Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]2[C:60]3[CH:61]=[CH:62][C:63]([C:65](O)=[O:66])=[CH:64][C:59]=3[N:58]=[CH:57]2)=[CH:52][CH:51]=1>C(Cl)Cl.O>[F:49][C:50]1[CH:51]=[CH:52][C:53]([N:56]2[C:60]3[CH:61]=[CH:62][C:63]([C:65]([N:1]4[CH2:2][CH:3]([N:5]5[CH2:6][CH2:7][N:8]([C:11]([C:13]6[S:14][CH:15]=[CH:16][N:17]=6)=[O:12])[CH2:9][CH2:10]5)[CH2:4]4)=[O:66])=[CH:64][C:59]=3[N:58]=[CH:57]2)=[CH:54][CH:55]=1
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1ccc(F)cc1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)ncn2-c1ccc(F)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5e (0.058 g, 0.178 mmol) and HATU (0.081 g, 0.214 mmol) in CH2Cl2 (3 mL) was added Et3N (0.099 mL, 0.713 mmol). The mixture was stirred at room temperature for 30 min, and then 60f (0.050 g, 0.196 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water (6 mL) was added and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product Cpd 1167 was purified by preparative reverse phase chromatography. MS m/z (M+H+) 491.2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][C:16]=1[C:17](OCC)=[O:18].CC([O-])=O>>[O:18]=[C:17]1[N:7]2[CH:6]=[C:5]([C:8]([NH2:10])=[O:9])[CH:4]=[CH:3][C:2]2=[N:11][C:12]2[S:13][C:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][C:16]1=2
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1N
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: CC(=O)[O-]
Product: NC(=O)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Yield: 4.1 %

Procedure:
From 4.7 g (0.030 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 7.5 g (0.030 mol) of 2-amino-5-phenyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966), following the procedure of Example 22, there is obtained 0.4 g of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide, monoacetate; mp 348°-352° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][CH2:22]O)[C:9]([C:11]1[NH:12][C:13](=[O:19])[C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:20][CH2:21][CH2:22][N:12]2[C:13](=[O:19])[C:14]([Br:18])=[CH:15][C:16]([CH3:17])=[C:11]2[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)c(=O)[nH]c1C(=O)N(CCCO)Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(Br)c(=O)n2c1C(=O)N(Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (5, 1.5 g, 3.9 mmol) in tetrahydrofuran (30 mL), triphenylphosphine (1.5 g, 5.9 mmol) and diisopropyl azodicarboxylate (1.2 g, 5.9 mmol) were added at 0° C. The mixture was stirred at room temperature for 16 h. After completion, solvent was removed under reduced pressure and the crude was purified by flash chromatography eluting with 40% ethyl acetate in hexane. Appropriate fractions were concentrated under reduced pressure to afford 2-benzyl-8-bromo-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione (6) as yellow solid. Yield: 0.9 g, 64%; MS (ESI) m/z 361.18 [M+1]+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][PH3+].[Li]CCCC.[CH3:11][O:12][C@H:13]1[C@@H:18]([CH3:19])[CH2:17][O:16][C@@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]1=O>O1CCCC1.C(OCC)(=O)C>[CH3:2][O:3][C@H:4]1[C@@H:18]([CH3:19])[CH2:17][O:16][C@@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]1=[CH:13][O:12][CH3:11]
Reactant: COC[PH3+]
Reactant: CCCCCCCCC[C@@H]1OC[C@H](C)[C@H](OC)C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCC[C@@H]1OC[C@H](C)[C@H](OC)C1=COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred suspension of methoxymethylphosphonium chloride (1,130 mg) in dry tetrahydrofuran (3 ml) there was added n-BuLi (1.9 ml, 1.6M in n-hexane) at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (2S,4S,5S)-4-methoxy-5-methyl-2-nonyltetrahydro-2H-pyran-3-one (273 mg) in dry tetrahydrofuran (3 ml) was added to the resulting deep orange solution. After 30 min, the mixture was allowed to warm to room temperature, and stirred for an additional 2 hrs. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel chromatography (n-hexane: ethyl acetate=10:1 as an eluent) gave (2S,4S,5S)-4-methoxy-5-methyl-3-methoxymethylene-2-nonyltetrahydro-2H-pyran (249 mg,83% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: C[S-]
Reactant: Brc1ccc(Br)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CSc1ccc(Br)cn1
Temperature: 10 °C
Yield: 104 %

