 4-[2-(N,N-diethylamino)-ethoxy] -3,5-dimethyl-β,β-diphenylpropiophenone fumarate (Melting point 226° C. [decomposition]), are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:16]=[C:15]([NH:17]CC4C=CC(OC)=CC=4OC)[N:14]=[C:13]([N:29]4[C@H:34]([C:35]([F:38])([F:37])[F:36])[CH2:33][CH2:32][C@H:31]([C:39]([NH:41][CH:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[O:40])[CH2:30]4)[CH:12]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.FC(F)(F)C(O)=O.CCCCCC>CCOC(C)=O>[NH2:17][C:15]1[N:14]=[C:13]([N:29]2[C@H:34]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:32][C@H:31]([C:39]([NH:41][CH:42]3[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]3)=[O:40])[CH2:30]2)[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([NH2:1])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[N:16]=1
Reactant: COc1ccc(CNc2nc(-c3ccc4c(N)n[nH]c4c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
To cis-1-[6-(3-amino-1H-indazol-6-yl)-2-({[2,4-bis(methyloxy)phenyl]methyl}amino)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (250 mg, 0.38 mmol) was added trifluoroacetic acid (TFA) (6 mL). After 3 hours, LCMS analysis indicated the reaction to be completed. The reaction mixture was concentrated under vacuum, and the resulting residue was co-evaporated from toluene (2×50 mL), then from CH3CN (50 mL). To the resulting pink solid was added a saturated aqueous NaHCO3 solution and EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. This material was purified by flash chromatography (gradient: 100% CH2Cl2 to 90:10:1 CH2Cl2:CH3OH:NH4OH). The cleaner fractions were combined and concentrated under vacuum to afford a yellow solid. This material was dissolved in EtOAc (˜2 mL), and the resulting solution was transfered to a microwave vial. The vial was capped, and heated to 70 C. Hexane was added dropwise until the solution became cloudy, then the mixture was allowed to cool to room temperature. A spatula was used to scrap the solid, and the mixture was filtered. The collected pink solid was washed with hexanes and a white solid precipitate from the filtrate. This white solid was collected by filtration to afford the desired product (35 mg). LC-MS (ES) m/z=503 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.05-1.34 (m, 5H), 1.56 (m, 1H), 1.63-1.85 (m, 7H), 2.07 (m, 1H), 2.33, (m, 1H), 3.06 (bs, 1H), 3.53 (m, 1H), 5.39 (s, 2H), 6.29 (s, 2H), 6.78 (s, 1H), 7.63 (dd, J=8.5, 1.1 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.99 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[NH:19][C@@H:18]([C:20]([OH:22])=[O:21])[C:17]([CH3:24])([CH3:23])[S:16]2)=[CH:11][CH:10]=1>O>[C:1]([N:19]1[C@@H:18]([C:20]([OH:22])=[O:21])[C:17]([CH3:24])([CH3:23])[S:16][C@H:15]1[C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)SC(c2ccc(Cl)cc2)N[C@H]1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccc(Cl)cc1
Reaction time: 0.13 h

Procedure:
5.6 ml of acetic anhydride are given to a suspension containing 2.71 g (10 mmoles) of 2-(4-chlorophenyl)-5,5-dimethylthiazolidine-4(S)-carboxylic acid in 5.6 ml of hot water and the mixture is kept at 100° C. for 8 minutes. A complete solution is obtained. On cooling, the product precipitates to give the title compound in a yield of 2.39 g (76.1%) which is recrystallized from ethanol by adding water, m.p.: 203°-205° C., [α]D22 =+111.5° (c=1.44, dimethylsulphoxide).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH:5][C@H:6]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@H:8]([CH2:9][CH2:10][C@@H:11]3[C:27]2=[CH:26][CH2:25][C@@:24]2([CH3:32])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7]1>CC(O)=O>[C:1]([OH:4])(=[O:3])[CH3:2].[OH:5][C@H:6]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@H:8]([CH2:9][CH2:10][C@@H:11]3[C:27]2=[CH:26][C:25](=[O:3])[C@@:24]2([CH3:32])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)C3=CC[C@]12C
Solvent: CC(=O)O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)C3=CC(=O)[C@]12C
Temperature: 60 °C
Yield: 116.2 %

