Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C[O-].[Na+].CO>[Pd]>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:2][OH:3])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(O)cc1
Temperature: 45 °C

Procedure:
To a five-gallon stainless steel reactor, a solution of 4-hydroxyacetophenone (2500 g, 18.4 moles) and a 25% solution of sodium methoxide in methanol (39.1 g, 0.26 moles) in methanol (10,000 g, 312.5 moles), and palladium on carbon catalyst (ESCAT 10, 125 g) were charged. The reactor is purged three times with nitrogen (100 psi). Hydrogen is then charged to a pressure of 300 psi and the reactor is heated to 45° C. The temperature is maintained at 45° C. for three hours at a constant hydrogen pressure of 500 psi. The reactor is cooled to 30° C. and then discharged (12,245 g). The analysis of the solution gave a conversion of 97.6% and a selectivity of 96.0% (note Table 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][N:32]1[CH2:33][CH2:34][CH:29]([C:25]2[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1cccc(Oc2cc(Cl)cc(Cl)c2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4cc(Cl)cc(Cl)c4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(3,5-dichlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 497.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]#[N:14])[C:7]=2[CH:15]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+]>C(OC(=O)C)(=O)C.[Ni].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][NH:14][C:16](=[O:18])[CH3:17])[C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)N(CC#N)CCO2
Reactant: CC(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc2c(c1)N(CCNC(C)=O)CCO2
Reaction time: 12 h

Procedure:
The compound obtained in Step E (590 mg; 2.88 mmol) is dissolved in a Parr reactor with acetic anhydride. Raney nickel (10% by weight, 60 mg) and sodium acetate (1.5 eq.; 4.33 mmol; 355 mg) are then added. The mixture is left for 12 hours at 50° C. under a hydrogen pressure of 40 psi. After returning to ambient temperature, the solution is filtered over Celite and the filtrate is evaporated. The residue obtained is taken up in water and then extracted three times with ethyl acetate. The organic phases are combined, dried over MgSO4, and then concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on silica gel (eluant: PE/AcOEt (4/6) then AcOEt/MeOH (95/5)). The title product is obtained in the form of white crystals after washing with ether.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>C1COCC1>[OH:41][C:37]1[CH:36]=[C:35]([NH:34][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:33])[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C(C)(C)C)n1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)c2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 50, 70 mg, 0.157 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (21 mg, 0.1924 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 67% yield (0.056 g, 0.1046 mmol).
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][NH2:29])[CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:12][C:2]([F:1])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([NH:29][CH2:28][CH2:27][NH:26][C:22]1[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][N:23]=1)=[O:7]
Reactant: O=C(O)/C=C/C(F)(F)C(F)(F)F
Reactant: Cc1ccnc(NCCN)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(NCCNC(=O)/C=C/C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(E)-4,4,5,5,5-Pentafluoropent-2-enoic acid (29 mg, 0.15 mmol) was dissolved in DMF (1 ml), oxalyl chloride was added (13 μl, 0.15 mmol) and the solution was stirred at room temperature for 5 minutes. To this solution was added a solution of N′-(4-methyl-2-pyridyl)ethane-1,2-diamine (19 mg, 0.1 mmol) in DMF (0.5 ml) and diisopropylethylamine (51 μl, 0.3 mmol) and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate, washed with sat. sodium bicarbonate solution and brine and dried over magnesium sulfate. The volatiles were removed under reduced pressure and the residue obtained was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 18.5 mg (0.057 mmol, 57%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:19](=[O:25])[CH2:20][C:21](OC)=[O:22])=[C:10]([C:15]([O:17][CH3:18])=[O:16])[N:11]2[CH3:14])=[CH:7][CH:6]=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:21](=[O:22])[CH2:20][C:19]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([F:4])=[CH:6][CH:7]=2)[N:11]([CH3:14])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])=[O:25]
Reactant: COC(=O)CC(=O)c1c(C(=O)OC)n(C)c2cc(F)ccc12
Reactant: CNC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C(=O)CC(=O)N(C)C)c2ccc(F)cc2n1C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A stream of gaseous dimethylamine is passed into a mixture of 13 g (44.4 mmol) of methyl 3-[6-fluoro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxo-propanoate, obtained in step 1.2., and 0.2 g (1.63 mmol) of 4-(N,N-dimethyl)aminopyridine in 80 ml of toluene. Immediately a condenser, surmounted by a balloon flask, is fitted and the solution is stirred at 100° C. for 20 h. The mixture is cooled to ambient temperature and concentrated under reduced pressure. 200 ml of dichloromethane, water and hydrochloric acid (1N) are added. The organic phase is separated off, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: cyclohexane/dichloromethane: 50/50, then dichloromethane/ethyl acetate 100/0 to 0/100).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][CH:12]=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>>[CH2:1]([O:8][CH:9]1[CH2:10][CH:11]=[CH:12][CH:13]1[Br:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCC(OCc2ccccc2)C1
Reactant: O=C1CCC(=O)N1Br
Product: BrC1C=CCC1OCc1ccccc1

