Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)C=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:30](=[O:31])[CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[C:19]2[C:20](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:21]=[CH:22][CH:13]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(N)cc1OCCc1ccc2ccccc2c1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[4-methoxy-3-(naphthylmethoxy)phenyl]-2,2-diphenylethanamide (Exemplary Compound 49) was prepared using the same experimental conditions used to prepare Example 52 (Scheme X). From 4-methoxy-3-(2-naphthylethoxy)phenylamine (350 mg, 1.25 mmol) and diphenylacetyl chloride (290 mg, 1.25 mmol) in 10 mL of dimethyl acetamide containing triethylamine (1 mL, 7.17 mmol) stirred at room temperature for 16 h., was obtained 375 mg of product in (64%) yield as a white solid after recrystallization from ethyl acetate/hexane: mp 170-172° C. 1H NMR (400 MHz, Me2SO-d6) δ3.69 (s, 3H); 5.13 (s, 1H); 5.46 (s, 2H); 6.93 (d, 1H, J=8.7); 7.20-7.37 (m, 10H); 7.50-7.65 (m, 5H); 7.94-8.09 (m, 3H); 10.28 (s, 1H). Anal. Calcd for C32H27NO3: C, 81.16; H, 5.75; N, 2.96. Found: C, 80.95; H, 5.76; N, 3.03.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C>O.C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Fc1cccc(Cl)c1Br
Reactant: Cc1ccc(N)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A mixture of 2-bromo-1-chloro-3-fluorobenzene (32 g, 153 mmol), p-toluidine (16.4 g, 153 mmol), sodium tert.butylate (27.5 g, 286 mmol), (±)-BINAP [2,2′-Bis-(diphenylphosphino)-1,1′-binaphthalin, 0.66 g, 1.1 mmol) and toluene (250 ml) is stirred under nitrogen for about 30 minutes. After the addition of Palladium-bis-(dibenzylidenaceton) (0.8 g, 1 mmol), the mixture is heated to 110° C. (slight reflux) for 14-20 hours. The mixture is then cooled to 30° C., water (60 ml), concentrated hydrochloric acid (60 ml) as well as charcoal and cellite (5 g each) are added and stirring is continued for an hour. The mixture is filtered and the filtrate is separated into the phases. The organic phase is washed with water (3 times, 70 ml each) and concentrated in vacuo to obtain 37.2 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. The product can be used in the next step (Step 1.2) as such; alternatively in can be kugelrohrdistilled in vacuo.
Reaction SMILES: COCCN1CCC([S:15]([N:18]2[CH2:23][CH2:22][CH:21](OC3C=CC(OC(F)(F)F)=CC=3)[CH2:20][CH2:19]2)(=[O:17])=[O:16])(C(OC)=O)CC1.C(=O)([O-])[O-].[K+].[K+].[CH3:42][O:43][CH2:44][CH2:45]Br.C[N:48](C)C=O>>[CH3:42][O:43][CH2:44][CH2:45][NH:48][S:15]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)(=[O:16])=[O:17]
Reactant: COCCBr
Reactant: CN(C)C=O
Reactant: COCCN1CCC(C(=O)OC)(S(=O)(=O)N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCNS(=O)(=O)N1CCCCC1
Temperature: 35 °C
Yield: 50 %

