Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[C:10](C(O)=O)[C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Yield: 91 %

Procedure:
Two hundred and thirty-five milligrams of 5-(p-chlorobenzoyl)-1,4-dimethyl-3-hydroxycarbonyl-pyrrole-2-acetic acid is dissolved in 5 ml of trifluoroacetic acid and the resulting solution is heated to reflux for 1.5 hours. After most of the solvent is removed in vacuo, the residue is treated with 10 ml of water. The resulting residue is filtered and dried in vacuo to give 5-(p-chlorobenzoyl)-1,4-dimethyl-pyrrole-2-acetic acid (Zomepirac) in 91% yield, m.p. 184°-185° C.
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([CH2:12]O)[CH2:10][N:9]([CH:14]([CH3:16])[CH3:15])[C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:26])=O.N1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:26][CH2:12][CH:11]1[CH2:10][N:9]([CH:14]([CH3:16])[CH3:15])[C:8](=[O:17])[C:7]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)N1CC(CO)C(c2ccccc2)(c2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
A solution of 43 g. (0.14 mole) of 3,3-diphenyl-4-hydroxymethyl-1-isopropyl-2-pyrrolidinone in 250 ml. of chloroform was treated with 33 g. (0.28 mole) of thionyl chloride over a one minute period followed by the dropwise addition of 22 g. (0.23 mole) of pyridine over a 30 minute period. The mixture was refluxed 18 hours and then poured onto ice. The cold mixture was made basic by the addition of sodium hydroxide. The chloroform layer was separated, dried over sodium sulfate and concentrated. The residue was crystallized using charcoal from a 25% ethyl acetate -- 75% isopropyl ether mixture. The crystalline solid was recrystallized from a 75% ethanol -- 25% water mixture and then from isopropyl ether. The dried 4-chloromethyl-3,3-diphenyl-1-isopropyl-2-pyrrolidinone weighed 23 g. and melted at 114°-116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.[OH-:16].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][N:9]=2)[CH:3]=1
Reactant: Cc1ccnc(-c2cc(C=O)ccn2)c1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccnc(-c2cc(C(=O)O)ccn2)c1
Reaction time: 8 h
Yield: 77 %

Procedure:
A suspension of 4′-methyl-2,2′-bipyridine-4-carboxaldehyde (3.5 g, 15 mmol) in 95% EtOH (150 ml) was added a solution of AgNO3 (3.15 g) in water (32 ml). The suspension was stirred rapidly and 1M NaOH (79 ml) solution was added dropwise over 20 min to form Ag2O. The dark black solution was stirred for an additional 15 hrs. EtOH was removed by rotary evaporator and filtred to remove Ag2O and unreacted metallic Ag. The residue was washed with 1.3M NaOH (2*20 ml) and H2O 20 ml. The combined basic filterate was extracted with DCM to remove unreacted aldehyde and adjusted to pH 3.5 with 1:1(v/v) 4N HCl/AcOH to afford white compound. After keeping overnight at −10° C. the compound was collected and dried to afford pure compound 2.9 g (77%). Mass Spect. (FAB) MW 215 [M+]; NMR assigned.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:12]([CH3:17])=[N:13][O:14][C:15]=2[CH3:16])=[CH:4][C:3]=1[I:18].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CN1C(=O)CCC1>[CH:19]1([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])=[CH:4][C:3]=2[I:18])[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: Cc1noc(C)c1-c1cc(I)c(Br)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Product: Cc1noc(C)c1-c1cc(I)c(NC2CC2)c([N+](=O)[O-])c1
Temperature: 130 °C