Procedure:
CrO3 (8.0 g, 100 wt %, 80.0 mmol) is added to a solution of Compound 1.19 (8.0 g, 18.6 mmol) in AcOH (150 mL). The resulting reaction mixture is heated at 60° C. for about 24-36 h. Upon complete disappearance of the precursor, acetic acid is evaporated under vacuum, and the crude material is dissolved in diethyl ether (400 mL). The organic layer is washed with water (2×100 mL), saturated brine solution (100 mL) and dried over MgSO4 (40 g). The solvent is removed under vacuum and the crude material is purified by column chromatography [49(W)×600(L) mm, 60-120 Mesh silica, 120 g] eluting with ethyl acetate/hexane (1:5) [10 mL fractions, 3 mL/min elution, monitored by TLC and detected with UV light (254 nm) lamp; Rf for Compound 1.20=0.28 and Rf for Compound 1.19=0.61 in EtOAc/Hexane (1:4)] to afford Compound 1.20 (5 g, 60.5% yield) as a colorless solid. Table 9 describes the measured properties of the product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:9][C:10]1[C:15]([C:16](OCC)=[O:17])=[C:14]([CH3:21])[N:13]=[C:12]([S:22][CH3:23])[N:11]=1)[CH3:8]>C1COCC1>[CH2:7]([NH:9][C:10]1[C:15]([CH2:16][OH:17])=[C:14]([CH3:21])[N:13]=[C:12]([S:22][CH3:23])[N:11]=1)[CH3:8]
Reactant: CCNc1nc(SC)nc(C)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1nc(SC)nc(C)c1CO
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a lithium aluminum hydride solution (LAH, 1.0 M solution in THF, Aldrich, 450 mL) was added a solution of ethyl 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (57 g) in THF (1000 mL). The reaction mixture was stirred overnight. After cooling to 0° C., the reaction mixture was cautiously quenched with a 1:9 mixture of H2O/THF until gas evolution has ceased, then diluted with H2O (500 mL) and stirred well for 2 h. The resulting slurry was extracted with ethylacetate several times. The aqueous layer was then filtered through Celite and washed with ethylacetate again. The combined organic layers were washed with brine, dried and concentrated under reduced pressure to give 41.0 g (85% yield) of [4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]methanol as a light yellow crystal, which was used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][C:19](=[N:22][O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CS(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][C:8]([N:16]2[CH2:17][CH2:18][C:19](=[N:22][O:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[CH2:20][CH2:21]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1C(F)(F)F
Temperature: 110 °C
Reaction time: 18 h

Procedure:
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (0.2 g, 0.78 mmol), 2d (0.2 g, 0.71 mmol), and diisopropylethylamine (0.2 mL, 1.2 mmol) were combined in 2 mL of DMSO and stirred at 110° C. for 18 h. The mixture was cooled to room temperature, diluted with aqueous NaHCO3 (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated under vacuum to afford the crude 57a.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1.[H-].[Na+].[Br:36][C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[C:40]([O:47][CH3:48])=[CH:39][C:38]=1[CH2:49]Br.O>CN(C)C=O.C(OCC)(=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH2:6][N:7]([CH2:49][C:38]1[CH:39]=[C:40]([O:47][CH3:48])[C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:37]=1[Br:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CC(C)(C)OC(=O)CCCOc1cnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1
Reactant: COc1cc(CBr)c(Br)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)c(Br)cc1C(F)(F)F
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate (300 mg) is dissolved in N,N-dimethylformamide (4 ml) and thereto is added sodium hydride (60%) (33 mg) under ice-cooling, and the mixture is stirred for 15 minutes and thereto is added 1-bromo-2-bromomethyl-4-methoxy-5-trifluoromethyl-benzene (327 mg) and the mixture is stirred at room temperature overnight. Thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-methoxy-4-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (256 mg). MS (m/z): 746/748 [M+H]+