Procedure:
Part I: Preparation of methyl 1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxylate. The unsubstituted piperidine sulfonamide from part H (3.0 g, 6.45 mmol) was dissolved in dry dimethylformamide (15 mL) and potassium carbonate (1.3 g, 9.7 mmol) and 2-bromoethyl methyl ether (908 uL, 9.7 mmol) were added. The reaction was stirred at 35° C. for sixteen hr and then concentrated in vacuo. The residue was taken up in ethyl acetate and filtered through Celite. The filtrate washed with water two times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the N-methoxyethyl piperidine sulfonamide as a white solid (1.65 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3C(OC(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][N:3]=1>CO>[ClH:1].[ClH:1].[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)[nH]1
Solvent: CO
Product: Cl
Product: Clc1ncc(-c2cnc([C@@H]3CCCN3)[nH]2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cold (0° C.) 4 NHCl in dioxanes (5 mL) was added via syringe to (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152d-1, 0.50 g, 1.43 mmol) in a 100 mL pear-shaped flask followed by MeOH (1.0 mL). The suspension was stirred at room temperature for 4 h before it was concentrated down to dryness and placed under high vacuum for 1 h. There was isolated intermediate (S)-2-chloro-5-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyrimidine trihydrochloride as a pale yellow solid (with an orange tint) which was used without further purification.
Reaction SMILES: [C:1]12([CH2:15][C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.Cl.O([NH2:20])C.N1C=CC=CC=1>CO.Cl>[C:1]12([CH2:15][CH:14]([NH2:20])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CC2(CCCCC2)Oc2ccccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: NC1CC2(CCCCC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 1A (3.022 g, 13.99 mmol) in methanol (50 mL) was added methoxylamine hydrochloride (1.17 g, 14.0 mmol) and pyridine (5.7 mL, 70.5 mmol). The mixture was stirred overnight at room temperature and was then evaporated in vacuo. The residue was partitioned between ethyl acetate and H2O, and the organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue thus obtained was dissolved in methanol (50 mL) and was hydrogenated (balloon) over 10% Pd-on-carbon in the presence of 4 drops of conc. HCl overnight at room temperature. After this time, the catalyst was filtered off (Celite), and the filtrate was evaporated in vacuo. The residue was taken up in ether (50 mL) and was extracted with 1N HCl (3×20 mL). These acidic extracts were then basified to pH 10 with 2N NaOH and were extracted with ethyl acetate (3×20 mL). The organic extracts were dried over Na2SO4, filtered and evaporated in vacuo to yield the title compound as a yellow oil, 880 mg (29%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.52 (m, 1H), 7.06 (m, 1H), 6.82 (td; J=7.4, 1.3 Hz; 1H), 6.69 (dd; J=8.1, 1.3 Hz; 1H), 3.83 (dd; J=11.1, 6.3 Hz; 1H), 2.08 (dd; J=13.5, 6.3 Hz; 1H), 1.90 (m, 1H), 1.74 (m, 2H), 1.31-1.57 (m, 8H); MS (ESI) m/z 218 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Sc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 305 was used, starting from 4-chloro-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 397 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9](=[O:19])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11](=[O:12])[C:6]=2[C:5](SC)=[N:4][C:3]1=[O:28].C1(C)C=CC=CC=1.[Cl:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>C(OCC)C>[Cl:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:5]2[C:6]3[C:11](=[O:12])[N:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:9](=[O:19])[N:8]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:7]=3[N:2]([CH3:1])[C:3](=[O:28])[N:4]=2)=[CH:39][CH:38]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CSc1nc(=O)n(C)c2c1c(=O)n(-c1ccccc1)c(=O)n2-c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cn1c(=O)nc(Nc2ccc(Cl)cc2)c2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c21
Temperature: 25 °C
Yield: 52.5 %

Procedure:
To 8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 26 (149 mg) obtained in Step 6 was added toluene (2 ml), 4-chloroaniline 27 (97 mg) was added, and the mixture was stirred under reflux for 3.5 hrs. After allowing to cool to room temperature, diethyl ether was added. The crystals were collected by filtration, washed with diethyl ether and dried to give 5-(4-chloro-phenylamino)-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 28 (94 mg, yield 53%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[Cl-].[NH4+]>O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:20]([N:33]2[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]2)=[O:21])[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: OC1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (124.6 mg) was dissolved in tetrahydrofuran (2.5 ml) under a nitrogen atmosphere, and then triethylamine (0.105 ml) and phenyl chloroformate (0.094 ml) were added dropwise thereto while cooling in an ice bath, followed by stirring at room temperature for 1 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, which was dissolved in N,N-dimethylformamide (1.25 ml), and then 4-hydroxypiperidine (253 mg) was added thereto at room temperature, followed by stirring for 2 hrs. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:4, then ethyl acetate) to provide the titled compound (169 mg, 90%) as pale yellow powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=1[F:43])C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[O:26][C:22]3[CH:21]=[C:20]([N:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:43])[CH:11]=4)[S:16]([CH3:19])(=[O:18])=[O:17])[C:39]([CH:40]4[CH2:41][CH2:42]4)=[CH:38][C:23]=3[C:24]=2[C:34]([NH:36][CH3:37])=[O:35])=[CH:28][CH:29]=1
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(O)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(N-(4-(benzyloxy)-3-fluorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (350 mg, 0.565 mmol) was dissolved in ethyl acetate (8.0 mL) and ethanol (8.0 mL). 10% of Pd/C (30.1 mg, 0.283 mmol) was added followed by the addition of H2 (1 atmosphere, balloon). The mixture was stirred for 2 h at RT and filtrated through Celite. The filtrate was concentrated to dryness and rinsed twice with hexane to give the desired product as a white solid which was used without further purification. LCMS (m/z, ES+)=529 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[CH3:13][N:14]([CH3:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1>>[CH3:22][N:21]([CH3:23])[C:17]1[CH:16]=[C:15]([N:14]([CH3:24])[CH3:13])[CH:20]=[CH:19][C:18]=1[C:6]([C:5]1[CH:11]=[CH:12][C:2]([NH2:1])=[CH:3][C:4]=1[C:9]([OH:8])=[O:10])=[O:7]
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Nc1ccc2c(c1)C(=O)OC2=O
Product: CN(C)c1ccc(C(=O)c2ccc(N)cc2C(=O)O)c(N(C)C)c1

