Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:10]([OH:12])=O)[S:9][C:5]=2[N:4]=[C:3]1[CH2:13][O:14][CH3:15].S(Cl)(Cl)=O.[CH3:20][O:21][C:22]([CH2:24][CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23].C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[C:27]1([N:26]([CH2:25][CH2:24][C:22]([O:21][CH3:20])=[O:23])[C:10]([C:8]2[S:9][C:5]3[N:4]=[C:3]([CH2:13][O:14][CH3:15])[N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:12])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCc1nc2sc(C(=O)O)cc2n1C
Reactant: COC(=O)CCNc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1nc2sc(C(=O)N(CCC(=O)OC)c3ccccc3)cc2n1C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A suspension of 0.50 g (2.2 mmol) of 1-methyl-2-methoxymethylthieno[2,3-d]imidazol-5-yl-carboxylic acid in 20 mL of methylene chloride was mixed with 2.0 mL (3.2 g, 27 mmol) of thionyl chloride and refluxed for 60 minutes, during which time the solid gradually dissolved. After distillation of the liquid components, the crude product was taken up twice more in methylene chloride. After the solvent had been eliminated once more, the crude acid chloride was taken up in 20 mL of tetrahydrofuran and added dropwise to a mixture of 0.42 g (2.3 mmol) of N-(2-methoxycarbonylethyl)aniline and 0.92 mL (6.6 mmol) of triethylamine in 30 mL of tetrahydrofuran. After 16 hours stirring at 50° C., the solvent was eliminated and the crude product obtained was purified by chromatography (silica gel; methylene chloride/ethanol=100:1). Yield: 0.66 g (77% of theory); Rf value: 0.47 (silica gel; methylene chloride/ethanol=19:1).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:13])=O.CN(C)C=O>ClCCl>[S:1]1[CH2:6][CH2:5][CH:4]([C:7]([Cl:13])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCSCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCSCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To an ice cold solution of 1.36 g (9.32 mmol) tetrahydro-thiopyran-4-carboxylic acid in 25 mL of dichloromethane (DCM) was added dropwise 1.1 mL (12.6 mmol) of oxalyl chloride, and the resulting mixture was stirred at 0° C. for 2 h. Then 2 μL of dimethylformamide (DMF cat) was added, and the reaction mixture was stirred at rt for 2 h, and concentrated to give 1.43 g (93%) of desired tetrahydro-thiopyran-4-carbonyl chloride as a brown oil as indicated by 1H NMR. The product was used without any further purification in the next step toward the preparation of 6-(4-Benzyloxy-phenyl)-7-(tetrahydro-thiopyran-4-yl)-3-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyrimidine (below, entry 375).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[C:38]([F:41])([F:40])[F:39])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([CH2:30][N:27]4[CH2:26][CH2:25][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:29][CH2:28]4)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1ccc(CN2CCN(C(C)C)CC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 551.3 [M+H]+; tR=3.23 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 9:1+0.1% NH3aq).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29][OH:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:33][N:32]=[N:31][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:25]([CH2:29][OH:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2cccc(CO)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2cccc(CO)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 96 h

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-hydroxymethylbenzimidazole (0.4 g), sodium azide (0.98 g) and ammonium chloride (0.8 g) in DMF (4 ml) was stirred for 4 days at 110-120° C. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried. After removal of the solvent, the residue was crystallized from ethyl acetate-methanol to give colorless needles, m.p. 152-153° C.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[CH:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=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>[CH:14]([C:16]1[CH:21]=[C:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH2:11][O:12][CH3:13])[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: COCOc1cc(C#N)ccc1I
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)ccc1-c1cccc(C=O)c1
Temperature: 100 °C
Yield: 89.9 %

