Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (0.5 g, 1.32 mmol)in 30 mL of dimethylformamide was treated with excess ethyl bromoacetate (0.7 mL, 6.60 mmol). After heating at 70° C. for 1 h, triethylamine (0.9 ml, 6.6 mmol) was added dropwise; the reaction mixture was then heated at 70° C. for an additional 30 min, after which it was partitioned between saturated sodium bicarbonate and dichloromethane. The organic extract was concentrated in vacuo, and the residue was applied to a 10 g SCX column which was washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo to afford an orange oil, which was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol, then 9:3 dichloromethane-methanol provided 0.31 g (51%) of the title compound as a yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[C:14]=2Br)[CH:9]=1)(=[O:7])[CH3:6].C1(C(=CC(=C(C=1)C)C)C)C>C(Cl)Cl>[C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[CH:14]=2)[CH:9]=1)(=[O:7])[CH3:6]
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Agent: Cc1cc(C)c(C)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2cc(C(C)=O)ccc2c1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
30 Grams of anhydrous aluminum chloride are added portionwise to a mixture made of 41.85 g of 2-acetyl-5-bromo-6-methoxynaphthalene, 22.15 g of durene and 180 ml of anhydrous methylene chloride cooled to -5° C., in such a manner that the temperature of 20° C. is not exceeded. The reaction mixture is kept for 2 hours at room temperature after the end of the addition and then it is worked as in example 1 obtaining 27.1 g of product with a yield equal to 90.6% calculated on the basis of the starting material 2-acetyl-5-bromo-6-methoxynaphthalene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:5][C:6]1[C:7]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:8]=2[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1.[CH3:40][Sn](C)(C)C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:7]2[C:6]([CH2:5][C:4]3[CH:31]=[CH:32][C:33]([CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)=[C:2]([CH3:40])[CH:3]=3)=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[S:9][C:8]=2[CH:25]=1
Reactant: C[Sn](C)(C)C
Reactant: COc1ccc2c(Cc3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2c(Cc3ccc(CN4CCCC4)c(C)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 130 °C
Reaction time: 25 h
Yield: 73 %

Procedure:
3-[3-Bromo-4-[(1-pyrrolidinyl)methyl]benzyl]-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 138, Part A) (93 mg, 0.15 mmol) in toluene (2 mL) in a pressure tube was treated with tetrakis(triphenylphosphine)palladium (0) (17 mg,) and tetramethyltin (0.2 mL) at ambient temperature. The mixture was flushed with argon and allowed to stir in the dark in the sealed tube at 130° C. for 25 h. The cooled reaction mixture was directly fractionated through flash chromatography with 5% triethylamine in ethyl acetate to afford the title compound as a colorless oil (61 mg, 73%) after the solvent removal.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]([N+:18]([O-])=O)=[C:6]([CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]#[N:10])[N:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[NH:18][C:9]([NH2:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: N#CC(Cc1ccccc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1nc2c(Cc3ccccc3)c(N)[nH]c2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-Amino-1,6-dihydro-5-nitro-6-oxo-α-(phenylmethyl)-4-pyrimidine acetonitrile as prepared above (10.0 g) in 1N NaOH (600 mL) is added sodium dithionite (35 g). The reaction mixture is heated at 90° C. for 35 min and is acidified to pH 4 with 4N HCl while still hot. The reaction mixture is cooled in an ice bath and the precipitate is collected by filtration. It is dried over P2O2 under vacuum (4.0 g). The crude (undecarboxy-ated) product is dissolved in 300 mL conc HCl and quickly filtered through a glass frit before it crystallized out. The resulting suspension is boiled for five minutes and cooled. The product 2,6-Diamino-3, 5-dihydro-7-(phenylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one is collected by filtration (1.98 g, 23%) mp >250° C. (dec). ##STR13##
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:13])[C:6]=1[S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8].[C:14](OC)(OC)(OC)[CH3:15]>>[CH3:14][C:15]1[NH:1][C:2]2[S:3][CH:4]=[C:5]([CH3:13])[C:6]=2[S:7](=[O:9])(=[O:8])[C:10]=1[C:11]#[N:12]
Reactant: COC(C)(OC)OC
Reactant: Cc1csc(N)c1S(=O)(=O)CC#N
Product: CC1=C(C#N)S(=O)(=O)c2c(C)csc2N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (2-amino-4-methylthiophene-3-sulfonyl)acetonitrile (0.50 g) in trimethyl orthoacetate (1 ml) was heated at 120-130° C. for 2 h and then concentrated in vacuo at ˜50° C. for 1 h. The residue was suspended in a mixture of absolute ethanol (5 ml) and triethylamine (0.32 ml) and stirred at reflux for ½ h, then at 0° C. for ½ h and filtered. The filtrate was heated at reflux for one more hour, concentrated in vacuo, dissolved in ethyl acetate (10 ml) and extracted with 1 M NaOH (10 ml). The aqueous phase was washed with ethyl acetate (2×5 ml), cooled to 0° C. and acidified with 10 M HCl, pH being adjusted to 0-1. After stirring for 1 h at 0° C. the precipitate was collected by filtration and dried to give the title compound as a practically pure beige solid. Yield 0.09 g (16%). An analytically pure sample was obtained by recrystallization from methanol; mp 347-349° C. (decomp.); 1H-NMR(DMSO-d6) δ (ppm): 12.7 (br, 1H), 7.09 (s, 1H), 2.40 (s, 3H), 2.32 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 153.9, 143.5, 131.5, 119.6, 116.6, 113.8, 89.6, 20.4, 15.3; IR 3226, 3030, 2903, 2227(C≡N), 1580, 1526, 1281 and 1134 (SO2). Elemental analysis, % found (calc. for C9H8N2O2S2): C 44.69 (44.98); H 3.22 (3.36); N 11.33 (11.66); S 26.76 (26.69).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])=[C:23]([C:24]([N:11]2[CH2:10][CH2:9][C:7]3[N:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[N:4]=[CH:5][C:6]=3[CH2:12]2)=[O:25])[CH:27]=1)(=[O:18])=[O:17]
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1ncc2c(n1)CCNC2
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2nc(C(F)(F)F)ncc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (CA [74737-17-7]; WO2004069162) and 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.3). MS (m/e): 498.4 (M+H+).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)C>C1C=CC=CC=1>[O:6]1[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][C:8]=2[CH:4]=[CH:5]1
Reactant: CCOC(=O)Cc1ccc(OCC(OCC)OCC)cc1
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc2occc2c1
Reaction time: 0.67 h
Yield: 29.4 %

