Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:39][CH3:40])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[O:39][CH3:40]
Reactant: COc1ccc(N)cc1O
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5cc(C)nn5C)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 25, 100 mg, 0.240 mmol) and THF (1.5 mL). To the resulting solution was added 5-amino-2-methoxyphenol (39 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The solid precipitate that formed was filtered and washed with 1 mL of ice cold THF yielding 61% (34 mg, 0.065 mmol) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].Cl.[N:47]1[CH:52]=[CH:51][C:50]([CH2:53]Cl)=[CH:49][CH:48]=1>>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:53][C:50]4[CH:51]=[CH:52][N:47]=[CH:48][CH:49]=4)[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1ccncc1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccncc4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine (5 mmol) and 4-picolyl chloride hydrochloride to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CCO)cc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (2.94 g) and 1-fluoro-4-nitrobenzene (3.0 g) in dimethylformamide (21 mL) was added potassium carbonate (4.41 g) and the solution was stirred at 120° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the title compound having the following physical data.
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:8]1([Mg]Cl)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH:8]1([CH:3]2[CH2:4][O:5][CH2:6][CH2:7][N:2]2[OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: ON1CCOCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCOCC1C1CCCCC1
Reaction time: 1 h
Yield: 24 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of cyclohexylmagnesium chloride (2.0 M in diethyl ether, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 50% diethyl ether in hexanes to give the title compound (0.220 g, 24%) as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:34]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCBr
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc2c(C)cc(=O)oc2c1
Yield: 91.7 %

Procedure:
35.2 g (0.2 mole) of 7-hydroxy-4-methyl-coumarin, 27.6 g (0.2 mole) of potassium carbonate, 55.4 g (0.2 mole) of 1-bromotetradecane and 600.0 ml of dry dimethylformamide are stirred in a steam bath overnight. The mixture is cooled and extracted into 1.5 liters of diethyl ether. The ether layer is washed 5 times with saturated saline. It is dried (Na2SO4) and evaporated. The ether is replaced with 800 ml of hexane. The mixture is recrystallized therefrom, yielding 68.3g (92%) of 7-tetradecyloxy-4-methyl-coumarin, m.p. 61°-62° C.
Reaction SMILES: [C:1]([NH:5][C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])[CH3:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@H](C(O)=O)C)=O)C1C=CC=CC=1.C(N1CCC[C@H]1C(O)=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[C:61]([NH:69][CH:70]([S:74][C:75](=[O:82])[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:71](O)=[O:72])(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(#N)C.O1CCCC1>[C:1]([N:5]([C:71](=[O:72])[CH:70]([S:74][C:75](=[O:82])[C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1)[NH:69][C:61](=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(NC(SC(=O)c1ccccc1)C(=O)O)c1ccccc1
Reactant: C[C@H](NC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)N1CCC[C@H]1C(=O)O
Agent: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)O)N(C(=O)C(NC(=O)c1ccccc1)SC(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
12.1 g (50 millimoles) of tert.-butyl alanylproline (prepared by coupling benzyloxycarbonylalanine with tert.-butyl proline using dicyclohexylcarbodiimide, followed by hydrogenolytic elimination of the protective group) were dissolved in 150 ml of dry acetonitrile, a solution of 15.8 g (50 millimoles) of N-benzoyl-α-(benzoylthio)-glycine in 150 ml of dry tetrahydrofuran and 10.3 g (50 millimoles) of dicyclohexylcarbodiimide were added and the mixture was stirred overnight at room temperature. The precipitated dicyclohexylurea was filtered off under suction, and the filtrate was evaporated down under reduced pressure. The residue was chromatographed with 1:1 cyclohexane/ethyl acetate over a column containing deactivated silica gel. 20.2 g (75%) of tert.-butyl N-[N-benzoyl-α-(benzoylthio)glycyl]-alanylproline were obtained as a diastereomer mixture. Crystallization from cyclohexane/ethyl acetate gave 7.5 g of a low-melting isomer of melting point 97°-100° C.; 7.8 g of a high-melting isomer of melting point 147°-150° C. were obtained from the mother liquor after crystallizing the product twice from cyclohexane/ethyl acetate. Cleavage of the two isomers separately, using 6 N HCl/dioxane in a procedure similar to that described in Example 1b, gave N-[N-benzoyl-α-(benzoylthio)-glycyl]-alanylproline as diastereomer I (obtained in crystalline form from ethyl acetate, melting point 185°-188° C., Rf=0.18 in system I, [α]D20 =+29° (c=1 in chloroform)) and diastereomer II (obtained in crystalline form from ethyl acetate, melting point 203°-206° C., Rf=0.18 in system I, [α]D20 =-167° (c=1 in chloroform)).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][CH2:29][CH2:30]O)([CH3:21])[CH3:20])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:37][CH2:30][CH2:29][CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:32])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:34])[C:9]=2[CH3:33])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:35])[CH:17]=[CH:16][N:15]=1)([CH3:21])[CH3:20]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2CCCO)c1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2CCCBr)c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-[3-({1-[2-(3-hydroxypropyl)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide (Example 323h) (0.4 g) dissolved in THF (10 mL) was treated with carbon tetrabromide (0.277 g) under nitrogen. The resulting mixture was cooled to 0° C. before adding triphenylphosphine (0.219 g). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated and the residue purified (SiO2 chromatography eluting with 50% DCM in ethyl acetate) to give the subtitle compound as a solid (0.135 g). 1H NMR δ (CDCl3) 7.65-7.56 (m, 1H), 7.55-7.46 (m, 1H), 7.43-7.34 (m, 1H), 7.26-7.17 (m, 4H), 6.80-6.71 (m, 1H), 6.64-6.55 (m, 1H), 3.38 (t, 2H), 3.08-2.82 (m, 3H), 2.14 (s, 3H), 1.91 (d, 6H), 1.29-1.18 (m, 2H), 0.91-0.81 (m, 2H), 0.66-0.55 (m, 2H)
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:26])[N:15]([CH3:25])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(C)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2C
Yield: 96.9 %