Procedure:
A mixture of 2,5-dibromopyridine (7) (1100 g, 4.64 mol), tetrabutylammonium bromide (55 g, 0.037 equivalent) and a 15% aqueous sodium thiomethoxide solution (2387 g, 1.1 equivalent) was heated at 85 to 90° C. for 3.5 hours. After the reaction mixture was cooled to 10° C., the resulting solid was filtered off. The organic layer was washed with cold water (1 L) and concentrated to obtain the crude product (8) (985 g, yield 104%). The crude product (8) (908 g) was purified by recrystallization using 2-propanol (2.1 L) and water (4.2 L) to obtain a compound (8) as crystals (831 g, yield 91.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CO.[C]=O.C(N(CC)CC)C.[C:35]([O:38][CH2:39]C)(=[O:37])C>[Pd].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.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>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([C:35]([O:38][CH3:39])=[O:37])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(NC2=C(c3ccc(I)cc3)C(=O)NC2=O)cc1F
Agent: [Pd]
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2=C(Nc3ccc(C)c(F)c3)C(=O)NC2=O)cc1

Procedure:
A mixture of 3-(3-Fluoro-4-methylphenyl-amino)-4-(4-iodophenyl)-1H-pyrrole-2,5-dione (Example A705, 126 mg, 0.3 mmol), tetrakis(triphenyl phosphine)-palladium(0) (35 mg, 0.03 mmol) and methanol (10 mL) was placed in a 50 mL two necked round bottomed flask. One arm of the flask was sealed with a septum and to the other arm was fitted a reflux condenser, topped with a multiway tap connected respectively to vacuum, a carbon monoxide cylinder and to a balloon. Using the multiway tap, the flask was alternately evacuated and flushed with carbon monoxide, and the process repeated several times to unsure an atmosphere of carbon monoxide within the flask. The balloon was charged with carbon monoxide and this was then opened to the reaction flask for the duration of the reaction in order to maintain a slight positive pressure of carbon monoxide within the flask. Triethylamine (100 uL, 0.7 mmol) was added and the mixture heated at reflux for 16 hours. The mixture was cooled and diluted with ethyl acetate and the resulting solution washed with aqueous hydrochloric acid (1M, 50 mL), water (50 mL) and brine (50 mL). The organic solution was dried over magnesium sulphate and evaporated to afford a solid. This was chromatographed on silica gel using dichloromethane-ether (98:2 v/v) as eluent to afford the tide compound, a solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:23]([O:24][CH2:25][CH3:26])=[N:22][CH:21]=[CH:20][C:10]=1[C:11]([N:13](C(C)C)C(C)C)=[O:12].C[Si](C)(C)N[Si](C)(C)C.[Na].CO>C1COCC1>[CH2:25]([O:24][C:23]1[N:22]=[CH:21][CH:20]=[C:10]2[C:9]=1[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:13][C:11]2=[O:12])[CH3:26]
Reactant: CCOc1nccc(C(=O)N(C(C)C)C(C)C)c1-c1cc(F)ccc1N
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1nccc2c(=O)[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-amino-5-fluorophenyl)-2-ethoxy-N,N-diisopropylisonicotinamide (170 mg, 0.473 mmol) in THF (3153 μl), was added sodium hexamethyldisilazane (946 μl, 0.946 mmol, 1.0 M in THF). The reaction mixture was stirred at room temperature for 30 min. Methanol was added and the mixture was concentrated under reduced pressure. The residue was then triturated with diethyl ether (25 mL) and stirred for 1 h. The mixture was filtered through a frit, and the filter cake was collected and dried to afford the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:31](I)=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33].F[B-](F)(F)F.[C:39]([PH+](C(C)(C)C)C(C)(C)C)(C)(C)[CH3:40]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:31]([CH:39]=[CH2:40])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(I)c4)CS(=O)(=O)C[C@@H]32)c1
Reactant: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: F[B-](F)(F)F
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N

Procedure:
To a degassed solution of (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (example 1k) (0.60 g, 1 mmol) in anhydrous dioxane (4 mL) was added under argon Cs2CO3 (0.665 g, 2.0 mmol), 2,4,6-trivinyl-cyclotriboroxane pyridine complex (0.365 g, 1.5 mmol) and tri-tert-butyl-phosphonium tetrafluoroborate (0.044 g, 0.15 mmol) in dioxane was added under argon the Pd2(dba)3 (0.028 g, 0.03 mmol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated. The title compound was obtained after flash-chromatography on silica gel (hexane-EtOAc 3:1 to 2:1) and crystallization from CH2Cl2-hexane as white crystals: HPLC RtA=2.22 min; ESIMS [M+NH4]+=504.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:38])=[N:13][C:14]2[CH2:15][CH2:16][N:17]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O.CCOC(C)=O>[CH2:31]([O:30][C:28]([N:17]1[CH2:16][CH2:15][C:14]2[N:13]=[C:12]([CH3:38])[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[C:19]=2[CH2:18]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2c3c(nc(C)c2C(OC(C)(C)C)C(=O)O)CCN(C(=O)OCc2ccccc2)C3)cc1
Yield: 85.4 %

