Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[C:3]([O:7][C:8]([N:10]1[CH2:17][C:16]2[O:15][C:14]([C:18]([OH:20])=[O:19])=[N:13][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:21][O:19][C:18]([C:14]1[O:15][C:16]2[CH2:17][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][C:12]=2[N:13]=1)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1Cc2nc(C(=O)O)oc2C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1nc2c(o1)CN(C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 52.6 %

Procedure:
Iodomethane (0.098 mL, 1.58 mmol) was added to a stirred solution of 4,6-dihydro-pyrrolo[3,4-d]oxazole-2,5-dicarboxylic acid 5-tert-butyl ester (0.10 g, 0.39 mmol) and K2CO3 (0.10 g, 0.78 mmol) in DMF (2 mL). The mixture was stirred at 100° C. for 5 minutes under microwave irradiation, diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 4,6-dihydro-5H-pyrrolo[3,4-d]oxazole-2,5-dicarboxylic acid 5-(1,1-dimethylethyl) 2-methyl ester (0.055 g, 96% yield) as a pale yellow solid that was used in the next step without further purification. C12H16N2O5 LCMS: Rt 2.31, m/z 269 [M+H]+ (using method, LC-MS Method 4).
Reaction SMILES: [Li+:1].CCC[CH2-].[CH:6]([NH:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([N-]C(C)C)(C)C.[Li+].[CH2:37]=[O:38]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[Li+:1].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]([CH2:37][OH:38])([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C=O
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20 %

Procedure:
Lithium diisopropylamide was prepared by the addition of 2.45M N-butyllithium (69 mL, 168.8 mmol) in hexanes to a solution diisopropylamine (24 mL, 171.2 mmmol) in tetrahydrofuran (40 mL) at 0° C. with stirring for 20 minutes. Then a solution of N-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (18 g, 78.5 mmol) in tetrahydrofuran (35 mL) was added to the solution of lithium diisopropylamide over 15 minutes to form a slurry, followed by hexamethylphosphoramide (2 mL). The resulting solution was stirred for 25 minutes, then stream of gaseous formaldehyde (prepared by heating paraformaldehyde (16.4 g, 189 mmol) at 175-200° C. over 5-10 minutes) was passed through the solution, which was allowed to immediately warm to room temperature. The slurry was concentrated at ambient temperature, acidified to pH 4 with 6M hydrochloric acid, saturated with solid sodium chloride, and extracted with ethyl acetate (8×100 mL). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo. Chromatography over silica gel, and eluting with 1% methanol/methylene chloride, afforded N-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid as a white solid (4 g, 20%). mp 156.6-157.3° C.; 1HNMR (DMSO-d6) δ 1.25-1.37 (m, 2H), 1.38 (s, 9H), 1.85 (dm, J=13.7 Hz, 2H), 2.78-2.94 (br m, 2H), 3.41 (s, 1H), 3.70 (dm, J=12.8 Hz, 2H), 4.87 (br s, 1H), 12.34 (s, 1H); Anal. Calcd. for C12H21NO5 : C, 55.58; H, 8.16; N, 5.40. Found: C, 55.72; H, 8.10; N, 5.53.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[C:34]2C=CC(F)=C[CH:35]=2)[CH2:23][CH2:22]1.C(B1OC(C)(C)C(C)(C)O1)=C>>[CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:18])[F:19])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[CH:34]=[CH2:35])[CH2:25][CH2:26]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Agent: C=CB1OC(C)(C)C(C)(C)O1
Product: C=Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine using vinylboronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=504, obsd.=504).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[Cl:35])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCc1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4Cl)cc3)c2cc1OC
Yield: 117.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-chlorophenyl)methanol (37 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (92 mg, yield 100%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9]O)[OH:8])[OH:6])[OH:4].O.[NH2:12][NH2:13]>CO>[CH:9](=[N:12][NH2:13])[C@@H:7]([C@H:5]([C@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: NN
Solvent: CO
Solvent: O
Product: NN=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reaction time: 8 h

Procedure:
A solution of 2.0 g of L-arabinose in 5 ml of methanol and 5 ml of hydrazine hydrate was stirred overnight and then evaporated in vacuo. A 5 ml portion of methanol was added to the residue. After standing overnight the oil solidified. The solid was collected and dried, giving 1.5 g of L-arabinose hydrazone.
Reaction SMILES: [Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]2[N:6]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].CI.[CH2:36](Cl)Cl>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]2[N:6]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:7](=[N:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[N:8]([CH3:36])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cn2c(Nc3ccc(OC)cc3)nc3cc(Cl)c(Cl)cc32)cc1
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(Cn2c(=Nc3ccc(OC)cc3)n(C)c3cc(Cl)c(Cl)cc32)cc1
Reaction time: 2 h