Procedure:
Cyclohexylamine (2.85 mL, 24.95 mmol) was added to a solution of Compound 17 (3.26 g, 12.47 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 3.8 g (97%) of white solids. M.P. 218° C. 1H NMR (DMSO-d6): δ 1.28 (m, 1H), 1.36 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.87 (m, 2H), 2.40 (s, 3H), 3.59 (s, 3H), 3.87 (m, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.86 (s, 1H), 10.49 (s, 1H). EIMS m/z 315 (M+1), 337 (M+23).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1cnc2[nH]ccc2c1
Solvent: CC(C)=O
Product: Brc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Into a 500 mL round bottomed flask were added 5-bromo-1H-pyrrolo[2,3-b]pyridine (10.11 g, 51.3 mmol) and 250 ml acetone. N-iodosuccinimide (NIS, 12.7 g, 56.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with cold acetone to afford 12.2 g (74%) of the title compound as a tan powder. 1H-NMR (500 MHz, d6-DMSO) δ=12.35 (br.s, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz 1H), 7.79 (s, 1H); MS: m/z 322.8/324.8 [MH+].
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:15][CH:16]([C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[OH:17])[C:11](=[O:14])[CH2:12]Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>O1CCCC1>[CH2:3]([N:10]1[C:11](=[O:14])[CH2:12][O:17][CH:16]([C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C(O)CN(Cc2ccccc2)C(=O)CCl)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C2CN(Cc3ccccc3)C(=O)CO2)OCCO1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.75 g) in tetrahydrofuran (50 ml) was added a solution of 2-[2-(N-benzyl-N-chloroacetylamino)-1-hydroxyethyl]-2-methyl-1,3-dioxolane (5.35 g) in tetrahydrofuran (15 ml) under ice-cooling. The mixture was heated under reflux for 4 hours and poured into a mixture of ice-water (100 ml) and ethyl acetate (150 ml). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of hexane and ethyl acetate (7:3, V/V) to give 4-benzyl-2-(2-methyl-1,3-dioxolan-2-yl)-5-oxomorpholine (4.65 g) as a syrup.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][C:6](=[O:21])[CH:5]=1.[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1Cl>CS(C)=O>[CH:18]1([CH2:17][O:16][C:9]2[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6](=[O:21])[CH:5]=[C:4]3[NH:3][C:28]2[C:27]([Cl:30])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:22])[CH2:19][CH2:20]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: COc1ccc2c(N)cc(=O)[nH]c2c1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCC1CC1
Temperature: 32 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Sodium hydride (60%, 14 g, 350 mmol) was added (caution: H2 gas evolution) to a solution of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (18 g, 69 mmol) and DMSO (200 mL) under N2. After 1 h at room temperature, 3,4,5-trichloropyridine (12.6 g, 69 mmol) was added portionwise with external cooling (internal temperature kept below 30° C.), and the reaction was warmed at 32° C. overnight. The reaction was quenched with water (40 mL) and adjusted to pH=6, with saturated potassium phosphate (KH2PO4). The resulting solids were collected by filtration, purified by silica gel chromatography (100:1; dichloromethane/methanol), and then triturated with ethyl acetate (300 mL) to give 22 g of 8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-quinolin-2(1H)-one as a straw yellow solid. MS (ESI): 406.1.
Reaction SMILES: [OH:1][C:2]1[CH2:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][C:4](=O)[CH:3]=1.C([O-])(=O)C.[NH4+:16].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[NH2:16][C:4]1[CH2:5][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:10][C:2](=[O:1])[CH:3]=1
Reactant: [NH4+]
Reactant: O=C1C=C(O)CC2(CCC2)C1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: NC1=CC(=O)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
10 g 8-hydroxyspiro[3.5]non-7-en-6-one and 10.1 g ammonium acetate are dissolved in 100 ml toluene and 3.2 ml acetic acid. The mixture is refluxed for 2 hours using a Dean-Stark trap. After cooling to room temperature the mixture is cautiously added to 200 ml of a saturated solution of sodium bicarbonate and 100 g ice. Then the mixture is stirred for 15 minutes, the solid product is collected by filtration and dried at 50° C. in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH:12]([NH2:14])=O>>[F:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:12][NH:14][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: Nc1cnc(F)cc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2cnc(F)cc12
Yield: 20 %

