Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])O.C(Cl)(Cl)Cl.S(Cl)(Cl)=O>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:8][CH2:11][CH2:13][N:14]=2)=[CH:9][CH:10]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Oc1ccc(C2=NCCO2)cc1
Temperature: 60 °C
Reaction time: 1.8 h

Procedure:
Phenyl ester of 4-hydroxybenzoic acid (19.28 grams, 0.09 mole) and monoethanolamine (5.55 grams, 0.0909 mole) are added to a reactor and stirred as a powder under a nitrogen atmosphere. Heating commences and fourteen minutes later, a temperature of 150° C. is achieved. After 108 minutes at 150° C., the reactor is cooled to 60° C., then chloroform (100 milliliters) is added. After boiling for 5 minutes, the chloroform is decanted off, and a second portion (100 milliliters) of chloroform is added. After boiling for 5 minutes, the chloroform is again removed by decantation. A third portion (100 milliliters) of chloroform is added followed by boiling for 5 minutes and decantation. Ethyl acetate (100 grams) is added to the powder product remaining in the reactor and stirring under a nitrogen atmosphere commences to provide a fine slurry. Thionyl chloride (21.41 grams, 0.18 mole) dissolved in ethyl acetate (50 grams) is added to the reactor inducing an exotherm to 29° C. three minutes later. The reactor is allowed to cool to 25° C and maintained therein for 237 minutes. The product is filtered off and the product recovered on the filter is washed with two portions (50 milliliters) of ethyl acetate. The filter cake of N-(2-chloroethyl)-4-hydroxybenzamide slightly damp with ethyl acetate is added to a beaker containing deionized water (300 milliliters) and stirred to a solution. Five percent aqueous sodium hydroxide solution is added dropwise to the solution until the pH reached 7. At this time, a white slurry of crystalline product is formed and is stirred for an additional ten minutes before filtration. The product is washed on the filter with two portions (50 milliliters) of deionized water, removed, added to a porcelain dish and then dried in a vacuum oven at 50° C. and 1 mm Hg for two hours. After this time, the product is removed and boiled in acetone (300 milliliters) After cooling to 25° C. 200 milliliters of the acetone is removed by rotary evaporation. The resulting product is recovered by filtration, washed on the filter with cold acetone (25 milliliters), removed, added to a porcelain dish and then dried in a vacuum oven at 50° C. and 1 mm Hg to a constant weight of 9.02 grams of crystalline white powder. Fourier transform infrared spectrophotometric analysis of a potassium bromide pellet of the product reveals the presence of the expected oxazoline >C=N--absorbance at 1636 cm-1, the hydroxyl group O--H stretching at 3442 cm-1 and the out-of-plane C--H bending vibration at 839 cm-1 indicative of para-disubstitution. An absorption characteristic of the oxazoline ring is observed at 945 cm-1. Proton magnetic resonance spectroscopy (250 MHz) further confirms the product structure as the 2-(4-hydroxyphenyl)oxazoline.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](=[O:28])=[O:27].CC(C)=O.[Li+:33].CC([N-]C(C)C)C.C1COCC1>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[C:11]2[C:26]([O-:28])=[O:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:33]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)nc(-c3ccccc3)nc21
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C([O-])c1cc2c(Cl)nc(-c3ccccc3)nc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of the N-sulfonyl compound 24 (1.504 g, 4.07 mmol) in dry THF (150 mL), cooled by dry ice/acetone, is added LDA-THF (3.8 mL, 1.5M solution in cyclohexane, 5.7 mmol). After 45 min, carbon dioxide is bubbled into the solution for 5 min, then the cooling bath is removed. When the solution has reached ambient temp., the solvents are evaporated, yielding 1.73 g of the salt 27 [containing (iPr)2NCO2Li] as pale yellow solid. The salt is used without purification in the next step. 1H-NMR (D6-DMSO): δ=6.44 (s, 1H), 7.50-7.75 (m, 6H), 8.33-8.40 (m, 2H), 8.53 (dd, J=8.0, 1.