Procedure:
4-Iodo-3-methoxymethoxy-benzonitrile (600 mg, 2.08 mmol), 3-formylphenylboronic acid (450 mg, 3.0 mmol), Pd(PPh3)4 (200 mg, 0.17 mmol) and Cs2CO3 (1.2 g, 3.7 mmol) were mixed in N,N-dimethylformamide (15 mL), degassed and heated at 100° C. for 2 hours. After which, the mixture is allowed to cool to room temperature, an aqueous work up is performed, and the residue purified to afford the desired product (500 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]1([C@H:66]([NH2:68])[CH3:67])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][C@@H:66]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH3:67])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: C[C@@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CC[C@H](C(=O)N[C@H](C)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. (1R)-1-Phenylethanamine (58 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (188 mg) as a light yellow solid. LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[C:15]([C:16]([OH:18])=O)[C:5]2=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:14]=[C:15]([C:16]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:18])[C:5]2=1
Reactant: Cn1c2ccc(F)cc2c2c(C(=O)O)cn(-c3ccccc3)c(=O)c21
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Cn1c2ccc(F)cc2c2c(C(=O)N3CCCC3)cn(-c3ccccc3)c(=O)c21
Reaction time: 20 h

Procedure:
A solution of 3.2 g (10 mmol) of 6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and of 3.2 g (20 mmol) of N,N'-carbonyldiimidazole in 65 ml of N,N-dimethylformamide is stirred for 4 h at 60° C. 2.5 ml (30 zmol) of pyrrolidine are added at room temperature and the reaction mixture is stirred for 20 h.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH:19]=[CH:18][N:17]=[CH:16]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:28][CH:27]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(-n2ccnc2)cc1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 78 mg of 4-(1H-imidazol-1-yl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1H-imidazol-1-yl)benzamide. MS (Q1) 375.3 (M)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][NH:5][C:4]2[N:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:5]2[C:4]3[N:13]=[CH:14][CH:15]=[CH:16][C:3]=3[C:2](=[O:1])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1n[nH]c2ncccc2c1=O
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (1.00 g, 4.56 mmol) and 2-chloro-5-(chloromethyl)pyridine [(Example 5, Step 1), 500 mg, 2.28 mmol] and 4-iodobenzylbromide (745 mg, 2.51 mmol, 1.1 equiv) were dissolved in degassed N,N-dimethylformamide (5 mL) and cooled to 0° C. The mixture was treated with sodium hydride (109 mg, 2.74 mmol, 1.2 equiv) portionwise over 5 minutes. After stirring for 2 hours at 0° C., the mixture was warmed to ambient temperature and stirred for an additional 2 hours. The mixture was treated with sodium bicarbonate (10 mL, aqueous saturated), poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered, concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 499.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([C:14](=[O:18])[CH2:15][C:16]#[N:17])[CH:11]=[CH:12][CH:13]=1.[OH-].[Na+]>C1COCC1>[NH2:17][CH2:16][CH2:15][CH:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=1)[OH:18]
Reactant: N#CCC(=O)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCC(O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of LAH (16 g, 90 mmol) in dry THF (200 mL) was added a solution of 3-(3-chlorophenyl)-3-oxopropanenitrile (10.4 g, 270 mmol) in dry THF (200 mL) dropwise at 0° C. under nitrogen atmosphere. The mixture was warmed to 25° C. and then heated at 60° C. for 3 hours. After cooling to 0° C., a saturated solution of sodium hydroxide was added dropwise and extracted with ethyl acetate (200 mL). The solution was dried over anhydrous sodium sulfate and concentrated to dryness. The crude 3-amino-1-(3-chloro-phenyl)-propan-1-ol obtained was used in the next step without further purification. (Yield 14.5 g). LC-MS: [M+H]+ 186.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:18]=2[N+:29]([O-])=O)=O)[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[ClH:32]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]2[NH:29][C:18]3[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[ClH:32]
Reactant: O=C(O)CC(CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CC(Cc1nc2ccc(-c3ccccc3)cc2[nH]1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-(4-chlorophenyl)-N-(3-nitro-[1,1′-biphenyl]-4-yl)glutaramic acid (0.52 g) in acetic acid (3 ml) iron powder (0.34 g) was added. The mixture was stirred vigorously at under reflux for 0.5 h. Then conc. HCl (2 ml) was added with caution. The resulting solution was stirred at reflux temperature for further 2 h. All volatiles were removed at the water aspirator and the residue was dissolved in acetic acid/conc. HCl 2:1 (3 ml). Water (3 ml) was added at reflux temperature and the mixture was left standing at rt overnight. The precipitate was collected by suction filtration and washed well with 1M HCl and water. After drying in vacuo 3-(4-chlorophenyl)-4-(5-phenyl-2-benzimidazolyl)butanoic acid•HCl (0.36 g) was obtained as beige coloured solid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[CH:7]=1.C([O-])(=O)C.[Na+]>CC(N(C)C)=O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:2]2[C:15]3[CH:14]=[C:13]4[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[CH:9][C:8]4=[CH:7][C:6]=3[O:5][CH2:4][C:3]=2[CH:18]=1
Reactant: COc1ccc(Br)c(COc2ccc3ccc(OC)cc3c2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)COc1cc3cc(OC)ccc3cc1-2
Temperature: 130 °C
Reaction time: 48 h