Procedure:
In a 1 L 3-necked flask equipped with a mechanical stirrer and a condenser was added polyphosphoric acid (80 gm) and benzene (450 mL). This mixture was heated to reflux for 15 min and then ethyl 4-[(2,2-diethoxy)ethoxy]phenylacetate (86 gm, 0.29 mol) in benzene (50 mL) was added and the reflux was continued for 40 min. The reaction mixture was cooled and the mobile phase was decanted off. This benzene solution was washed successively with H2O, sat. NaHCO3, and sat. NaCl before being dried over Na2SO4, filtered and evaporated to dryness. This residue was dissolved in 10-15% EtOAc in hexane and passed through a short silica gel column (5 cm×10 cm dia.) in the same solvent. The eluent was evaporated to dryness to give a yellow liquid which was further purified by preparative LC using 10% EtOAc in hexane as eluent to give 17.4 gm of ethyl benzofuran-5-ylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([C:10]2[C:11]([F:17])=[N:12][C:13]([F:16])=[CH:14][CH:15]=2)[OH:9])[CH:7]=1.N1C=CN=C1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].O>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([O:9][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30])[C:10]2[C:11]([F:17])=[N:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1C(O)c1ccc(F)nc1F
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(Br)cc1C(O[Si](C)(C)C(C)(C)C)c1ccc(F)nc1F
Temperature: 70 °C

Procedure:
(5-Bromo-2-methoxyphenyl)(2,6-difluoropyridin-3-yl)methanol (13.77 g, 41.7 mmol) and imidazole (3.41 g, 50.1 mmol) were dissolved in dry DMF (20 mL) under nitrogen. t-Butyl(chloro)dimethylsilane (6.92 g, 45.9 mmol) was added and the solution heated to 70° C. After 1 hour the mixture was cooled to RT. Water (200 mL) and diethyl ether (200 mL) were added and the phases mixed and separated. The organic was washed with water (200 mL) one more time then dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to 1:1 DCM: hexane gradient) gave 3-((5-bromo-2-methoxyphenyl)(tert-butyldimethylsilyloxy)methyl)-2,6-difluoropyridine as a thick oil that solidified on standing.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[N+:8]([O-:10])[C:7]3[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:12][CH2:13][NH:14][C:6]=3[N:5]2[CH:21]=1.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[C:15]1([C:11]2[C:7]3[N+:8]([O-:10])=[CH:9][C:4]4[N:5]([CH:21]=[C:2]([N:32]5[CH2:33][CH2:34][N:29]([CH2:22][C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)[CH2:30][CH2:31]5)[N:3]=4)[C:6]=3[NH:14][CH2:13][CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [O-][n+]1cc2nc(Cl)cn2c2c1C(c1ccccc1)=CCN2
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC(C)O
Product: [O-][n+]1cc2nc(N3CCN(Cc4ccccc4)CC3)cn2c2c1C(c1ccccc1)=CCN2
Temperature: 25 °C
Yield: 84.4 %