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20](O)=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1.CN(C(ON1N=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:39]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:40][C:20]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:24])([F:23])[F:1])[CH:5]=2)[CH:19]=[CH:18]3)=[O:21])[CH:34]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a mixture of 2-(3-(trifluoromethoxy)phenyl)quinoline-8-carboxylic acid (1 gram, 3.3 mmol) and HATU (1.71 g, 4.5 mmol) in DMF (30 mL) was added 3-aminopyridine (423 mg, 4.5 mmol) followed by DIPEA (1.03 mL, 6 mmol). The mixture was stirred 18 hours, water (150 mL) was added and the resulting precipitate was collected by filtration. The crude material was purified by chromatography (silica gel, gradient 0 to 100% Ethyl acetate in Pentane), the desired fraction was concentrated and the product recrystallized from methanol to obtain the product as a white solid (550 mg, 45% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cc[nH]c23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2NCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
7-(4-t-Butyloxycarbonylpiperazin-1-yl)indole (200 mg, 0.67 mmol) is dissolved in acetic acid (4 mL). To the solution, sodium cyanoborohydride (84 mg, 1.33 mmol) is added. The reaction mixture is stirred for about 2 hours at r.t. The mixture is then diluted with DCM and NaOH (1M) is added. The organic layer is separated, dried and concentrated. The residue is chromatographed on the silica gel and the product containing fractions are combined to give about 93 mg of the 7-(4-t-butyloxycarbonylpiperazin-1-yl)-2,3-dihydroindole (46%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:19][CH:20]([CH3:24])[C:21](Br)=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:21](=[O:22])[CH:20]([Br:19])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)C(=O)Br
Reactant: OCCOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)OCCOCc1ccccc1
Temperature: -5 °C

Procedure:
15.2 g of 2-benzyloxyethanol and 10.6 g of triethylamine were dissolved in 150 ml of toluene, and the solution was cooled to -5° C. A solution of 21.6 g of 2-bromopropionylbromide in 30 ml of toluene was added dropwise thereto at -5° to 0° C. with stirring. The reaction mixture was further maintained at room temperature for two hours. The mixture was then washed successively with 1% strength by weight sodium hydroxide solution and water, and the toluene solution was then dried and filtered. The toluene was distilled off under reduced pressure, and the end product of 2-benzyloxyethyl-2-bromopropionate was obtained in a yield of 26.7 g (nD20.5 1.5182)
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([O:18][C:19](=[O:30])[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([CH2:28]Br)=[CH:23][N:22]=1)([CH3:17])([CH3:16])[CH3:15].[NH4+].[Cl-]>CN(C=O)C.O.C(Cl)Cl>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:28][C:24]1[CH:23]=[N:22][C:21]([NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:30])=[C:26]([Cl:27])[CH:25]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1ncc(CBr)cc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1)C(=O)OCC
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Diethyl malonate (1.87 ml, 12.31 mmol) was added to a suspension of NaH (0.54 g, 12.31 mmol, 55%) in dry DMF (15 ml) at −8° C. This mixture was stirred for 15 min. before it was added dropwise to a solution of (5-bromomethyl-3-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester (3.30 g, 10.26 mmol) in dry DMF (50 ml) at 0° C. The resulting solution was stirred for 40 minutes at 0° C., then NH4Cl (5 ml, sat.) was added carefully. Stirring at room temperature overnight and concentration under reduced pressure gave a residue, which was dissolved in water/CH2Cl2. The aqueous layer was extracted with CH1Cl2 and the combined organic extracts were dried, filtered and concentrated under reduced pressure. Flash chromatography (1% MeOH in CH2Cl2) gave 2-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-ylmethyl)-malonic acid diethyl ester (2.45, 60%) as a sticky clear oil.
