Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:36][CH:35]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.6 %

Procedure:
Potassium ethyl malonate (3.2 g), 1-hydroxybenzotriazole (2.1 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 g) were successively added to a solution of 4-chloroaniline (2.0 g) in N,N-dimethylformamide (20 ml) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (4.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([O:10]C(=O)C)=[C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]([CH2:22][O:23]C(=O)C)=[N:6][CH:5]=1.[Cl-].[NH4+]>CO>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([OH:10])=[C:8]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]([CH2:22][OH:23])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(COC(C)=O)c(OCc2ccccc2)c1OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cnc(CO)c(OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
The compound 8 (9.5 g, 25.4 mmol) was dissolved in methanol (50 ml), and a sodium methylate methanol solution (7.35 ml, 38.1 mmol) was added. The solution was stirred at room temperature for 1 hour, an aqueous saturated ammonium chloride solution was added, and crystals were collected by filtration. Washing with water and diethyl ether afforded 5-benzyloxy-4-hydroxy-6-hydroxymethyl-nicotinic acid methyl ester 18 (4.68 g, 64%) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl.CO>C(O)CCCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a suspension of 2,6-dichloropurine (3.78 g; 0.02 mol) and m-anisidine (3.69 g; 0.03 mol) in n-pentanol (40 ml), triethylamine (7 ml; 0.05 mol) was added. The reaction mixture was stirred at 100° C. for 4 hours and then it was allowed to cool to the room temperature. The white precipitate was collected, washed with isopropanol (2×10 ml) and water (3×10 ml). The crude product was purified by the crystallization from methanol in the presence of activated charcoal to give white crystals. Yield: 4.36 g (77.8%). TLC (chloroform-methanol; 85:15): one single spot, free of starting material, HPLC purity: 98+%
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9][CH2:10]1
Reactant: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: C1COCCN1
Product: CC1CCN(c2cc(N3CCOCC3)ccc2[N+](=O)[O-])CC1
Yield: 99.9 %

Procedure:
The procedure of Example 4, step (b) was followed using 304 mg (1.19 mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the previous step) and 519 μL (5.95 mmol) of morpholine to afford 363 mg (106%) of the title compound as a yellow resin: Mass spectrum (ESI, m/z): Calcd. for C16H23N3O3, 306.2 (M+H), found 306.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7](Br)[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[C:16]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([CH3:16])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: COC(=O)c1c(N)c(Br)cc2cn[nH]c12
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1c(N)c(C)cc2cn[nH]c12
Temperature: 180 °C
Reaction time: 0.08 h
Yield: 42.9 %

Procedure:
To a solution of 500 mg (1.85 mmol) of 6-amino-5-bromo-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 16, in 10 mL of dioxane under an atmosphere of argon is added 767 mg (5.55 mmol) of K2CO3, 106 mg (0.09 mmol) of tetrakis(triphenylphsophine)palladium and 232 mg (1.85 mmol) of trimethylboroxine. The reaction mixture is stirred in a microwave oven at 180° C. for 5 minutes. After filtration over Celite and concentration in vacuo, the residue is purified sequentially by flash chromatography (SiO2, hexanes/ethyl acetate 6:4) and reverse phase chromatography to afford 163 mg of product (43% over two steps) as a pale yellowish solid; LC/MS:206/207 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5](=[O:19])[CH:6](Cl)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][SH:31])=[CH:25][CH:24]=1.COC(=O)C(SCCC1C=CC(F)=CC=1)CC1C=CC(C(C)(C)O[SiH2]C(C)(C)C)=CC=1>>[Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5](=[O:19])[CH:6]([S:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1
Reactant: Fc1ccc(CCS)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cl)Cc1ccc(CCCO)cc1
Agent: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Product: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CCCO)cc1)SCCc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-chloro-3-[4-(3-hydroxy-propyl)-phenyl]-propionic acid 2,2,2-trichloro-ethyl ester (0.74 g, 1.98 mmol) and 2-(4-fluoro-phenyl)-ethanethiol (0.34 g, 2.17 mmol) as described for 3-[4-(tert-butyl-dimethyl-silanyloxy-methyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid methyl ester. After repeated purification by flash chromatography with n-heptane/EtOAc 9:1 as the eluent the product was obtained as an oil (94 mg, 9.6%). 1H NMR (300 MHz, CDCl3): δ 7.10-7.11 (m, 6H), 6.94-6.98 (t, 2H), 4.65-4.75 (q, 2H), 3.64-3.68 (t, 2H), 3.58-3.61 (dd, 2H), 3.17-3.23 (dd, 2H), 2.80-2.97 (m, 5H), 2.65-2.70 (t, 2H), 1.86-1.89 (m, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:12])=[CH:4][C:3]=1[CH3:13].C[O-].[Na+].CO.CN([CH:22]=[O:23])C.Cl>C(OCC)(=O)C.[Cu](I)I>[CH3:22][O:23][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:12])=[CH:4][C:3]=1[CH3:13]
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c2c(c1Br)OC(C)C2
Agent: I[Cu]I
Agent: C[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(C)cc(C)c2c1OC(C)C2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 7-bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (10.0 g, 41.5 mmol) synthesized in Reference Example 79, copper iodide (I) (7.88 g, 41.5 mmol), 28% sodium methoxide/methanol solution (41.5 mL) and DMF (20.7 mL) was stirred at 120° C. for 2 hours. After cooled, 3N hydrochloric acid was added to the reaction solution to be neutralized, and it was diluted with ethyl acetate. Insolubles were removed by Celite filtration, and the obtained filtrate was washed with water and saturated saline. The organic layer was dried using magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 94:6) to give 5.5 g of the title compound as an oily product (yield: 69%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[C:14]=2[O:21][CH3:22])=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C@H:8]([NH:10][C:11]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[C:14]=3[O:21][CH3:22])=[O:12])[CH3:9])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1c(C(=O)N[C@H](C)c2cccc(Br)c2)ccn(C)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1c(C(=O)N[C@H](C)c2cccc(-c3ccc(F)cc3)c2)ccn(C)c1=O
Temperature: 100 °C