Procedure:
8-Chloro-1,2-dihydro-4-phenylimidazo[1,2-a]pyrido[3,2-e]pyrazine 5-oxide (3 g, 0.01 mol) and benzylpiperazine (3.6 g, 0.02 mol) were heated at 80° C., in isopropanol (100 ml) under an atmosphere of nitrogen for 16 hrs. As the reaction mixture cooled to room temperature, a yellow solid precipitated. The yellow solid was collected by filtration, washed with cold isopropanol and recrystallized from isopropanol to yield 1,2-dihydro-4-phenyl-8-(4-phenylmethylpiperazinyl)imidazo [1,2-a]pyrido[3,2-e]pyrazine 5-oxide (3.7 g), as orange needles, m.p. 184°-187° C. (Found: C,71.03; H,6.02; N,19.30%; C26H24N6O.O.1H2O requires C,70.92; H,6.00; N,19.09%), represented by the structural formula: ##STR30##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11].[Na+].[I-].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[CH:6][C:5]=1[CH3:11]
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC2CC2)cc1C
Yield: 35.3 %

Procedure:
4-Hydroxy-2-methyl-benzoic acid methyl ester (1.0 g, 6.0 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.45 g, 3.0 mmol, 0.5 eq) and K2CO3 (1.66 g, 12.0 mmol, 2.0 eq) were added ad the mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (0.53 mL, 5.4 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and the crude was extracted with DCM and dried. 0.42 g of title product (yield 32%) were recovered and used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[CH3:16][C:17]1[N:22]=[C:21]2[NH:23][C:24](=[O:26])[O:25][C:20]2=[CH:19][CH:18]=1>>[CH3:16][C:17]1[N:22]=[C:21]2[N:23]([CH2:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)[CH:9]=3)[C:24](=[O:26])[O:25][C:20]2=[CH:19][CH:18]=1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Reactant: Cc1ccc(-c2cccc(CO)c2)nc1
Product: Cc1ccc(-c2cccc(Cn3c(=O)oc4ccc(C)nc43)c2)nc1

Procedure:
Reaction of [3-(5-methylpyridin-2-yl)phenyl]methanol with 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one under Mitsunobu conditions gives the desired 5-methyl-3-[3-(5-methylpyridin-2-yl)benzyl]-3H-oxazolo[4,5-b]-pyridin-2-one, ESI 332 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Si:10]([O:9][CH2:8][C:7]1[C:2]([C:17]#[N:18])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1C#N
Temperature: 120 °C
Yield: 82 %

Procedure:
A mixture of 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 100.0 mmol, 1 eq.) and Zn(CN)2 (23.5 g, 200.0 mmol, 2.0 eq.) in DMF (100.0 mL) was purged with N2 for 5 min and added Pd(PPh3)4 (5.78 g, 5.0 mmol, 0.05 eq.). The mixture was heated at 120° C. for 2 h under N2, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82%) as a colorless oil. MS (ESI) m/z 249.1 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[OH:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:23]3[CH:22]=[C:21]([CH2:20][OH:19])[O:25][N:24]=3)=[O:27])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(CO)on1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CO)on1
Yield: 1.9 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(hydroxymethyl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.675 mmol) and 5-(hydroxymethyl)isoxazole-3-carboxylic acid (126 mg, 0.878 mmol). The product purified twice by Flash-chromatography (normal phase and reverse phase) and triturated using diethyl ether. Yield 1.9%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 4.28-4-43 (m, 2H), 4.52-4.63 (m, 1H), 4.68 (d, 2H), 6.57 (t, 1H), 6.77 (d, 1H), 7.70 (d, 1H), 7.78 (dd, 1H), 7.88 (dd, 1H), 8.07 (dd, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:10]2[C:11]([OH:14])=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.O[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(P(=C(C(OC)=O)C(OC)=O)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1noc2cccc(OCC(F)(F)F)c12
Agent: CCCCP(CCCC)(CCCC)=C(C(=O)OC)C(=O)OC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC(F)(F)F)c23)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
A mixture of 4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-ol (0.12 g, 0.50 mmol, EXAMPLE 1, step 2), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.13 g, 0.60 mmol), and dimethyl (tributylphosphoranylidene)malonate (0.32 g, 1.0 mmol, J. Org. Chem. 2003, 68, 1597-1600) in toluene (0.5 mL) was stirred at 80° C. for 16 h. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate 4:1) to give 0.14 g (65%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N+:11]([O-])([OH:13])=[O:12]>>[N+:11]([C:5]1[N:1]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:3][CH:4]=1)([O-:13])=[O:12]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: O=[N+]([O-])O
Product: CCOC(=O)c1nc([N+](=O)[O-])c[nH]1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
While cooling on ice, 16.08 g (114.7 mmol) of ethyl imidazole-2-carboxylate are dissolved in 71.7 ml of concentrated sulpfuric acid. 71.7 ml of 100% fuming nitric acid are then added dropwise. The reaction solution is stirred at 50 to 60° C. for 3 h and, after cooling, poured onto 800 ml of an ice/water mixture. The precipitated crystals are collected by suction filtration and washed with 1500 ml of ice-water.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([SH:11])[CH:3]=1.[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[S:11][C:4]=2[CH:3]=1
Reactant: Cc1ccnc(C#N)c1
Reactant: O=C(O)c1ccc(Cl)cc1S
Solvent: c1ccncc1
Product: Cc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Yield: 32 %