Procedure:
4-Benzyloxy-1-cyclopentene is brominated with N-bromosuccinimide in the 3-position. The 4-benzyloxy-3-bromo-1-cyclopentene obtained is reacted with 1-heptanol in the presence of silver oxide and the so obtained 4-benzyloxy-3-heptyloxy-1-cyclopentene is epoxidized with m-chloro-perbenzoic acid.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7][OH:8])[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][O:8][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1CO
Reactant: COc1ccc(CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1COC(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (±)-cis-3-ethyl-4-hydroxymethyl-N-toluenesulfonyl-2-azetidinone (3.3 mg) and p-methoxyphenylacetic acid (3.7 mg) in CH2Cl2 (0.6 ml) was added dicyclohexylcarbodiimide (DCC) (5 mg) followed by p-dimethylaminopyridine (DMAP) (1 mg). The mixture was stirred overnight, at room temperature and then purified via preparative tlc on a silica gel plate and developed with CH2Cl2 to yield the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])(C)C)[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:17])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(C)(C)O)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(CO)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared 2-[5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propan-2-ol (example C.14) (28 mg, 0.1 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (24 mg, 0.10 mmol) according to general procedure II. Obtained as a yellow solid (9 mg, 20%). MS (ISP) 445.0 [(M+H)+]; mp 194-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCc1ccc(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2ccc(F)cc2Cl)=N1

Procedure:
Similar procedure as described in example 15a was used, starting with 2-chloro-4-fluoro-benzylamine, rhodanine, mercuric chloride and DIEA to give 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one. LC-MS m/e 259 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[C:10](=[N:11]O)[CH2:9][S:8][CH2:7]1)=[O:5]>CCOCC.CO>[CH3:2][O:3][C:4]([C:6]1[C:10]([NH2:11])=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: COC(=O)C1CSCC1=NO
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cscc1N
Temperature: 25 °C
Yield: 111.3 %

Procedure:
HCl (1M solution in ether, 125 mL) was added slowly to a solution of 4-hydroxyimino-tetrahydro-thiophene-3-carboxylic acid methyl ester (34) (18.30 g, 104 mmol) in dry ether (200 mL) and dry methanol (50 mL) stirred at room temperature. The solution was further stirred at room temperature under argon for 24 h. The solids formed were filtered, washed by cold ether, and dried to yield 18.20 g (91%) of 4-amino-thiophene-3-carboxylic acid methyl ester as the hydrochloride salt. MP 198° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.22 (d, J=2.4 Hz, 1H), 8.37 (d, J=3.2 Hz, 1H) ppm; MS m/z=158 amu (M++1).
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]([F:38])([CH:12]([OH:37])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([NH:25][C:26]3[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH:22]=[C:21]([CH3:36])[CH:20]=2)=[CH:15][N:14]=1)[C:7]([O:9]CC)=[O:8]>C1COCC1>[F:38][C:6]([F:5])([CH:12]([OH:37])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([NH:25][C:26]3[N:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][N:27]=3)[CH:22]=[C:21]([CH3:36])[CH:20]=2)=[CH:15][N:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(O)C(F)(F)C(=O)O)nc2)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Sodium hydroxide (1 M, 0.190 mL, 0.190 mmol) and methanol (0.300 mL) were added to a solution of ethyl 2,2-difluoro-3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate (17.8 mg, 0.037 mmol) in THF (0.500 mL). The mixture was stirred at 40° C. for 2 hours and then cooled to room temperature and the crude reaction mixture was directly purified by reverse phase HPLC to afford 2,2-difluoro-3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoic acid. MS APCI C20H16F5N4O3 [M+H]455. found 455.0. 1H NMR (500 MHz, DMSO-d6)) δ10.28 (s, 1H), 8.83 (d, J=5.3 Hz, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.08 (d, J=11.1 Hz, 1H), 7.96 (s, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.27 (d, J=5.2 Hz, 1H), 7.21 (s, 1H), 5.17 (t, J=12.7 Hz, 1H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1

Procedure:
77 mg of solid yellow 3-{4-[3-(3-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH2:30])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]=[N+:9]=[N-:10])(=[O:3])[CH3:2].I[CH2:33][CH2:34][CH2:35][CH3:36].[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]=[N+:9]=[N-:10])(=[O:3])[CH3:2]
Reactant: CCCCI
Reactant: CC(=O)N(CCCN=[N+]=[N-])c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CCCN=[N+]=[N-])C(C)=O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.4 %