Procedure:
To a solution of (R)—N-(1-(3-bromophenyl)ethyl)-3-methoxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (Intermediate 12) (60 mg, 0.16 mmol) in DME (1.0 mL) was added 4-fluorophenylboronic acid (46.0 mg, 0.329 mmol), sodium carbonate (0.246 mL, 0.493 mmol), and tetrakis(triphenylphosphine)palladium(0) (38.0 mg, 0.0330 mmol) in a microwave vial. The reaction was degassed 3 times under argon and heated at 100° C. overnight. The reaction mixture was diluted with DCM and the organic portion dried over MgSO4, filtered and concentrated to give Example 47A which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[N:28][CH:29]=2)[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[CH:13]=1)=O>>[CH3:33][N:31]([CH3:32])[C:30]([C:27]1[N:28]=[CH:29][C:24]([O:23][C:21]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:10](=[O:9])[NH:1][C:2]3[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=3)[CH:22]=2)=[CH:25][N:26]=1)=[O:34]
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Product: CN(C)C(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (152 mg, 1.56 mmol) and 4-(2-dimethylcarbamoyl-pyrimidin-5-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (164b) (58 mg, 0.16 mmol) to give a white solid (64 mg, 94% yield). 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1 H) 8.47 (s, 2 H) 7.20-7.34 (m, 1 H) 7.07 (d, J=1.52 Hz, 2 H) 6.76 (d, J=2.02 Hz, 1 H) 3.73 (s, 3 H) 3.14 (s, 3 H) 2.98 (s, 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C22H24N6O4 m/z 437.00 (M+H+); Anal. Calcd. for C22H24N6O4.0.15 CHCl3: C, 58.55; H, 5.36; N, 18.50; Found: C, 58.59; H, 5.45; N, 18.61.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:11][CH2:12][CH2:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.Cl>O.C(Cl)Cl>[OH:11][CH2:12][CH2:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][CH2:19][N:20]([C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[S:21]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[CH:16][CH:15]=1
Reactant: O=S(=O)(NCCc1ccc(CCO)cc1)c1ccc(Cl)cc1
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)N(CCc1ccc(CCO)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 2.63 g. (16 mmole) octanoyl chloride in 25 ml. methylene chloride is slowly added dropwise at 0° C. to a mixture of 5.5 g. (16 mmole) 4-chlorobenzenesulphonic acid-4-(2-hydroxyethyl)-phenethylamide], 1.8 g. (18 mmole) triethylamine and 100 ml. methylene chloride. The reaction mixture is then maintained for 1 hour at 0° C. and for a further 2 hours at ambient temperature. It is subsequently shaken out with dilute hydrochloric acid and water, dried with anhydrous sodium sulphate and evaporated. After chromatography with silica gel/methylene chloride, there are obtained 3.8 g. (51% of theory) of the desired product: m.p. 55° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C([Li])CCC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3[CH:37]=[C:38]4[C@:43]([CH:45]=[O:46])([CH2:44][C:35]=3[CH:34]=[N:33]2)[CH2:42][N:41]([S:47]([C:50]2[CH:51]=[C:52]([CH3:56])[CH:53]=[CH:54][CH:55]=2)(=[O:49])=[O:48])[CH2:40][CH2:39]4)=[CH:28][CH:27]=1.O>O1CCCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3[CH:37]=[C:38]4[C:43]([C@H:45]([C:6]5[N:7]=[CH:8][CH:9]=[CH:10][N:11]=5)[OH:46])([CH2:44][C:35]=3[CH:34]=[N:33]2)[CH2:42][N:41]([S:47]([C:50]2[CH:51]=[C:52]([CH3:56])[CH:53]=[CH:54][CH:55]=2)(=[O:49])=[O:48])[CH2:40][CH2:39]4)=[CH:28][CH:27]=1
Reactant: Cc1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C=O)C2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)CC3([C@@H](O)c3ncccn3)C2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
To a stirred solution of 2-(tributylstannyl)pyrimidine (428 μl, 1.351 mmol) in dry tetrahydrofuran (5 mL) was added butyllithium (2.5 M in hexanes) (554 μl, 1.384 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours. A solution of (R)-1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (200 mg, 0.443 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was stirred for 1.5 hours at −78° C. Water (25 mL) was added and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was partitioned between acetonitrile (25 mL) and hexanes (15 mL). The hexane layer was discarded. The acetonitrile layer was concentrated in vacuo to give a pale orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)methanol (75 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.27 min, m+H=532.2.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[C:13]([C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:17]([C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[N:16]=1)=[O:14])=[O:6]>O1CCCC1>[CH3:33][O:32][C:29]1[N:28]=[CH:27][C:26]([N:17]2[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:19][C:15]([C:13]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][C@H:7]3[C:5]([OH:6])=[O:4])=[O:14])=[N:16]2)=[CH:31][CH:30]=1
Reactant: COC(=O)[C@@H]1COCCN1C(=O)c1cc(-c2ccccn2)n(-c2ccc(OC)nc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)N3CCOC[C@H]3C(=O)O)cc2-c2ccccn2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1N Aqueous solution of sodium hydroxide (3 mL) was added dropwise to the above-obtained (3S)-4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine-3-carboxylic acid methyl ester (387 mg) in tetrahydrofuran (5 mL) with ice cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was partitioned between 1N aqueous solution of hydrochloric acid (3.5 mL) and chloroform. Subsequently, the organic layer was dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was removed under reduced pressure, to thereby give (3S)-4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]morpholine-3-carboxylic acid as an amorphous product (338 mg, 90%).
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[CH:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>CCOCC>[Cl:12][C:8]1[CH:9]=[C:10]([Cl:11])[C:5]([SH:4])=[C:6]([CH:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH:7]=1
Reactant: CN(C)C(=O)Sc1c(Cl)cc(Cl)cc1C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Fc1ccc(C(c2ccc(F)cc2)c2cc(Cl)cc(Cl)c2S)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of 6.2 g of S-[4,6-dichloro-2-[bis(4-fluorophenyl)methyl]phenyl] N,N-dimethylthiocarbamate from stage (c) in ether was added dropwise, while cooling in ice, to a suspension of 0.8 g of lithium aluminum hydride in absolute ether. The mixture was stirred at room temperature for 90 min and was hydrolyzed, while cooling in ice, with 2 N sulfuric acid (pH 3). It was extracted several times with ether, the solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The thiophenol remained as residue (5.3 g of viscous oil, 100% yield) and was pure by TLC (100% toluene, Rf =0.66); melting point 95° C.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][CH:7]([C:10]([CH3:12])=[CH2:11])[CH2:6][CH:5]=1.O>CN(C)C.C(Cl)Cl>[C:10]([CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)([CH3:12])=[CH2:11]
Reactant: C=C(C)C1CC=C(O[Si](C)(C)C)CC1
Agent: CN(C)C
Solvent: ClCCl
Solvent: O
Product: C=C(C)C1CCC(=O)CC1
Reaction time: 2 h