Procedure:
To a solution of the title compound of Example 19, Step B (0.45 mmol, 203 mg) in DMF (3 mL) was added NaH (0.54 mmol, 21 mg of 60% suspension in mineral oil). After 10 min MeI (0.9 mmol, 56 μL) was added and the reaction was allowed to stand at ambient temperature for 2 h. Aqueous workup with CH2Cl2/saturated NaHCO3, followed by flash chromatography on silica eluting with 30% and 40% EtOAc in hexanes, afforded the product as a white solid. LC-MS (ESI, Method B): 1.93 min. m/z 470.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([NH:21][C:22]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=3[F:30])[N:11]2[C@@H:14]([CH3:20])[CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:7][N:6]=1)[CH3:3].CC(NC1N=C2C(N=C(NC3C(F)=CC(F)=CC=3F)N2[C@H](C)CCC(OC)=O)=CN=1)C>>[CH3:3][CH:2]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([NH:21][C:22]3[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=3[F:28])[N:11]2[C@H:14]([CH3:20])[CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:7][N:6]=1)[CH3:1]
Reactant: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n([C@@H](C)CCC(N)=O)c2n1
Agent: COC(=O)CC[C@@H](C)n1c(Nc2c(F)cc(F)cc2F)nc2cnc(NC(C)C)nc21
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n([C@H](C)CCC(N)=O)c2n1
Yield: 57 %

Procedure:
The title compound was prepared as (4S)-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}pentanamide with methyl(4R)-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}pentanoate (500 mg, 1.15 mmol) to give the title compound (273 mg, 57%): ES-MS (m/z) 422.3 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2>>[F:22][C:11]([F:10])([F:21])[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:16][CH2:15]2
Reactant: O=C=Nc1cccnc1
Reactant: FC(F)(F)c1ccc2c(c1)CCN2
Product: O=C(Nc1cccnc1)N1CCc2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 5-trifluoromethylindoline (D43) to give (E22) (0.12 g, 38%) m.p. 188°-189° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][C:21]=1[Cl:26]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Clc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCCCCC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a dry 250 ml three-neck flask with thermometer, reflux condenser (under nitrogen) and dropping funnel, 17.73 g of AlCl3 (0.133 mol) were suspended in 50 ml of 1,2-dichlorobenzene and cooled to 0° C. While stirring vigorously, 31.6 ml of lauroyl chloride (0.133 mol) were slowly added dropwise (1 hour). The mixture was then allowed to cool until the temperature had reached room temperature. Subsequently, the mixture was heated gradually to approximately 100-105° C., in the course of which a change in colour was evident (from ochre to dark red). Subsequently, the mixture was stirred at this temperature for 5 hours and left to stand overnight at room temperature. To separate the complex, this mixture was cautiously poured onto 200 g of ice (5% HCl) while stirring. The mixture became a mustard-coloured paste which was extracted in ethyl acetate. The organic layer was then removed in a separating funnel and washed to neutrality with saturated sodium hydrogencarbonate solution (2×50 ml) and water. After drying over sodium sulphate, the ethyl acetate was evaporated off. The remaining 1,2-dichlorobenzene was distilled off under reduced pressure. The residue was chromatographed through a column (length=20 cm, diameter=5 cm) on silica gel (Merck 0.040-0.063 nm) with dichloromethane as the eluent.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([CH3:35])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3([C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:29])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[C:9]([CH3:35])=[N:10][O:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3([C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:29])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1N

Procedure:
{5-[4′-(1-Methanesulfonylaminocarbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4-yl}-carbamic acid tert-butyl ester (0.25 g, 0.49 mmol)) in CH2Cl2 (2 mL) and TFA (2 mL) was stirred overnight then poured into EtOAc/NaHCO3 (aq). The organic layer was concentrated to yield the title compound that was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:7]2=[O:24])(=[O:3])[CH3:2].CO.[BH4-].[Na+]>C1COCC1>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:16])([F:15])[F:17])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])[C:7]2=[O:24])[CH3:2]
Reactant: CC(=O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Yield: 72.8 %