Reaction SMILES: C([O:5][C:6]([C:8]([CH3:26])=[CH:9][C:10]1[C:11](=[O:25])[C:12]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:13]=2[NH:14][C:15](=[O:19])[C:16]=1[O:17]C)=[O:7])(C)(C)C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:12]2[C:11](=[O:25])[C:10](/[CH:9]=[C:8](\[CH3:26])/[C:6]([OH:7])=[O:5])=[C:16]([OH:17])[C:15](=[O:19])[NH:14][C:13]=2[CH:20]=1
Reactant: COc1c(C=C(C)C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: C/C(=C\c1c(O)c(=O)[nH]c2cc(Cl)ccc2c1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
4-[2-(Tert-butoxycarbonyl)propenyl]-8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.32 g) in methylene chloride (4 mL) was added to boron tribromide (0.33 mL) in methylene chloride (4 mL) at room temperature under argon. The mixture was stirred at room temperature for 1.5 hours and then it was added to saturated aqueous sodium bicarbonate (24 mL). The mixture was stirred for 10 minutes and then it was acidified to pH 5 with concentrated hydrochloric acid. The suspension was cooled to -10° C. and the solid was filtered off, washed with water, and vacuum dried to give a white solid (0.16 g). The solid was dissolved in hot methanol (60 mL), filtered, and concentrated to 10 mL volume. The suspension was cooled in an ice bath and the solid was filtered off, washed with cold methanol, and vacuum dried to give a white solid (0.1051 g); mp=242.2°-243.0° C. (dec); 1H NMR (d6 -DMSO) 7.48 (s,1) for olefin proton; MS: m/z=264, 290, 308 (M+1). Analysis for C14H10ClNO5 : Calculated: C, 54.65; H, 3.28; N, 4.55; Found: C, 54.85; H, 3.48; N, 4.50.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][CH2:22][C:23]#[N:24])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl>O1CCCC1>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][CH2:22][C:23]4[NH:33][N:32]=[N:31][N:24]=4)[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccn3c(=O)c(CCC#N)cnc23)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(OCc2cccn3c(=O)c(CCc4nnn[nH]4)cnc23)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 58.9 %

Procedure:
A mixture of 1.07 g (2.65 mmoles) of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl ]-3-(2-cyanoethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 1.76 g 2.57 g (39.53 mmoles) of sodium azide and 45 ml of tetrahydrofuran was heated under reflux for 23 hours. After cooling, the resulting reaction solution was poured into ice water and then acidified with dilute hydrochloric acid. The precipitate so formed was separated by filtration and recrystallized from acetonitrile to obtain 0.70 g (59% yield) of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-[2-(1H-tetrazol-5-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one in the form of white crystals. These crystals had a melting point of 238°-239° C. (dec.).
Reaction SMILES: [OH-].[Li+].C([O:5][P:6]([CH2:15][C@@H:16]([OH:18])[CH3:17])([CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:7])C.BrCC1CCC=CC1.C(OP(C(OCC)(OCC)C)=O)C.C(OP(C[C@@H](O)CCl)(CC1CCC=CC1)=O)C.[Cl:57][C:58]1[CH:59]=[C:60]([C@@H:65]([NH2:67])[CH3:66])[CH:61]=[CH:62][C:63]=1[Cl:64]>O.C(O)C>[Cl:57][C:58]1[CH:59]=[C:60]([C@@H:65]([NH:67][CH2:17][C@H:16]([OH:18])[CH2:15][P:6]([CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]2)(=[O:7])[OH:5])[CH3:66])[CH:61]=[CH:62][C:63]=1[Cl:64]
Reactant: CCOP(=O)(CC1CC=CCC1)C[C@H](C)O
Reactant: C[C@H](N)c1ccc(Cl)c(Cl)c1
Agent: BrCC1CC=CCC1
Agent: CCOP(=O)(CC1CC=CCC1)C[C@@H](O)CCl
Agent: CCO[PH](=O)C(C)(OCC)OCC
Solvent: CCO
Solvent: O
Product: C[C@H](NC[C@H](O)CP(=O)(O)CC1CC=CCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 0.13 g of lithium hydroxide in 3 ml of water is added to a solution in 5 ml of ethanol of 1.1 g of 3-{N-1(S)-(3,4-dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl-(cyclohex-3-enylmethyl)-phosphinic acid ethyl ester [obtainable as described in Example 2 starting from bromomethylcyclohex-3-ene and 1,1-diethoxyethylphosphinic acid ethyl ester via 3-chloro-2(R)-hydroxy-propyl-(cyclohex-3-enylmethyl)-phosphinic acid ethyl ester and further reaction thereof with 1(S)-(3,4-dichlorophenyl)ethylamine] and the mixture is heated at 60° for 24 hours, then cooled to room temperature and concentrated by evaporation under reduced pressure. The residue is taken up in water, rendered neutral with aqueous phosphoric acid solution and again concentrated by evaporation under reduced pressure. The white solid that remains behind is taken up in hot methanol and filtered. Removal of the methanol yields a hygroscopic solid which, after crystallisation from cyclohexane/petroleum ether (60°-80°), yields 3-{N-[1(S)-(3,4-dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl-(cyclohex-3-enylmethyl)-phosphinic acid in the form of a hygroscopic solid; 1H-NMR spectrum (in CD3OD): δ=7.68 (1H), 7.58 (1H), 7.40 (1H), 6.60 (2H, CH=CH), 4.22 (1H,q,CH), 4.13 (1H,m), 2.97 (1H, dd, CHN), 2.63 (1H, dd,CHN), 2.33-1.21 (14H,m). The hydrochloride melts at 105°-206°.