Procedure:
4.1 g of a 37% strength solution of HF in trimethylamine were added dropwise with stirring at room temperature to 8.0 g (0.038 mol) of 1-trimethylsilyloxy-4-isopropenyl-1-cyclohexene in 100 ml of CH2Cl2, and the mixture was subsequently stirred for 2 hours. Water was added, extraction was carried out with CH2Cl21 and the combined organic phases were dried and concentrated. 4.7 g (90% of theory) were obtained of a colorless oil which was reacted without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][OH:18])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:16]=[C:14]1[O:18][CH2:17][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13]1
Reactant: O=C(O)C[C@H](CO)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1C[C@@H](NC(=O)OCc2ccccc2)CO1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
(R)-3-(Benzyloxycarbonylamino)-4-hydroxybutanoic acid (INTERMEDIATE 2, 27.7 g, 109.38 mmol) was dissolved in toluene (648 ml). p-Toluenesulfonic acid (367 mg, 2.13 mmol) was added to the solution and the resulting mixture was heated at reflux under Dean-Stark conditions for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Diethyl ether (200 ml) was added, and formation of crystals was observed upon standing. The crystals were filtered in vacuo. The mother liquors were concentrated in vacuo and additional diethyl ether (40 ml) was added. More crystals appeared which were filtered in vacuo. Both sets of crystals combined to give the title product (22.8 g, yield: 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=O)[CH:6]=[CH:5]2>[Pd].C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([CH2:13][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5]2
Reactant: Cc1cc2ccc(C(=O)CCC(=O)O)cc2cc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc2ccc(CCCC(=O)O)cc2cc1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The β-isomer, 3-(6,7-dimethyl-2-naphthoyl)propanoic acid (6.58 g, 0.026 mole) was dissolved into 200 ml of THF in a hydrogenation pressure bottle. To the solution was carefully added 30% Pd/C (700 mg). The whole mixture was shaken for 15 hrs under H2 (40 psi) at room temperature. After releasing pressure, Pd/C was removed by passing the THF solution through the celite pad. The solution was concentrated to afford 4-(6,7-Dimethyl-2-naphthyl)butanoic acid as a gray solid material (6 21 g, 0.026 mole, 100% yield). mp 141.0°-142.0° C., 1H NMR (CDCl3) δ1.98-2.12 (m,2H), 2.36-2.41 (m,8H), 2.81 (t, J=7.4 Hz,2H), 7.22 (d, J=8.3 Hz,1H), 7.49-7.55 (m,3H), 7.65 (d, J=8.3 Hz,1H), IR (KBr) cm-1 3700-3450, 2920, 1698, Anal. Calcd. for C16H18O2 : C, 79.31; H, 7.49. Found: C, 79.28; H, 7.49.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26](I)[S:27][C:20]=12)[NH2:14]>>[F:10][C:11]1[CH:12]=[C:13]([NH2:14])[CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[S:27][C:20]=12
Reactant: C#CCN1CCOCC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCOCC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 78.2 %