Procedure:
A solution of benzyl 3-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (intermediate 14) (25 mg, 0.048 mmol) in MeOH (1.5 mL) with 1N NaOH (0.48 mL) was stirred at 65° C. for 1 h then at room temperature overnight. The mixture was diluted with water and EtOAc, then neutralized with 1N HCl (0.48 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC (10% MeOH/90% H2O/0.1% CF3CO2H, Phenomenex-LUNA 21.1×100 mm, C18, 5 μm column). The product-containing fractions were combined and MeOH removed and the remaining aqueous solution lyophilized to provide 2-(6-((benzyloxy)carbonyl)-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetic acid (20.6 mg, 81% yield) as a white powder. 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.59 (m, 8H), 7.05 (br. s., 1H), 5.13 (br. s., 2H), 5.03 (s, 1H), 4.44 (d, J=18.10 Hz, 1H), 4.13 (d, J=18.10 Hz, 1H), 3.22-3.47 (m, 2H), 2.85 (s, 3H), 2.48 (s, 3H), 1.01 (s, 9H). LCMS (M+H) calcd for C30H35N2O5: 503.25. found: 503.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([OH:12])[CH2:11][C:5]=2[CH:4]=1.[C:15](OC(C)=C)(=[O:17])[CH3:16]>C(OC(C)C)(C)C>[C:15]([O:12][C@@H:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11]1)(=[O:17])[CH3:16]
Reactant: C=C(C)OC(C)=O
Reactant: COc1ccc2c(c1)CC(O)CCC2
Solvent: CC(C)OC(C)C
Product: COc1ccc2c(c1)C[C@H](OC(C)=O)CCC2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of (RS)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (221 g), isopropenyl acetate (380 ml) and lipase PS (Amano) (221 g) in diisopropyl ether (4.8 l) was stirred at ambient temperature for 4 days. The reaction mixture was filtrated (celite) and evaporated under reduced pressure. The residue was purified by flash chromatography (silica gel, using dichloromethane and dichloromethane-methanol (20:1) successively as eluents). The first eluate gave (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl acetate (138.2 g) as a pale yellow oil and the second eluate (S)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (104.4 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Li+].CC([N-]C(C)C)C.CN([CH:21]=[O:22])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH:21]=[O:22]
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(I)cc1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 1,3-dichloro-5-iodobenzene (4.0 g, 14.6 mmol) in THF (30 mL), LDA (2.0 M in THF/heptane/ethylbenzene, 9.6 mL, 16.9 mmol) was added dropwise at −78° C. and stirred for 1 h at the same temperature. A solution of DMF (1.7 mL, 22.0 mmol) in THF (5 mL) was added slowly at −78° C. and stirred for 3 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to afford compound A35-1 (1.4 g, 32%) as colorless oil.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=2[C:3]1=O.[CH2:15]([C:17]([NH:22][C:23]([NH2:25])=[S:24])([CH2:20][OH:21])[CH2:18][CH3:19])[CH3:16]>C(O)C.C(OCC)(=O)C>[CH2:15]([C:17]([NH:22][C:23]1[S:24][C:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=3)[C:3]=2[N:25]=1)([CH2:20][OH:21])[CH2:18][CH3:19])[CH3:16]
Reactant: N#Cc1ccc2c(c1)CCC(Br)C2=O
Reactant: CCC(CC)(CO)NC(N)=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(CC)(CO)Nc1nc2c(s1)CCc1cc(C#N)ccc1-2
Yield: 54.3 %