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:33])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]\[C:22]3[CH:26]=[CH:25][N:24]([CH2:27][C:28]([O:30]CC)=[O:29])[N:23]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.Cl>C(#N)C>[ClH:1].[C:28]([CH2:27][N:24]1[CH:25]=[CH:26][C:22](/[CH:21]=[C:16]2/[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:3][CH2:4]3)=[O:33])[CH2:19][CH2:18][CH:17]/2[SH:20])=[N:23]1)([OH:30])=[O:29]
Reactant: CCOC(=O)Cn1ccc(/C=C2/CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Agent: Cl
Solvent: CC#N
Product: O=C(O)Cn1ccc(/C=C2/CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of (Z)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)-1H-pyrazol-3-yl]methylidene}-4-sulfanylpiperidine hydrochloride (309 mg) was added 3N hydrochloric acid (10 ml), and the mixture was stirred at 60° C. for 1 hour. After the mixture was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 40/60, v/v) to afford the title compound (227 mg, yield: 67%) as a colourless crystalline solid.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[CH:10]=[CH:9]2)C.[OH-].[Li+]>CO>[CH3:16][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][C:4]([OH:17])=[O:3])[CH:7]=2)[N:12]=1
Reactant: CCOC(=O)Cc1ccc2nc(C)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2cc(CC(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 21.7 %

Procedure:
To a solution of (2-methyl-quinolin-6-yl)-acetic acid ethyl ester (100 mg, 0.436 mmol) in methanol (2 mL) was added 4 M aqueous solution of lithium hydroxide (0.55 mL, 2.18 mmol). The reaction mixture was stirred at room temperature for 14 h then it was concentrated in vacuo, diluted with water, and treated with 1 N aqueous hydrochloric acid until pH 5. The aqueous layer was extracted with ethyl acetate (3×), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 19 mg of product as a light beige solid. 1H NMR 500 MHz (DMSO) δ 2.65 (s, 3H), 3.76 (s, 2H), 7.40 (d, 1H), 7.60 (dd, 1H), 7.77 (d, 1H), 7.86 (d, 1H), 8.20 (d, 1H); MS (m/z) 202 [M+H+]+.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH:5]([O:35][CH2:36][CH3:37])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH2:15][CH:16]=[CH2:17])=[CH:9][C:8]=1[CH3:34])C.[Li+].[OH-]>>[CH2:36]([O:35][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:18]2[S:22][C:21]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)=[N:20][C:19]=2[CH3:33])[CH2:15][CH:16]=[CH2:17])=[CH:9][C:8]=1[CH3:34])[C:4]([OH:38])=[O:3])[CH3:37]
Reactant: C=CCC(Oc1ccc(CC(OCC)C(=O)OCC)c(C)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Li+]
Agent: [OH-]
Product: C=CCC(Oc1ccc(CC(OCC)C(=O)O)c(C)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C

Procedure:
In analogy to the procedure described in example 10 d], 2-ethoxy-3-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-enyloxy}-phenyl)-propionic acid ethyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 2-ethoxy-3-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-enyloxy}-phenyl)-propionic acid as a mixture of two diastereomeric racemates as colorless solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH:16]=[CH:17][C:13]=3[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH:16]=[CH:17][C:13]=3[CH:12]=2)[C:8]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc2c(c1)C=CS2(=O)=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)c2ccc3c(c2)C=CS3(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