Procedure:
To a mixture of 4-(4-bromo-3-iodo-5-nitrophenyl)-3,5-dimethylisoxazole (1 g, 2.36 mmol, 1 equiv.) in a pressure tube was added NMP (10 mL) and cyclopropylamine (982 μL, 14.2 mmol, 6 equiv.). The mixture was heated to 130° C. for 60 minutes in a microwave reactor. The reaction was concentrated under reduced pressure and purified by flash column chromatography to provide N-cyclopropyl-4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[CH:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH3:27][CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH3:27][CH:28]([NH:38][C:9](=[O:11])[CH:8]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCC(C)N
Reactant: O=C(O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: CCOC(=O)Cl
Product: CCCCCCCCCC(C)NC(=O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 3-phenyl-3-(3-nitrophenyl)propenoic acid via mixed anhydride formation using ethyl chloroformate, followed by reaction with 1-methyldecylamine, substantially according to the procedure of Preparation 21. This gave a 92% yield of an oil.
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]1[C:9]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=2)=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.C(N(CC)CC)C.CC1C=CC(OC2C=CC(CN[C:46]([C:48]3[N:52]([CH3:53])[N:51]=[C:50]([CH2:54][CH3:55])[C:49]=3[Cl:56])=[O:47])=CC=2)=CC=1>O>[Cl:7][C:8]1[C:9]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:46]([C:48]3[N:52]([CH3:53])[N:51]=[C:50]([CH2:54][CH3:55])[C:49]=3[Cl:56])=[O:47])=[CH:21][CH:20]=2)=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1
Reactant: CCc1nn(C)c(C(=O)NCc2ccc(Oc3ccc(C)cc3)cc2)c1Cl
Reactant: NCc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1nn(C)c(C(=O)NCc2ccc(Oc3ncc(C(F)(F)F)cc3Cl)cc2)c1Cl
Reaction time: 1 h

Procedure:
Into 50 ml solution of ethyl acetate containing 2.49 g of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzylamine and 1.21 g of triethylamine, was dropped 2.07 g of 4-chloro-3-ethyl-1-methyl-5-pyrazolecarboxylic acid chloride synthesized in Example 2. After the completion of dropping, the mixture was stirred for 1 hour, poured into iced water and then extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium carbonate, water and a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, the solution was concentrated under a reduced pressure. The residue was purified on silica gel column chromatography to obtain 3.35 g of the titled compound (No. 75) shown in Table 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.[Br:10]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:10][CH2:5][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccc(O)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a solution of 3-hydroxybenzyl alcohol (4 g, 32.2 mmoles) in methylene chloride (250 ml), cooled at 0° C., tetrabromomethane (12.82 g, 38.6 mmoles) and triphenylphosphine (12.67 g, 48.3 mmoles) are added. The mixture is kept under stirring at 0° C. for 10 minutes, then evaporated at reduced pressure. The crude product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 8/2. 3.5 g of the expected compound are obtained.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][NH:24][C:21]=4[N:22]=[CH:23][C:18]3=[N:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH:26]1[C:20]2[N:19]3[C:15]([C@@H:12]4[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]4)=[CH:16][N:17]=[C:18]3[CH:23]=[N:22][C:21]=2[NH:24][CH:25]=1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@@H](c3cnc4cnc5[nH]ccc5n43)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@H]1CC[C@@H](c2cnc3cnc4[nH]ccc4n32)CC1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
To a mixture of (cis)-N,N-dibenzyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine (1.0 g, 2.3 mmol) in EtOH (30 mL) was added Pd(OH)2 on carbon (0.64 g, 0.46 mmol) and the resulting mixture was shaken under hydrogen pressure of about 30 psi on a Parr shaker at about 50° C. for about 7 h. The catalyst was filtered off using a pad of Celite® and the filtrate was concd under reduced pressure. The material was purified by chiral chromatography (Table 2, method 34). The collected fractions were combined, concd under reduced pressure and chased with EtOH (20 mL). The resulting solid was dried in a heated vacuum oven at about 60° C. to yield (cis)-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine (0.353 g, 60%) as a white solid: LC/MS (Table 1, Method a) Rt=0.85 min; MS m/z 256 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][O:33]C(=O)C)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[OH-].[K+]>>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[O:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH2:31][CH2:32][OH:33])(=[O:28])=[O:29])[CH2:25][CH2:26]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCOC(C)=O)CC2)nc1N
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCO)CC2)nc1N

Procedure:
[4-Amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) was reacted with sodium acetate in an analogous manner as described in Example 227 to give acetic acid 3-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl ester. The crude acetic acid 3-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl ester was hydrolyzed with 5% potassium hydroxide to give [4-amino-2-[1-(3-hydroxy-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone. HR-MS (ES, m/z) calculated for C20H26N5O5SF2 [(M+H)+] 486.1617, observed 486.1623.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CN(C)C=O>O.CO>[CH3:1][C:2]1([CH3:10])[C:3](=[O:9])[CH:4]=[C:5]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)[CH2:6][CH2:7]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)CCC(=O)CC1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)CCC(Nc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 25 °C