Procedure:
A solution of N-(6-acetyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (12.1 g, 33.1 mmol) in THF (150 mL)/MeOH (150 mL) under nitrogen was treated with sodium borohydride (25.0 g, 660 mmol) portionwise over 18 h at r.t. The suspension was then poured into a mixture of ice/concentrated EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel 60, DCM/MeOH 9:1) affording colorless crystals, which were recrystallized in EtOAc to provide N-[6-(1-hydroxy-ethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (8.85 g, 24.1 mmol, 73%) as a white powder, m.p. 263-268° C., 1H-NMR (DMSO-d6, 400 MHz) 8.41 (s, 1H), 7.49 (s, 1H), 5.66 (m, 1H), 5.03 (br s, 1H), 3.18 (s, 3H), 1.36 (d, J=6.2 Hz, 3H).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1Br)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>COCCOC>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][C:25]([F:24])([F:37])[F:36])[CH:11]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 84.3 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid-t-butyl ester (5.1 g, 16.71 mmol) in DME (60 ml)/2M Na2CO3 (29.25 ml, 58.50 mmol) was treated with 2-trifluoromethoxyphenylboronic acid (5.16 g, 25.08 mmol), and Pd[PPh3]4 (3.87 g, 3.33 mmol) in a microwave oven at 150° C. for 15 min. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 8-10% ethyl acetate/hexanes gradient to afford 4.65 g of colorless oil (t-butyl ester). This material was dissolved in 4N HCl/dioxane (40 ml) and stirred at 60° C. for 2 h and then at rt overnight. Concentration under reduced pressure afforded the product as colorless oil (4.17 g, 24%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28])(=[O:23])=[O:22]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:25]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1ccccc1Cl
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-chloro-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 6 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light red foam (25%). MS (ESI): m/z=527.066 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7](O)[CH3:8])[N:5]=[C:4]([CH3:10])[CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C(O)(=[O:22])C>CC(O)CC>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:3]2[C:4]([CH3:10])=[N:5][N:6]([CH2:7][CH2:8][OH:22])[C:2]2=[O:1])=[CH:14][CH:13]=1
Reactant: CC(=O)O
Reactant: Cc1cc(O)n(C(C)O)n1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCC(C)O
Product: CC1=NN(CCO)C(=O)C1=Cc1ccc(O)cc1
Reaction time: 16 h

Procedure:
2.85 g of 5-hydroxy-1-hydroxyethyl-3-methyl-1H-pyrazole and 2.45 g of 4-hydroxybenzaldehyde in 30 mL of 2-butanol were allowed to reflux. After 16 h, the reaction mixture was cooled, then poured onto 100 mL of glacial acetic acid and filtered. This gave 3.3 g of a by-product, probably the acetal of the following formula:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:3]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:13]=2)[CH:3]=1
Reactant: Cc1ccc(N)c(-c2nc(C(F)(F)F)cs2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)C2CC2)c(-c2nc(C(F)(F)F)cs2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a stirred solution of the product obtained in Step E (0.46 g, 1.8 mmol) and triethylamine (250 μL, 1.8 mmol) in anhydrous tetrahydrofuran (THF, 15 mL) cooled to 0° C. was added dropwise a solution of cyclopropanecarbonyl chloride (160 μL, 1.8 mmol) in THF (5 mL). The mixture was stirred at 0° C. for 30 min and then at room temperature overnight. The reaction mixture was filtered and the solids were washed with ethyl acetate. The filtrate was evaporated to dryness and the residue purified by recrystallization from hexane to yield 0.41 g (71% yield) of the title compound as a white solid melting at 155°-156° C. 1H NMR (400 MHz, CDCl3) δ 11.75 (s,1H), 8.61-8.63 (m,1H), 7.76 (s, 1H), 7.55 (s,1H), 7.26-7.27 (m,1H), 2.37 (s,3H), 1.56-1.62 (m,2H), 1.07-1.13 (m,2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:30])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([Cl:30])=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)O)cc(Cl)c1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Cl)cc(Cl)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 4-benzyloxy-3-chloro-5-methoxybenzoic acid (541 mg), toluene (5.4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (578 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])/[C:24]#[N:25])=[C:19]([F:35])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:35])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(F)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(F)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 44.4 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(2,3-difluoro-phenyl)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 62a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([CH3:27])[CH:23]=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: Cc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)c1c[nH]c2c(-c3cc(C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A41) the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5]2[C:7]([O:14][CH3:15])=[CH:8][CH:9]=[C:10]([CH2:11][C:12]#[N:13])[C:4]=2[O:3]1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].[OH2:23].Cl>C(#N)C>[C:12]([C:11]([C:10]1[C:4]2[O:3][C:2]([CH3:16])([CH3:1])[O:6][C:5]=2[C:7]([O:14][CH3:15])=[CH:8][CH:9]=1)([CH2:7][CH2:5][C:4]([O:3][CH3:2])=[O:23])[CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])#[N:13]
Reactant: O
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CC#N)c2c1OC(C)(C)O2
Agent: Cl
Solvent: CC#N
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c2c1OC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of Compound 12a (9.0 g, 41 mmol) obtained in Step A in acetonitrile (135 mL) were added a 40% methanolic solution of Triton B (1.9 mL, 4.1 mmol) and methyl acrylate (37 mL , 410 mmol), and the mixture was stirred at room temperature for 30 minutes. Water and 1 mol/L hydrochloric acid were added, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=5/2) to give Compound 12b (11 g, 68%) as a pale yellow oil.