Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:16]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]2[C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)=[N:17]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][C:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:16]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]2[C:24]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)=[N:17]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 3-[2-(2-t-butoxycarbonylmethyl-1-cycloheptenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.15 g) in dry dichloromethane (0.5 ml) at room temperature was added trifluoroacetic acid (0.46 ml). After stirring for one day at room temperature, the solution was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate. The separated aqueous layer was acidified with 1N-hydrochloric acid to pH 3 and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ethanol--water to give 3-[2-(2-carboxymethyl-1-cycloheptenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]- pyridine (0.083 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.[CH:13]([NH2:16])([CH3:15])[CH3:14].CO>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:13]([NH:16][CH:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)([CH3:15])[CH3:14]
Reactant: COc1cccc2c1CCC2=O
Reactant: CC(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cccc2c1CCC2NC(C)C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxy-1-indanone (0.71 g) and iso-propylamine (8 ml) in dichloromethane (10 ml) was added 1M solution of titanium(IV) chloride in dichloromethane (11 ml) at -60° C. for 15 minutes. The reaction mixture was stirred for 3 hours at the same temperature. Methanol (15 ml) was added to the reaction mixture. After being stirred for 2 hours at room temperature, the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate and 1N aqueous NaOH solution. The insoluble material was filtered off by zeolite. The organic layer was washed with brine. The dried solvent was evaporated in vacuo to give 1-isopropylamino-2,3-dihydro-4-methoxy-1H-indene (0.89 g). MS (m/z): 206 (M+ +1) NMR (CDCl3, δ): 7.18 (1H, dd, J=7.8, 7.8 Hz), 6.97 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=7.8 Hz), 4.30 (1H, t, J=6.7 Hz), 3.83 (3H, s), 3.20-2.87 (2H, m), 2.80-2.60 (1H, m), 2.50-2.35 (1H, m), 2.00-1.68 (1H, m), 1.13 (3H, d, J=6.9 Hz), 1.12 (3H, d, J=6.9 Hz)
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:10]=1>>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:11]1[CH:10]=[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Cl
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Product: Cc1noc(NS(=O)(=O)c2cccc(-c3ccccc3)c2)c1Cl
Yield: 63 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared in the same manner as described in Example 204 from 5-amino-4-chloro-3-methylisoxazole and 3-biphenylsulfonyl chloride in 63% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. 84-86° C.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[CH2:15][OH:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2]>C(O)C.[Ni]>[CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH:14]([CH3:17])[CH2:15][OH:16])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CCc1cc(=O)c2cc(C(C)CO)ccc2o1
Agent: [Ni]
Solvent: CCO
Product: CCC1CC(=O)c2cc(C(C)CO)ccc2O1
Reaction time: 2 h
Yield: 108.8 %

Procedure:
2-(2-Ethyl-4-oxo-4H-1-benzopyran-6-yl)propan-1-ol (4.1 g) was taken up in ethanol (100 ml), Raney Nickel (5.0 g) was added and the mixture hydrogenated at 45 psi for 2 hours. The catalyst was removed by filtration (Hyflo supercel) and replaced with a fresh batch (5.0 g) and hydrogenation at 45 psi continued for a further 3 hours. The catalyst was removed by filtration and the filtrate evaporated to yield 2-(2,3-dihydro-2-ethyl-4-oxo-4H-1-benzopyran-6-yl)propanol as a pale green oil (4.5 g), I.R. carbonyl absorption 1690 cms-1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:30])=[C:10]([C:19]([NH:21][NH:22]C(OC(C)(C)C)=O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[ClH:31]>O1CCOCC1>[ClH:31].[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:30])=[C:10]([C:19]([NH:21][NH2:22])=[O:20])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)NNC(=O)OC(C)(C)C)c(C)nc21
Agent: Cl
Solvent: C1COCCO1
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NN)c(C)nc21
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Intermediate 62 (0.19 g, 0.46 mmol) was dissolved in 4M hydrogen chloride in dioxane (5 ml) and the reaction mixture stirred overnight at 20° C. Concentration in vacuo afforded Intermediate 63 as a white solid (0.161 g). LCMS showed MH+=319; TRET=1.72 min.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:11]([O:14]CC)(=[O:13])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:17])[CH:3]=1.[SH-:18].[Na+]>O>[SH:18][C:2]1[N:7]2[N:8]=[C:9]([S:11]([OH:14])(=[O:13])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:17])[CH:3]=1