Procedure:
A mixture of 4,4-dimethylcyclohexane-1,3-dione (563 mg, 4.02 mmol), 3-(trifluoromethyl)aniline (500 μL, 645 mg, 4.02 mmol), Ytterbium(III) trifluormethanesulfonate (12.5 mg, 20 μmol, 0.5 mol %) and N,N-dimethylformamide (2.5 mL) is stirred at room temperature over night. Methanol and water are added and the mixture is filtered. The precipitate is washed with water and dried under reduced pressure. Yield: 654 mg; ESI mass spectrum [M+H]+=284, Retention time HPLC: 1.18 min (Z005—001).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH:10]=O)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[N:9][CH:8]=[C:4]2[CH:3]=1
Reactant: O=CNCc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Brc1ccn2cncc2c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a 100-mL round-bottom flask, was placed a solution of N-((4-bromopyridin-2-yl)methyl)formamide (compound 39.2, 3.0 g, 90%, 12.6 mmol) in dichloromethane (20 mL). The solution was cooled to 0-5° C. then trifluoroacetic anhydride (1.93 mL, 13.9 mmol) was added drop-wise. The resulting solution was stirred for 1 h at room temperature, then the pH was adjusted to 7 by careful and slow addition of aqueous sodium carbonate (sat.). The aqueous phase was extracted with dichloromethane (3×20 mL) and the combined organic layers were washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/1) as the eluent to yield the title compound as a brown solid (1.0 g, 40%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](Br)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]=C.N(C(OCC)=O)=NC(OCC)=[O:15].BrC1C(O)=CC=CN=1.C(O)C=C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.C([O-])(O)=O.[Na+]>[O:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2](=[O:15])[CH2:1]1
Reactant: C=CCOc1cccnc1Br
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: Oc1cccnc1Br
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C=CCO
Product: O=C1COc2cccnc21
Temperature: 50 °C

Procedure:
3-(allyloxy)-2-bromopyridine. Diethyl azodicarboxylate (1 eq.) is added dropwise to a stirring mixture of 2-bromo-3-hydroxypyridine (0.92 eq,), allyl alcohol (0.92 eq), and PPh3 (1.1 eq) in THF (0.2 M) at 0° C. under a N2 atmosphere. The reaction mixture is warmed to 50° C. in an oil bath. Reaction progress is monitored by TLC until judged complete. The reaction mixture is cooled to ambient temperature and diluted with saturated NaHCO3 solution. The aqueous solution is extracted with EtOAc, and the organic layer is dried over Na2SO4 and concentrated. The product that may be thus obtained is purified by column chromatography to afford the title compound.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:10]([NH:12][C@@H:13]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:14]([NH:16][C@H:17]([C@@H:26]1[C@H:30]([CH:31]2[CH2:33][CH2:32]2)[O:29]C(C)(C)[O:27]1)[CH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]>CO.Cl>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:10]([NH:12][C@@H:13]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:14]([NH:16][C@@H:17]([CH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C@@H:26]([OH:27])[C@H:30]([CH:31]1[CH2:32][CH2:33]1)[OH:29])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@H]([C@H](CC2CCC(=O)CC2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)[C@H](C2CC2)O1
Agent: Cl
Solvent: CO
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCC(=O)CC1)[C@@H](O)[C@@H](O)C1CC1
Yield: 6.7 %