Procedure:
Reaction of 5-amino-2-fluoropyridine-4-carboxylic acid with formamide at 140° C. as above gave 6-fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (-20%). 1H NMR (DMSO) 6 12.48 (1H, m), 8.74 (1H, s), 8.16 (1H, s), 7.63 (1H, d, J=3 Hz).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([OH:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([OH:13])[CH2:5][CH2:4]1)[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: CN[C@@H]1CC[C@@H](O)c2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CC[C@@H](O)c4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,4R)-1,2,3,4-tetrahydro-4-(methylamino)-1-naphthalenol and its enantiomer (70 mg, 0.39 mmol) (i.e. the product of Example 28, Step A) and triethylamine (0.082 mL, 0.59 mmol) in 2 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (181 mg, 0.43 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 3 h, diluted with 5 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 0-20% of acetone in ethyl acetate as eluant to give 160 mg of the title compounds, compounds of the present invention as a white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([Sn](C)(C)C)=[CH:16][CH:15]=1.O>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: Brc1ccccc1-c1cccs1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccccc2-c2cccs2)cc1
Temperature: 100 °C

Procedure:
A vigorously stirred solution of 3.4 g (14 mmol) of 1-bromo-2-(2-thienyl)benzene and 3.77 g (15 mmol) of 4-methylphenyltrimethylstannane in 50 mL of dimethylformamide under a nitrogen atmosphere was treated with 427 mg of bis(triphenylphosphine) palladium(II) chloride and the resulting mixture heated at 100° C. for 4.5 hours. The reaction mixture was cooled, poured into 250 mL of water and the resultant mixture extracted with ethyl ether. The combined extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was dissolved in hexane/ether (100:5) and chromatographed on silica gel, eluting with hexane/ether (100:5) to give 2.25 g of he product. 1H NMR (200 MHz, CDCl3): 2.33 (s, 3H), 6.48 (dd, 1H), 6.83 (dd, 1H), 7.08 (m, 4H), 7.16 (dd, 1H), 7.35 (m, 3H), 7.46 (dd, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]([O-:48])(=[O:47])[CH3:46].[Na+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26][O:48][C:45](=[O:47])[CH3:46])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCOC(C)=O)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 40 °C
Reaction time: 17 h
Yield: 32.4 %

Procedure:
To the product of Example 145 (21 mg, 32 μmol) in acetone (2 mL) was added tetra-n-butylammonium iodide (24 mg, 65 μmol). The solution was stirred at 40° C. for 17 h prior to the addition of sodium acetate (50 mg, 0.64 mmol). The reaction solution was heated at 75° C. for 48 h. After cooling the solution was diluted with EtOAc (25 mL), washed with saturated NaHCO3 (20 mL) and water (2×20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude sample was chromatographed (silica gel, DCM) to provide the title compound (7 mg, 33%). 1H-NMR (CDCl3) δ 7.87 (1H, s), 7.60 (1H, dd), 7.30–7.35 (3H, m), 7.17–7.22 (3H, m), 6.60 (1H, dd), 6.48 (1H, d), 5.27 (2H, s), 4.72 (1H, s), 4.39 (2H, t), 4.16 (2H, t), 3.69 (2H, q), 3.16 (2H, s), 3.08 (3H, s), 2.43 (6H, s), 2.06 (3H, s), 0.91 (3H, t); MS(ESI): 675 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]2[N:24]([CH3:25])[C:15]3=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]3[N:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C=O)C.[CH2:31]([S-:33])[CH3:32].[Na+]>O>[CH2:31]([S:33][C:2]1[C:3]([C:12]2[N:24]([CH3:25])[C:15]3=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]3[N:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH3:32]
Reactant: Cn1c(-c2ncc(C(F)(F)F)cc2Cl)nc2cc(C(F)(F)F)cnc21
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cc(C(F)(F)F)cnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a mixture of 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.71 g) and DMF (4 ml) was added sodium ethanethiolate (0.24 g) while ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-(3-ethylsulfanyl-5-trifluoromethylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.76 g), which is hereinafter referred to as “the present compound 4”.