A solution of 3-cyclopentyl-2-(1,1-dioxo-benzo[b]thiophen-5-yl)-propionic acid (36 mg, 0.12 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 67 μL, 0.14 mmol) which produced gas evolution and it was stirred at 0° C. for 10 min and it was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to ˜1.5 mL. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 20 mg, 0.13 mmol), 2,6-lutidine (20 μL, 0.18 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (1 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and transferred to a separatory funnel where it was extracted with methylene chloride (3×10 mL). The organic layers were then washed with a 1 N aqueous hydrochloric acid solution (20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1,1-dioxo-benzo[b]thiophen-5-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (23 mg, 43%) as an off-white foam (as a racemic mixture): ES-HRMS m/e calcd for C23H29N3O4S (M+H)+ 444.1952, observed 444.1949; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 3 H, CH3), 1.05 (s, 3H, CH3), 1.11 (m, 2H, CH2), 1.37-1.78 (m, 8H, 4×CH2), 2.06 m, 1 H, CH), 3.87 (s, 2H, NCH2), 3.93 (t, J=7.5 Hz, 1H, ArCHCO), 4.64 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.35 (d, J=6.9 Hz, 1H, Ar), 7.51 (d, J=2.1 Hz, 1H, Ar), 7.58 (dd, Jo=7.8 Hz, Jm=1.3 Hz, 1H, Ar), 7.61 (d, Jm=1.3 Hz, 1H, Ar), 7.67 (d, J=6.9 Hz, 1H, Ar), 7.79 (d, Jo=7.8 Hz, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: Br[CH2:2][C:3]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:6]2[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][CH2:30][OH:31]>>[CH:16]1([N:13]2[C:6]3[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=3[CH:4]=[C:3]([CH2:2][O:31][CH2:30][CH2:29][O:28][CH3:27])[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COCCO
Reactant: CSc1ncc2cc(CBr)c(=O)n(C3CCCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Bromomethyl-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.33 g, 3.75 mmol) was dissolved in 2-methoxyethanol (10 mL) to which potassium carbonate (0.778 g, 5.63 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered and the salts washed with ethyl acetate. The combined organics were evaporated to give 8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a waxy solid (1.00 g, 76.3%). 1H NMR δ (400 MHz, CDCl3) 8.60 (s, 1H), 7.71 (t, J=1.6 Hz, 1H), 5.95 (m, 1H), 4.52 (d, J=1.6 Hz, 1H), 3.76 (m, 2H), 3.63 (m, 2H), 3.41 (s, 3H), 2.60 (s, 3H), 2.32 (m, 2H), 2.06 (m, 2H), 1.87 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:11][N:10]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[C:19]([NH:23][S:24]([C:27]1[S:28][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:31]=1)(=[O:26])=[O:25])([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:19]([NH:23][S:24]([C:27]1[S:28][C:29]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:11][N:10]=3)[C:5]([Cl:18])=[CH:4][N:3]=2)=[CH:30][CH:31]=1)(=[O:25])=[O:26])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cc(Nc2nc(Br)ncc2Cl)n[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C(C)(C)C)[nH]n3)n2)s1
Temperature: 95 °C
Yield: 23.3 %

Procedure:
A mixture of 2-bromo-N-(5-tert-butyl-1H-pyrazol-3-yl)-5-chloropyrimidin-4-amine (250 mg, 0.87 mmol), PdCl2(dppf)CH2Cl2 (106 mg, 0.13 mmol, 0.15 eq), N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide (336 mg, 1.13 mmol, 1.3 eq), Na2CO3 (323 mg, 3.18 mmol, 3.5 equiv.) in dioxane was heated at 95° C. for 2 h under N. The reaction mixture was cooled to room temperature, and extracted with THF. The combined layers were concentrated and purified by silica gel chromatography (EA/PE 1:2) to afford N-tert-butyl-5-(4-(5-tert-butyl-1H-pyrazol-3-ylamino)-5-chloropyrimidin-2-yl)thiophene-2-sulfonamide (95 mg, 21%). LC-MS (m/z)=427 [M+H]+