Procedure:
Condensation of 4-aminophthalic anhydride and N,N,N',N'-tetramethyl-m-phenylenediamine by the method of part A of Example 3 affords 2-(2,4-bis(dimethylamino)benzoyl)5-aminobenzoic acid.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH:13]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]2)[CH2:12][CH2:11]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](O)[CH3:34].C(OCC)(=O)C>[Pd]>[C:6]1([CH2:7][CH2:2][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH:13]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][CH2:22]2)[CH2:12][CH2:11]3)[CH:34]=[CH:33][CH:3]=[CH:4][CH:5]=1
Reactant: CCO
Reactant: O=C1c2ccc(-c3ccccc3)cc2CCC1CCN1CCC(c2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1c2ccc(CCc3ccccc3)cc2CCC1CCN1CCC(c2ccccc2)CC1
Yield: 99.9 %

Procedure:
Compound 3 (100 mg, 0.23 mmol) was dissolved in a mixture of 4:1 ethanol/ethyl acetate solution (25 mL) and stirred with 10% Pd on carbon (20 mg) at room temperature and under a hydrogen gas (balloon) for 18 hours. The reaction mixture was filtered through a Celite pad and evaporated to dryness. The residue was triturated with hexanes to afford the title compound as a yellow solid (103 mg, 99.9%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH2:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:20][C@H:18]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=3[N:10]=2)[CH3:19])[N:25]=[CH:24][N:23]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1Cc1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1Cc1ccccc1
Temperature: 90 °C
Yield: 35.6 %

Procedure:
A mixture of (S)-1-(1-benzyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (320 mg, 1.19 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (184 mg, 1.19 mmol) and DIPEA (1.06 mL, 5.95 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial overnight. The resultant mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-10% [2M NH3 in MeOH] in DCM) to afford 394 as a white solid (164 mg, 36%). LCMS (Method K): RT 3.58 min [M+H]+ 388.1 1H NMR (DMSO-d6, 400 MHz): δ 7.94 (1H, s), 7.69 (1H, d, J=7.9 Hz), 7.61 (1H, dd, J=8.9, 4.5 Hz), 7.13-7.28 (5H, m), 6.95-7.05 (3H, m), 5.65 (1H, qn, J=7.9 Hz), 5.46 (2H, q, J=9.91, 5.5 Hz), 3.12 (1H, d, J=5.5 Hz), 1.49 (3H, d, J=6.77 Hz)
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl.C(=O)(O)[O-].[Na+]>CCCCCC.CN(C)C=O>[Cl:1][CH2:2][C:3]([O:11][Si:18]([CH3:21])([CH3:20])[CH3:17])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCl)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CCC(CCl)(CCCC)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, ice-cold solution of 7.22 g. of 4-chloromethyl-4-hydroxy-1-octyne and 7.16 g. of imidazole in 28 ml. of dimethylformamide is added 6.5 ml. of trimethylchlorosilane via a syringe during 15 minutes. The resulting mixture is stirred at room temperature overnight, diluted with hexane and poured into a mixture of ice and saturated sodium bicarbonate solution. The hexane solution is separated, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 11.8 g. of a colorless liquid which is vacuum distilled at b.p. 50°-57° C./3.5-4 mm. to give 9.7 g. of product as a colorless liquid; PMR δ 3.58 (s), 2.50 (d), 1.99 (t), 0.87 (s, OTMS).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([CH3:23])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([CH3:23])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[N:9][CH:10]=1
Reactant: Cc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Reactant: CS(N)(=O)=O
Product: Cc1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O