Procedure:
A mixture of 4-chloro-2-mercaptobenzoic acid (3.0 g, 15.9 mmol), 2-cyano-4-methylpyridine (1.9 g, 16.0 mmol) and pyridine (15 ml) was refluxed for 9 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration, subjected to a silica gel column chromatography, eluted with ethyl acetate-methanol (5:1, v/v) and recrystallized from chlorobenzene-hexane to give the titled compound (1.47 g, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[C:7]([O:12]C)[C:8]=1[N+:9]([O-:11])=[O:10].Cl.N1C=CC=CC=1>>[OH:12][C:7]1[CH:6]=[C:5]([CH2:14][C:15]([OH:17])=[O:16])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(CC(=O)O)cc(OC)c1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(CC(=O)O)cc(O)c1[N+](=O)[O-]
Temperature: 145 °C

Procedure:
A stirred mixture of 3,5-dimethoxy-4-nitrophenylacetic acid (0.4 g, Reference Example 13) and pyridine hydrochloride (6 g) was heated at 145° C., under argon, for 4 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, then with brine, then dried and then evaporated to give a 1:1 mixture of the title compound and starting material (0.37 g) which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1OB(O)O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C(CCO)=CC=CC=1.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>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9]
Reactant: OB(O)Oc1cccs1
Reactant: N#Cc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccnc(-c2cccs2)c1
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
2-Chloro-4-cyanopyridine (0.50 g, 3.6 mmol) and 2-thienylboric acid (0.69 g, 5.4 mmol) were dissolved in toluene-ethanol (4:1, v/v, 25 ml), and to the mixture, a solution of potassium carbonate (1.3 g, 9.0 mmol) in water (5 ml) was added. The mixture was deairated under reduced pressure for 15 minutes. Tetrakis(triphenylphosphine)palladium (0.21 mg, 0.2 mmol) was added to the mixture under nitrogen atmosphere, and the mixture was refluxed for 20 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel (60 g) column chromatography and eluted with hexane-ethyl acetate (3:1, v/v) to give solid, which was recrystallized from ethanol to give the titled compound (0.35 g, 52%).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.[CH3:29]C1C=C(CS)C=CC=1>>[OH:26][CH2:25][C@H:24]([NH:23][C:21]1[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=[C:13]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:29])[CH:2]=2)[N:22]=1)[CH3:27]
Reactant: Cc1cccc(CS)c1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Product: Cc1cccc(CSc2nc(N[C@H](C)CO)c3ncc(=O)[nH]c3n2)c1
Yield: 43.2 %

Procedure:
The titled compound (75 mg) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (0.20 g) and 3-methyl-benzenemethanethiol (75 mg).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[OH:11].[CH3:12]C(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[CH3:12][C:5]12[CH2:6][CH2:7][CH:8]=[CH:9][C:10]1=[CH:1][C:2](=[O:11])[CH2:3][CH2:4]2
Reactant: CC(C)=O
Reactant: OC1CCc2ccccc2C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC12CCC=CC1=CC(=O)CC2

Procedure:
1,2,3,4-Tetrahydro-2-napthol is reduced according to Preparation 9. The resulting diene is cyclopropanated with Simmons-Smith reagent, oxidized with Jones reagent, then the cyclopropane ring opened with acid to form dienone 4.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]([S:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:12][N:13]=1)=O)(C)(C)C>C([O-])(O)=O.[Na+]>[NH2:8][C:9]1[S:10][C:11]2[S:14][CH2:15][CH2:16][C:17](=[O:19])[C:12]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(SCCC(=O)O)s1
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1nc2c(s1)SCCC2=O

Procedure:
3-[2-(tert-butoxycarbonylamino)thiazol-5-yl]sulfanylpropanoic acid (300 mg, 1.0 mmol) was dissolved in polyphosphoric acid (3.08 g, 14 mmol) and heated at 60˜80° C. for 2 hours. The reaction mixture was diluted with ice-cold water and neutralized with NaHCO3 to pH (8˜9) and the solid formed, filtered and washed with water and dried to give the title compound a yellow solid (150 mg, 80% yield)1H NMR (400 Mz, d6-DMSO) δ2.67 (t, 2H), 3.34 (t, 2H), 7.18 (s, 2H).