Procedure:
6-Bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.23 g, 0.90 mmol) was dissolved in 10 mL of ethanol and N-[1-ethyl-1-(hydroxymethyl)propyl]thiourea (133 mg, 1.32 mmol), prepared in step 5 of example 2, was added and the mixture was heated to reflux for 1 h. The mixture was cooled, diluted with ethyl acetate and washed with H2O, NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (3% acetone/hexane) afforded 2-{[1-ethyl-1-(hydroxymethyl)propyl]amino}-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile (160 mg, 55%) as a white solid. HRMS: calcd for C18H21N3OS+H+, 328.14781. found (ESI-FTMS, [M+H]1+), 328.14836; Analytical HPLC: purity 93.3% at 210-370 nm, 10.3 min.; 96.4% at 254 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150 ×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23](=[N:29]O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[O:15][N:29]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:22]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2cccc(C(F)(F)F)c2F)n1
Yield: 14.1 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid (0.420 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.085 g (14%) of ethyl 5-(2-fluoro-3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.CC1(C)C(C)(C)[O:16][B:15](B2OC(C)(C)C(C)(C)O2)[O:14]1.C([O-])(=O)C.[K+].O>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C>[F:10][CH:9]([F:11])[O:8][C:6]1[CH:7]=[C:2]([B:15]([OH:16])[OH:14])[CH:3]=[N:4][CH:5]=1
Reactant: FC(F)Oc1cncc(Br)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: OB(O)c1cncc(OC(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
3-Bromo-5-(difluoromethoxy)pyridine (813 mg, 3.63 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.84 g, 7.25 mmol), potassium acetate (1.07 g, 11 mmol), and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (296 mg, 0.36 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (201 mg, 0.36 mmol) were suspended in dioxane (35 ml) and stirred at 90° C. overnight. After usual work-up with water and ethyl acetate, the reaction crude was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 495 mg (72% yield) of the title compound as a yellow oil. Purity 95%.
Reaction SMILES: CO.Cl.Cl.Cl.[CH2:6]([NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[NH:18])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH3:35][C:36]([CH3:38])=O>>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH3:35][C:36]1([CH3:38])[N:15]=[C:14]([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[N:18]1
Reactant: CCCCCCCCCNC(=N)NC(=N)NCc1ccccc1
Reactant: CC(C)=O
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccccc2)N1

Procedure:
140 ml of methanol, 100 ml of acetone and 0.5 ml of concentrated hydrochloric acid were added to 8.0 g (19.1 mmol) of N1-benzyl-N5-nonyl-biguanide dihydrochloride. The mixture was refluxed for 20 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of ethanol, and to the solution were added 60 ml of water and 8.4 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of 70% aqueous acetonitrile, and to the solution was added 4.8 g (38.2 mmol) of oxalic acid dehydrate. The mixture was dissolved under heating, and then cooled. The resulting crystals were recrystallized from 70% aqueous acetonitrile to obtain 8.1 g of colorless crystals having a melting point of 105 to 107° C.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[C:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21])(=[O:8])=[O:7])(C)C>FC(F)(F)C(O)=O>[O:21]=[C:17]1[C:16](=[CH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([NH2:5])(=[O:7])=[O:8])[CH2:20][CH2:19][O:18]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1C=C1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1C=C1CCOC1=O
Yield: 88.8 %

Procedure:
A solution of 5.0 g (0.016 mol) of the product of Example 2 in 70 mL trifluoroacetic acid was stirred at room temperature overnight and was then evaporated to yield 3.6 g (88%) of the title compound: m.p. 178°-180°; IR (nujol) 3330, 3230, 3220, 1720, 1640, 1340, 1160 cm-1 ; NMR (DMSO-d6, 200 MHz) δ 3.12 (2H, m), 4.36 (2H, t, J=7 Hz), 7.5-7.7 (3H, m), 7.93 (1H, m), 8.07 (1H, m).
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]4[CH2:20][CH2:19]4)[CH:13]=[CH:12][C:11]=3[CH3:22])=[O:8])[S:5][CH:6]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2ccc(Cl)cc2)c1C

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-methylthiophene-2-carboxamide a with commercially available 4-chlorophenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 197). HPLC Ret time=3.67 min. LCMS [M+H]+ 425.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=3[S:8][C:7]=2[C:6]([CH:20]=[O:21])=[CH:5][CH:4]=1.S(=O)(=O)([OH:24])N.Cl([O-])=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=3[S:8][C:7]=2[C:6]([C:20]([OH:24])=[O:21])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)c2sc3c(NC(C)=O)cccc3c12
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)O)c2sc3c(NC(C)=O)cccc3c12
Temperature: 10 °C

Procedure:
To a solution of 1-methoxy-6-acetamido dibenzo[b,d]thiophene-4-carbaldehyde (800 mg, 0.00266 mol) in THF(15 ml) and water(2 ml) was added sulfamic acid (387 mg, 0.004 mmol) while stirring at 10° C. A solution of 80% sodium chlorite (360 mg, 0.004 mmol) in water (2.0 mL) was added drop wise to the above reaction mixture over a period of 5 min and was allowed to stir at 110° C. for additional 30 min. Water (150 ml) was added to obtain a precipitate which filtered and dried under vacuum (350 mg).