Procedure:
A mixture of 2-[(2-bromo-5-methoxybenzyl)oxy]-7-methoxynaphthalene (9.35 g, 25 mmol), dichlorobis(triphenylphosphine) palladium (1.75 g, 2.5 mmol), and sodium acetate (6.15 g, 75 mmol) in anhydrous dimethylacetamide (500 mL) was stirred at 130° C. under nitrogen for two days. After cooling, the catalyst was filtered off and the dimethylacetamide removed under vacuum. The residue was slurried in methanol (200 mL) and the desired product was isolated by filtration to afford 2.9 g (40%) of a tan solid: mp 190-191° C.; 1H NMR (DMSO-d6): δ 3.81 (3H, s), 3.85 (3H, s), 5.14 (2H, s), 6.92 (1H, d, J=2.6 Hz), 7.00-7.03 (2H, m), 7.18 (1H, d, J=2.4 Hz), 7.29 (1H, s), 7.79 (1H, d, J=9.0 Hz), 7.92 (1H, d, J=8.7 Hz), 8.26 (1H, s); MS m/z 293 ([M+H]+).
Reaction SMILES: CN(C)CCCN=C=NCC.[NH2:12][C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16](=[O:24])[N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:18]=1[NH2:19].[CH3:27][O:28][C:29]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([CH2:41][C:42](O)=O)=[CH:32][N:33]=[CH:34]2.ON1C2C=CC=CC=2N=N1>ClCCl.O>[CH2:20]([N:17]1[C:18]2[N:19]=[C:42]([CH2:41][C:31]3[C:30]4[C:35](=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:29]=4[O:28][CH3:27])[CH:34]=[N:33][CH:32]=3)[NH:12][C:13]=2[C:14](=[O:26])[N:15]([CH3:25])[C:16]1=[O:24])[CH:21]([CH3:22])[CH3:23]
Reactant: COc1ccc2cncc(CC(=O)O)c2c1OC
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (20.6 ml, 0.11 mol) is added to a mixture of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (20 g, 0.094 mol), (5,6-dimethoxy-isoquinolin4-yl)-acetic acid (26.7 g, 0.094 mol), and 1-hydroxybenzotriazole (19.2 g, 0.142 mol) in 1:1 dichloromethane-water (400 ml). The reaction is stirred at ambient temperature for 4.5 hours and the resultant solid collected by filtration. Slurrying in water (500 ml), filtration and washing with water (250 ml) followed by drying, further tritruation with methanol and drying gives an intermediate together with slightly less pure material from concentration of the methanol triturate. The intermediate (16.08 g) is dissolved in water (100 ml) and methanol (100 ml) followed by the addition of 4M aqueous sodium hydroxide (56 ml) and the resultant solution is heated at 70° C. over night. After cooling to ambient temperature, the methanol is evaporated and the residue acidified to pH 1 with concentrated hydrochloric acid. The resultant hydrochloride salt is collected by filtration and dried. The product is then be converted to the free base by treatment with aqueous sodium hydroxide to pH 11 and washing with water to afford 3-isobutyl-8-(5,6-dimethoxy-isoquinolin4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione [MH]+ 424.6.
Reaction SMILES: [CH:1]1([NH:6][C:7]([C:9]2[C:13]([CH:14]=[CH2:15])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[O:11][N:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([NH:6][C:7]([C:9]2[C:13]([CH2:14][CH3:15])=[C:12]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[O:11][N:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=Cc1c(C(=O)NC2CCCC2)noc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1c(C(=O)NC2CCCC2)noc1-c1ccc(C(F)(F)F)cc1
Yield: 50 %