Reactant: [SH-]
Reactant: CCOS(=O)(=O)c1nc2nc(C)cc(Cl)n2n1
Agent: [Na+]
Solvent: O
Product: Cc1cc(S)n2nc(S(=O)(=O)O)nc2n1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
The product obtained in Step 3 (6 g) was added to a solution of 8.1 g sodium hydrosulfide in 100ml of water all at once with stirring under a nitrogen at room temperature. The mixture was heated at 60° C. for four hours with stirring and cooled to room temperature. The resultant yellow solution was washed twice with 100 ml of ethyl acetate. The pH of the aqueous layer was lowered to 1.0 with concentrated hydrochloric acid for crystallization. The crystals were collected by filtration and washed with 20 ml of water; 3.2 g of the objective compound was obtained as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][CH2:9][C:10](=[O:33])[NH:11][CH:12]1[CH2:15][N:14]([CH:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[CH:24]=[N:23]3)[CH2:18][CH2:17]2)[CH2:13]1)=[O:7].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:27]([C:25]1[CH:24]=[N:23][N:22]([CH:19]2[CH2:20][CH2:21][CH:16]([N:14]3[CH2:15][CH:12]([NH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]4[CH:34]=[CH:35][CH:36]=[C:3]([C:2]([F:38])([F:1])[F:37])[CH:4]=4)=[O:33])[CH2:13]3)[CH2:17][CH2:18]2)[CH:26]=1)#[CH:28]
Reactant: C[Si](C)(C)C#Cc1cnn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-Trifluoromethyl-N-({1-[4-(4-trimethylsilanylethynyl-pyrazol-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-benzamide (as prepared in Example 29, 52.5 mg, 0.09 mmol) in THF (4 mL) was added TBAF (Aldrich, 47 mg, 0.18 mmol) and the reaction was stirred at RT over night followed by column chromatography purification (0-100% ethyl acetate in hexanes with 7N NH3 in MeOH) resulting in the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:18][CH2:17][C@H:16]([S:19]([CH2:21][C:22]3C=CC(Cl)=CC=3)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:42].C(=O)([O-])O.[Na+].C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1CC#N.C(Cl)Cl.C(OCC)(=O)C>[C:21]([S:19][C@H:16]1[CH2:17][CH2:18][C@H:13](/[CH:12]=[CH:11]/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:30])([F:29])[F:1])=[CH:4][CH:5]=2)[CH2:14][CH2:15]1)(=[O:42])[CH3:22]
Reactant: O=S(Cc1ccc(Cl)cc1)[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N#CCC1CCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)S[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
In 11 ml of a mixed solvent of tetrahydrofuran-acetonitrile (8:3) were dissolved 178 mg (0.39 mmol) of 4-chlorobenzyl trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexyl sulfoxide, and 168 mg (1.57 mmol) of 2,6-lutidine were added to the solution. To the mixture were added 165 mg (0.79 mmol) of trifluoroacetic anhydride with stirring at 0° C. After 3 minutes, an aqueous sodium hydrogencarbonate solution was added to the mixture, followed by extraction with ethyl acetate. The oily residue obtained by evaporation of the solvent was dissolved in 10 ml of methylene chloride, and 119 mg (1.17 mmol) of triethylamine were added to the mixture at 0° C., followed by addition of 62 mg (0.79 mmol) of acetyl chloride to the resulting mixture. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with an aqueous sodium hydrogencarbonate solution and an aqueous NaCl solution. After the mixture was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 5 g of silica gel and eluted with a mixed solvent of methylene chloride-hexane (1:1), followed by purification over Rover column [GrosseB, a mixed solvent of ethyl acetate-hexane (1:19)] to obtain 98 mg (yield: 70w) of the title compound having a melting point of 113 to 115° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([O:27]C(C)(C)C)=[O:26])=[O:11])=N1.F[C:33](F)(F)C(O)=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([OH:27])=[O:26])=[O:11])=[CH:33]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1n[nH]c2ccccc12
Product: O=C(N[C@H]1C(=O)N(c2ccccc2)C[C@H]1C(=O)O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
The tert-butyl ester (230 mg, 0.547 mmol) of Example 25 was dissolved in trifluoroacetic acid (3 ml) and stirred for 20 min at room temperature after which time the reaction was concentrated in vacuo. Resuspension of the residue in CH2Cl2 and filtration gave the title compound (206 mg, 79%) as a colorless solid. Anal calcd for C19H16N4O4.8/10CF3CO2H: C,54.41; H,3.55; N,12.32; F,10.03. Found C,54.52; H,3.76; N,12.45; F,10.35. DSC=130.85°-140.96° C. at 97.64 J/g. MS calc. for C19H16N4O4 364, found 364.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH:11]=2)[C:7]([NH:18][C:19]([C:21]2[NH:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)=[O:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:28][CH2:29][CH2:30]O>>[CH3:16][C:13]1([CH3:17])[CH2:14][CH2:15][C:10]([C:8]2[C:7]([NH:18][C:19]([C:21]3[NH:25][CH:24]=[C:23]([C:26]#[N:27])[N:22]=3)=[O:20])=[CH:6][CH:5]=[C:4]([C:1]3([CH3:2])[NH:28][CH2:29][CH2:30][O:3]3)[N:9]=2)=[CH:11][CH2:12]1