Procedure:
Prepared from 4-(prop-2-ynyl)morpholine (24 mg, 0.19 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (39 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=5 Hz, 1H), 7.59 (s, 1H), 7.03 (m, 1H), 6.53 (m, 3H), 3.79 (m, 6H), 3.59 (s, 2H), 2.66 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O1CCCC1>CO>[F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(Nc2ccc(F)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1csc(Nc2ccc(F)cc2)n1

Procedure:
The reaction described in Preparation 50 was repeated, but using 12.04 g of ethyl 2-p-fluoroanilinothiazole-4-carboxylate, 6 g of sodium borohydride, 120 ml of anhydrous tetrahydrofuran, and 70 ml of absolute methanol, giving the title compound as colorless prisms.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[Cl:11][C:12]1[C:21]([NH2:22])=[C:20]([NH:23][CH2:24][C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[Cl:11][C:12]1[C:21]2[N:22]=[CH:1][N:23]([CH2:24][C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH:26]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Fc1ccc(-c2cc(Cn3cnc4c(Cl)nc5ccccc5c43)on2)cc1
Temperature: 110 °C
Yield: 58.7 %

Procedure:
Pyridine hydrochloride (3 mg, 0.02 mmol) and triethyl orthoformate (0.3 mL, 1.7 mmol) were added to a solution of 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (0.4294 g, 1.164 mmol) in toluene (10 mL), and the reaction was heated at 110° C. for 16 hours. A solid was present and was isolated by filtration. The filtrate was concentrated under reduced pressure and triturated with diethyl ether to provide a solid. The two solids were combined and purified by column chromatography on silica gel (eluting with 1:1 ethyl acetate:hexane) to provide 0.259 g of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinoline as a white solid, mp 219.0-220.0° C.