Procedure:
To a stirred solution of N-cyclopentyl-5-(4-(trifluoromethyl)phenyl)-4-vinylisoxazole-3-carboxamide (70 mg, 0.2 mmol) in ethanol (2 mL), palladium on carbon (5%) (5 mg) was added and the reaction mixture was then placed under a hydrogen atmosphere (balloon) for 2 hours. After this time the crude mixture was filtered through celite and concentrated in vacuo. Purification by silica gel chromatography eluting with heptane increasing to heptane to 15% ethylacetate in heptane afforded the title compound (36 mg, 0.1 mmol).
Reaction SMILES: C(OC([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:7]1=[O:19])=O)C>C(O)(=O)C>[N:8]1([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:10][C:11](=[O:12])[CH2:6][C:7]1=[O:19]
Reactant: CCOC(=O)C1C(=O)CCN(N2CCCCC2)C1=O
Solvent: CC(=O)O
Product: O=C1CCN(N2CCCCC2)C(=O)C1
Yield: 36 %

Procedure:
The oil from step 3 was dissolved in 10% acetic acid (250 ml) and the solution boiled under reflux for one hour. The cooled reaction mixture was evaporated, and the residue purified by flash chromatography (CH2Cl2: acetone 9:1-1:1) to give 4.00 g (36%) of the title compound as a semi-solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[OH:22].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][C:11]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:22][CH2:12]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(CCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1(c2ccc(Cl)c(Cl)c2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
3.00 g (9.05 mmole) of 3-(3,4-dichlorophenyl)-3-butenol t-butyldimethylsilyl ether [prepared as described in Example 1(b)] were dissolved in 60 ml of methylene chloride, and 2.52 g (30.0 mmole) of sodium hydrogencarbonate and 3.88 g (15.7 mmole) of 3-chloroperbenzoic acid (content: 70%) were added to the resulting solution. The mixture was then stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with methylene chloride and then washed with a 1 N aqueous solution of sodium hydroxide and with a saturated aqueous solution of sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The resulting residue was then purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and diethyl ether ranging from 24:1 to 19:1 by volume as the eluent, to obtain 2.70 g of the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:15](O)(=[O:20])[CH2:16][C:17](O)=[O:18].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([N:5]1[C:15](=[O:20])[CH2:16][C:17](=[O:18])[N:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCNC(=O)NC1CCCCC1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution was prepared by adding 15.87 gm (0.080 mole) of 1-(1-butyl)-3-cyclohexylurea and 8.33 gm (0.080 mole) of malonic acid to 35 mL of reagent grade acetic acid in a 250 mL 3-neck, round bottom flask equipped with a thermometer, pressure equalizing dropping funnel capped by a drying tube, nitrogen inlet and magnetic stirrer. The stirred mixture was gradually heated to 60° C. in a silicone oil bath. All of the solid dissolved before the temperature reached 60° C. A total of 32 mL of acetic anhydride was added to the dropping funnel and slowly (over a period of about 45 min.) dropped into the stirred reaction flask. The temperature was gradually increased to approximately 90° C. for 7 hours, then allowed to cool to room temperature and stand overnight.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[C:15]([O-])(O)=O.[Na+]>CCO.CC(O)=O.O.[Fe]>[NH2:11][C:10]1[C:2]([Br:1])=[C:3]([CH:7]=[C:8]([F:14])[CH:9]=1)[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C([O-])c1cc(F)cc([N+](=O)[O-])c1Br
Reactant: O=C([O-])O
Agent: [Fe]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)cc(N)c1Br
Temperature: 85 °C
Yield: 87 %

Procedure:
To a solution of 2-bromo-5-fluoro-3-nitrobenzoate (20 g, 278 mmol) in EtOH/CH3COOH (200 mL/200 mL) was added iron powder (25 g, 55 mmol). The mixture was vigorously stirred and heated to 85° C. for 1 h. After cooling, the mixture was diluted with water and basified with NaHCO3 (PH=8), extracted with ethyl acetate (450 ml×3). The combined organic layer was washed with brine (500 ml), dried over MgSO4, filtered, and evaporated in vacuum. The residue was applied to flash column chromatography (silica gel) to give methyl 3-amino-2-bromo-5-fluorobenzoate (15.6 g, 87%) as red oil.