Reactant: NCCO
Reactant: CC(=O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)n1
Product: CC1(C)CC=C(c2nc(C3(C)NCCO3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [6-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in the previous step) and 2-aminoethanol according to the procedure in Example 1, step (h).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]4[N:27]=[CH:26][N:25]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][O:29]5)[N:24]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH:34]([B-](F)(F)F)=[CH2:35].[K+].ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.O>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO.C(Cl)Cl>[CH3:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([CH:34]=[CH2:35])=[CH:7][N:6]2[C:8]=1[C:12]1[S:13][C:14]([C:23]2[N:27]=[CH:26][N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1
Reactant: C=C[B-](F)(F)F
Reactant: Cc1nc2ccc(Br)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=Cc1ccc2nc(C)c(-c3nc(-c4ccccc4)c(-c4ncn(C5CCCCO5)n4)s3)n2c1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture (suspension) of [A] 6-bromo-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine (1.04 g, 2.00 mmol), Potassiumvinyltrifluoroborate (0.402 g, 3.00 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.163 g, 0.200 mmol) and Cesium Carbonate (1.95 g, 6.00 mmol) in 1,2-Dimethoxyethane (70 mL, 700 mmol) and Water (14 mL, 780 mmol) was heated to 95° C. under atmosphere of N2 for 4 hours. The mixture was cooled to r.t., diluted with EtOAc (40 mL), filtered through Celite. The filtrate was diluted further with EtOAc (500 mL), washed with water, brine, dried over Na2SO4, filtered, rotavaped to give a crude product. Chromatograph in a 40 g ISCO column using MeOH/DCM (0/100 to 5/95) gave a solid product (0.747 g, 79.7% yield). LCMS: (FA) ES+ 468. 1H NMR (400 MHz, d1-chloroform) δ 9.97 (s, 1H), 8.29 (s, 1H), 7.95-7.98 (m, 2H), 7.56-7.62 (m, 2H), 7.42-7.46 (m, 3H), 6.71-6.78 (dd, J=17.57, 10.79 Hz, 1H), 5.76-5.81 (d, J=17.57 Hz, 1H), 5.48-5.51 (dd, J=8.53, 3.26 Hz, 1H), 5.33-5.36 (d, J=11.04 Hz, 1H), 4.06-4.10 (m, 1H), 3.70-3.77 (m, 1H), 2.81 (s, 3H), 2.00-2.18 (m, 3H), 1.63-1.74 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([CH2:13][C:14]([NH2:16])=O)[N:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.N>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:11]([CH2:13][C:14]#[N:16])[N:12]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1-c1ccccc1
Agent: N
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#CCc1nc(-c2ccc(Cl)cc2)sc1-c1ccccc1
Yield: 96.5 %

Procedure:
To a solution of 2-(4-chlorophenyl)-5-phenylthiazol-4-yl acetamide (3.4 g) and phosphorus oxychloride (3 ml) in chloroform (50 ml) was added one drop of pyridine, and the mixture was refluxed for 8 hours. Cold diluted aqueous ammonia was poured into the mixture and the organic layer was collected. After removing the solvent under reduced pressure, ethanol was added to the residue and crystal was collected by filtration to obtain 2-(4-chlorophenyl)-5-phenylthiazol-4-yl acetonitrile (3.1 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-])=O>CO.[Pd]>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH2:11]
Reactant: CNc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(OC)cc1N
Reaction time: 3 h

Procedure:
The title compound of Example 14 Step A (3 mmol, 547 mg) and 10% Pd—C (ca. 50 mg) were stirred in 10 mL of MeOH under H2 (balloon). After 3 h the solution was nearly colorless. The reaction mixture was filtered over celite and filter cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure affording a slightly orange solid. HPLC A: 0.44 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:32]2[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)c1nn(Cc2ccccc2Br)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccccc2-c2ccc(C(F)(F)F)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 45.8 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 78(b), 75 mg, 0.177 mmol), 4-trifluoromethylphenylboronic Acid (33.6 mg, 0.177 mmol), potassium carbonate (73.3 mg, 0.530 mmol), and tetrakis(triphenylphosphine)palladium (0) (6.13 mg, 5.30 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-[(5-hydroxy-6-(1-methylethyl)-3-oxo-2-{[4′-(trifluoromethyl)-2-biphenylyl]methyl}-2,3-dihydro-4-pyridazinyl)carbonyl]glycine (44 mg, 0.081 mmol, 45.8% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.81 (s, 1H), 12.99 (s, 1H), 10.05 (t, J=5.56 Hz, 1H), 7.77 (d, J=8.08 Hz, 2H), 7.61 (d, J=8.08 Hz, 2H), 7.35-7.49 (m, 2H), 7.21-7.35 (m, 2H), 5.27 (s, 2H), 4.06 (d, J=5.56 Hz, 2H), 3.09 (sept, J=6.82 Hz, 1H), 1.09 (d, J=6.82 Hz, 6 H). MS (ES+) m/e 490 [M+H]+.