Procedure:
A solution of 90 mg (0.3 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(S)-1-[(4R,5S)-5-cyclopropyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(4-oxocyclohexyl)ethyl]imidazole-4-propionamide in 1 ml of methanol and 1 ml of 2N hydrochloric acid is stirred at room temperature for 3 hours. Subsequently, the reaction solution is evaporated and, for purification, the residue is chromatographed on 20 g of silica gel using a 14:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There are obtained 13 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-3-cyclopropyl-2,3-dihydroxy-1-[(4-oxocyclohexyl)methyl]propyl]imidazole-4-propionamide as a colourless solid; MS: 684 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1([CH3:23])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][N:15]([CH3:18])[C:16]=2F)[CH2:6]1.O>CO>[CH3:4][C:5]1([CH3:23])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][N:15]([CH3:18])[C:16]=2[O:2][CH3:1])[CH2:6]1
Reactant: C[O-]
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(CSC2=NOC(C)(C)C2)c(C(F)(F)F)nn1C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
0.77 g (4.0 mmoles) of sodium methoxide (a 28% methanol solution) was added to a solution of 0.5 g (1.6 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 20 ml of methanol. The mixture was stirred for 4 hours under refluxing, to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 96.7%) of 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:19])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:6]2.[OH-].[K+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:19])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2
Reactant: CCOC(=O)C(O)c1ccc2cc(OC)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1ccc2cc(C(O)C(=O)O)ccc2c1

Procedure:
To a solution of 0.144 moies of ethyl 6-methoxy-2-naphthylglycolate dissolved in 220 ml. of isopropanol is added 38 g. (0.7 mole) of potassium hydroxide. This mixture is then heated at reflux temperature in a nitrogen atmosphere. The solution is concentrated in vacuo to a viscous oil, which is then dissolved in 500 ml. of water and filtered. The filtrate is acidified with 10% HCl and the precipitate is taken up in ether. The ether layer is dried, filtered and the filtrate concentrated to dryness. Recrystallization of residue from benzenecyclohexane 1:1 gives 6-methoxy-2-naphthylglycolic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([C:36]1[CH:37]=[C:38]([NH:42][C:43](=O)[O:44]C2C=CC=CC=2)[CH:39]=[CH:40][CH:41]=1)(=[O:35])[NH2:34]>>[CH3:32][NH:31][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:10]2[N:11]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43]([NH:42][C:38]4[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=4)[C:33]([NH2:34])=[O:35])=[O:44])=[CH:7][CH:6]=3)[N:9]=2)=[CH:23][CH:24]=1)=[O:30]
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: NC(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4cccc(C(N)=O)c4)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 13 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.
Reaction SMILES: CN([CH:4]([CH3:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=O)C.[NH2:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:13][C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:14][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH3:23])[N:15]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(C(=O)c1cccc(F)c1)N(C)C
Product: CCOC(=O)c1ccc(-c2cccc(F)c2)nc1C

Procedure:
The title compound was prepared from dimethylamino-(3-fluorophenyl)propan-1-one and ethyl 3-aminocrotonate using the general procedure outlined in D18. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.27 (d, 1H), 7.83 (m, 2H), 7.61 (d, 1H), 7.44 (m, 1H), 7.13 (m, 1H), 4.41 (q, 2H), 2.91 (s, 3H), 1.42 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:14]1([CH2:13][O:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=2)[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(OCC2CC2)ccc1O
Temperature: 25 °C
Yield: 104.8 %

Procedure:
A solution of 2′,5′-dihydroxyacetophenone (25.0 g), bromomethylcyclopropane (24.43 g), potassium carbonate (27.2 g) in acetonitrile (400 mL) was stirred with heating under reflux for 2.5 hr. Bromomethylcyclopropane (4.4 g) was added to the mixture, and the mixture was further stirred with heating under reflux for 14 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0-10:90, v/v) to give 1-[5-(cyclopropylmethoxy)-2-hydroxyphenyl]ethanone (35.5 g) as a yellow oil at purity 70%. A solution of the obtained 1-[5-(cyclopropylmethoxy)-2-hydroxyphenyl]ethanone (35.5 g), 1-bromo-3-methylbutan-2-one (35.5 g) synthesized above and potassium carbonate (66.3 g) in N,N-dimethylformamide (350 mL) was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. 1,8-Diazabicyclo[5.4.0]undec-7-ene (22.5 mL) and N,N-dimethylformamide (300 mL) were added to the obtained residue, and the mixture was stirred at 100° C. for 30 min. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (300 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (19.91 g, 45%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([CH:42]=[O:43])[CH:39]=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[C:38]([CH:42]=[O:43])[CH:39]=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncc(C=O)c4)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (Example 153) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carbaldehyde via General Procedure E to give, after purification by reverse HPLC, 11 mg of 238. MS (Q1) 487 (M+).