Procedure:
The title compound of Example 149, step 4 was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.36 (s, 1H), 8.10-8.12 (m, 2H), 6.98-7.05 (m, 2H), 6.87-6.92 (m, 1H), 3.64 (s, 3H), 3.45 (s, 3H), 2.22 (s, 3H). LCMS: 423.0 (M+1)+
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)C(=O)[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=1.O.[NH2:38][NH2:39].[C:40](=[O:43])([O-])O.[Na+]>CN(C=O)C>[F:35][C:32]([F:34])([F:33])[O:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][C:23]1[C:3]2[C:40](=[O:43])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:39][N:38]=1
Reactant: O=C(Cc1cccc(OC(F)(F)F)c1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=C([O-])O
Reactant: NN
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3cccc(OC(F)(F)F)c3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a suspension of 4-hydroxy-3-(3-trifluoromethoxyphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (477 mg, 0.94 mmol) produced in Synthesis Example 18 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 184 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(3-trifluoromethoxybenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (241 mg, yield 51%).
Reaction SMILES: Br[C:2]1[S:12][C:5]2[C:6]3[S:11][CH:10]=[CH:9][C:7]=3[S:8][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(N(CC)CC)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.[Cu]I>[CH2:13]([C:3]1[C:4]2[S:8][C:7]3[CH:9]=[C:10]([C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[S:11][C:6]=3[C:5]=2[S:12][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCCCCCC
Reactant: CCCCCCCCCCc1c(Br)sc2c1sc1ccsc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCC#Cc1cc2sc3c(CCCCCCCCCC)csc3c2s1
Temperature: 130 °C
Yield: 81.9 %

Procedure:
2-bromo-3-decanyldithieno[3,2-b:2′,3′-d]thiophene (92) (4.16 g, 0.01 mol) was mixed with 1-decyne (3.6 g, 0.026 mol), tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) and copper(I) iodide (0.19 g, 1.0 mmol) in triethylamine (80 mL). This mixture was bubbled with nitrogen for 5 minutes and then heated up to 130° C. under argon for 16 hours. Triethylamine was evaporated and hexane (150 mL) was added. This mixture was filtered to remove solid salts. The organic layer was washed with 1 M hydrochloric acid (50 mL) and brine (50 mL) then dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel eluting with hexane to yield the target compound (3.87 g, 93.0%). 1HNMR, solvent CD2Cl2. δ 7.36 (d, 1H), 7.30 (d, 1H), 2.82 (t, 2H), 2.49 (t, 2H), 1.63-1.27 (m, 28H), 0.88 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCCC1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[C:14]=3[F:21])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2ccc(Br)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1F
Temperature: 80 °C
Yield: 92.2 %

Procedure:
To the mixture of 6-bromo-2-oxindole (5 g, 24 mmol) (Combi-blocks) and 3-chloro-2-fluorobenzaldehyde (3.7 g, 24 mmol) (Oakwood) in methanol (200 mL) was added piperidine (2 g, 24 mmol) (Aldrich) dropwise. The mixture was then heated at 80° C. for 2 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.8 g, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([O:20][Si](C(C)(C)C)(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(O[Si](C)(C)C(C)(C)C)CC1NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)C1(O)CC1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 2-(benzyloxycarbonylamino)-1-(tert-butyldimethylsilyloxy)cyclopropanecarboxylate (1.45 g, 3.69 mmol) in THF (35 mL) under N2 was added HF.pyridine (1.0 mL, 38 mmol). The reaction mixture was stirred for 5 h. After this time, additional HF.pyridine (1.0 mL, 38 mmol) was added and stirring was continued for 19 h. The reaction mixture was then cooled to 0° C. and diluted with Et2O (150 mL). The mixture was then carefully quenched with saturated aqueous NaHCO3 until gas evolution ceased. At this time, the organic layer was separated and the remaining aqueous layer was extracted with Et2O (300 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography eluting with 20%-50% EtOAc/hexanes afforded the title compound (0.960 g, 93%): 1H NMR (300 MHz, CDCl3) δ 7.34-7.30 (m, 5H), 5.11-4.83 (m, 3H), 4.21 (q, J=7.2 Hz, 2H), 3.37-3.25 (m, 2H), 1.73-1.68 (m, 1H), 1.27 (t, J=7.2 Hz, 3H), 1.14-1.06 (m, 1H); ESI MS m/z 280 [M+H]+.