Reaction SMILES: C[Si](Cl)(C)C.[C:6]([O:10][C:11](=[O:14])[CH2:12]Br)([CH3:9])([CH3:8])[CH3:7].[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[C:21]([C:25](=[O:28])[CH2:26][CH3:27])[CH:20]=[CH:19][N:18]=1>C(OCC)C.O1CCCC1.[Zn]>[C:6]([O:10][C:11](=[O:14])[CH2:12][C:25]([C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[C:22]=1[O:23][CH3:24])([OH:28])[CH2:26][CH3:27])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCC(=O)c1ccnc(OC)c1OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
To a mixture of zinc (23.1 g; 353.9 mmol) in anhydrous diethyl ether (400 mL) was added trimethylsilyl chloride (0.5 mL). The mixture was stirred for 15 minutes at room temperature and refluxed. Bromoacetic acid tert-butyl ester (56.5 g, 290.0 mmol) was added dropwise and the reaction continued refluxing for an additional 1 hour. The mixture was then cooled to room temperature and cannulated to a solution of 1-(2,3-dimethoxy-pyridin-4-yl)-propan-1-one (13.8 g; 70.8 mmol) in anhydrous tetrahydrofuran (300 mL). The reaction was stirred for 16 hours at room temperature and quenched with saturated ammonium chloride solution. The aqueous layer was extracted with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure and purified by chromatography (SiO2; 2-10% ethyl acetate/hexane) to give the product 3-(2,3-dimethoxy-pyridin-4-yl)-3-hydroxy-pentanoic acid tert-butyl ester (6) (16.0 g).
Reaction SMILES: [CH:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of ethyl (3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (13.91 g) in tetrahydrofuran (200 mL)-ethanol (20 mL) was gradually added sodium borohydride (640 mg) at 0° C. After stirring at room temperature for 2 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give ethyl (3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (13.20 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 96-98° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=O.C(OC([N:22]1[CH2:27][CH2:26][CH:25]([C:28](=[S:30])[NH2:29])[CH2:24][CH2:23]1)=O)(C)(C)C>>[CH:6]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][C:5]=1[C:3]1[N:29]=[C:28]([CH:25]2[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]2)[S:30][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)c1ccc2c(c1)CCCC2
Product: c1cc2c(cc1-c1csc(C3CCNCC3)n1)CCCC2

Procedure:
The preparation is carried out as described starting from 8 g (31.6 mmol) of 2-bromo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 8 g (32.7 mmol) of 4-thiocarbamoylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:27])[CH:11]=2)[CH:6]=1.[CH3:29]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[O:26][CH3:29])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:27])[CH:11]=2)[CH:6]=1
Reactant: CO
Reactant: COC(=O)Cc1cc(C(O)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(C(OC)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of {6-fluoro-4-[hydroxy-(4-methanesulfonyl-phenyl)-methyl]-naphthalen-2-yl}-acetic acid methyl ester (90 mg, 0.23 mmol) in methanol (5 mL) was added 3 drops of concentrated sulfuric acid. The mixture was heated at reflux overnight. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The collected organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep® Flash column, 230-400 mesh, 0-40% ethyl acetate in hexane) gave {6-fluoro-4-[(4-methanesulfonyl-phenyl)-methoxy-methyl]-naphthalen-2-yl}-acetic acid methyl ester (37.6 mg, 39%) as a clear oil. MS (ESI+) cald. for C22H21FO5S [(M+H)+] 416, obsd. 417.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH2:11])[CH2:3][CH2:2]1.[CH2:12](C(CC)(CC)C([O-])([O-])[O-])[CH3:13]>C(OCC)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:11]=[C:12]2[CH3:13])[CH2:3][CH2:2]1
Reactant: Nc1ccccc1NC1CC1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CCOC(C)=O
Product: Cc1nc2ccccc2n1C1CC1
Yield: 94.4 %

Procedure:
A solution of 1.71 g (0.0115 mole) of N-cyclopropyl-1,2-phenylenediamine and 2.12 ml (0.0115 mole) of triethylorthoacetate in 50 ml of ethyl acetate was heated to reflux for 2 hours. The solvent was removed and the residue partitioned between chloroform and water. The organic phase was separated, dried over sodium sulfate and concentrated to give 1.87 g of a brown oil.