Procedure:
1.01 g (2.35 mmol) of 2-[4-[N-acetyl-N-(3-azidopropyl) amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 79 was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.34 mL (11.8 mmol) of 1-iodobutane and 190 mg (4.75 mmol) of sodium hydride (60% oil dispersion) were added and the mixture was stirred at room temperature for 45 minutes. An aqueous solution of ammonium chloride was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 726 mg of 2-[4-[N-acetyl-N-(3-azidopropyl)amino]-3-fluorophenyl]-5-butylamino-6,8-difluoro-4H-1-benzopyran-4-one (yield: 63%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:34][C:35]([CH3:38])=[CH:36][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:35]1[S:34][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[N:37][CH:36]=1
Reactant: Cc1cnc(CCl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (855 mg; compound B50) is reacted with 2-(chloromethyl)-5-methyl-1,3-thiazole (366 mg; compound D12) in the presence of potassium carbonate (554 mg) in DMF (10 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: [OH:1][C:2]([CH3:27])([C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH:12]([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:29].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[OH:1][C:2]([CH3:27])([C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:29])=[O:18]
Reactant: CCCCC(F)(F)C(C)(O)C=CC1CCC(=O)N1CC(O)CCCCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(F)(F)C(C)(O)C=CC1CCC(=O)N1CC(=O)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of 19 (37 mg, 0.09 mmol) in dimethylformamide (1 mL) containing pyridinium dichromate (165 mg, 0.45 mmol) was stirred at room temperature overnight. It was then poured into water and extracted with ether three times. The combined ether layer was washed with water and dried over magnesium sulfate. Removal of the solvent in vacuo gave 11.6 mg of 7-[2-(3-hydroxy-3-methyl-4,4-difluoro-1-octen-1-yl)-5- oxopyrrolidin-1-yl]-6-oxo-heptanoic acid (20). IR (CH2Cl2): 3600-2800 (br), 1730, 1690 cm-1 ; PMR (CDCl3); δ5.85-5.62 (m, 2H), 4.33-3.65 (m, 3H), 2.50-1.20 (m, 21H), and 0.92 (t, 3H); MS: m/z 385.2048 (M+ --H2O), calcd. for C20H29NO4F2, 385.2064.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=3[F:36])[N:24]=[CH:25][C:18]=12>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([C:26]4[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=4[F:36])[N:24]=[CH:25][C:18]=23)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A mixture of 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (431 mg, 2.3 mmol) and sodium hydride (92 mg, 3.82 mmol) in THF (10 mL) was stirred for 30 minutes at room temperature. Then 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 1.53 mmol) was added and stirred overnight at room temperature. The reaction mixture was quenched with water and the product extracted with ethyl acetate. The ethylacetate layer was dried over MgSO4, concentrated in vacuo, and purified by flash chromatography to afford compound A140 as a white solid (495 mg, 45%). Exact mass calculated for C21H24FN5O5S 477.15, found 478.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=2[CH3:17])[C:4]([CH3:7])=[CH:5][CH:6]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].I>>[C:18]([C:5]1[CH:6]=[C:2]([CH3:1])[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=2[CH3:17])[C:4]=1[CH3:7])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(-n2c(C)ccc2C)c(C)c1
Agent: I
Product: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)c(C)c1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, 2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (2.29 g, 10 mmol), acetic anhydride (5 mL), and hydriodic acid (0.13 mL, 1.7 mmol) reacted to give 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 6.99 (d, 1H), 6.85 (d, 1H), 6.79 (dd, 1H), 6.32 (s, 1H), 4.06 (q, 2H), 2.42 (s, 3H), 2.22 (s, 3H), 1.89 (s, 3H), 1.88 (s, 3H), 1.44 (t, 3H); MS (ESI) 272 (M +H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>>[F:21][C:16]1[CH:15]=[C:14]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([NH:12][CH3:13])=[O:11])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CNC(=O)CC(c1ccc(Br)cc1)c1ccc(F)c(F)c1
Product: CNC(=O)CC(c1ccc(-c2cn[nH]c2)cc1)c1ccc(F)c(F)c1

Procedure:
3-(4-Bromo-phenyl)-3-(3,4-difluoro-phenyl)-N-methyl-propionamide was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.55 [M+H]+ 341.93.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[CH3:28][O:27][C:25]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][C@H:16]2[NH2:15])=[O:26]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (10 ml) was added dropwise to a solution of (R)-methyl 3-(tert-butoxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (see step-2 product of A-17) (2.0 g, 6.87 mmol, 1.0 eq.) in methylene chloride (30 ml) at 0° C. The reaction mixture was then stirred at RT for 1 h. After completion (monitored by TLC), the reaction mixture was evaporated to afford the desired product as a colorless gummy solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[CH3:10]C([N-]C(C)C)C.IC.C(=O)([O-])O.[Na+]>C1COCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: Clc1cncc(Cl)c1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CI
Product: Cc1c(Cl)cncc1Cl
Reaction time: 0.08 h
Yield: 53 %

Procedure:
3,5-Dichloropyridine (2.04 g, 13.5 mmol) in THF (5 ml) was added dropwise to a solution of LDA [prepared from diisopropylamine (1.9 ml, 13.5 mmol) and n-butyllithium (1.6M, 8.4 ml, 13.5 mmol)] in THF (25 ml) at -70° C. After stirring at this temperature for 5 min, iodomethane (0.85 ml, 13.5 mmol) was added and the reaction mixture stirred for a further 1.5 h at -70° C. Saturated sodium hydrogen carbonate solution (20 ml) and dichloromethane (20 ml) was added and the organic phase separated, dried (MgSO4), and concentrated in vacuo. The residue was subjected to chromatography (SiO2 ; Et2 O-hexane,1:3) to afford the title compound (1.16 g) as a pale yellow solid. δH (CDCl3) 2.46 (3H, s, Me), and 8.36 (2H, s, pyridine H2, H6).