Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][C:9]1(CC1C=CC=CC=1)[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCCC1(Cc1ccccc1)CNC2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCCC1CNC2
Yield: 49.7 %

Procedure:
A mixture of benzyl-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (477 mg, 1.51 mmol, 1.0 eq) and palladium hydroxide on carbon (466 mg) in ethanol (10 mL) was stirred with hydrogenation under ballon pressure until no more hydrogen uptake. The reaction was then filtered through celite and concentrated under reduced pressure. The crude was purified using chromatography (MeOH/Ethyl Acetate) which gave 3,9-Diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (170 mg) in 47% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 11H) 1.57-1.70 (m, 1H) 1.70-1.79 (m, 2H) 1.79-2.01 (m, 2H) 2.43-2.58 (m, J=19.14, 12.69, 6.32, 6.32 Hz, 1H) 2.93-3.05 (m, 2H) 3.05-3.18 (m, 2H) 3.99 (br. s., 1H) 4.11 (br. s., 1H)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:12]=[CH:13][NH:14][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:29])=CC=1>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:12][C:13](=[S:29])[NH:14][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1nc(Cc2ccc3c(c2)OCO3)c[nH]1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: S=c1[nH]cc(Cc2ccc3c(c2)OCO3)[nH]1
Reaction time: 3 h

Procedure:
A solution of 4-benzo[1,3]dioxol-5-ylmethyl-1H-imidazole (Intermediate D4) (0.24 g, 1.18 mmol) in THF (4 mL) and water (4 mL) was treated with NaHCO3 (1 g, 11.9 mmol) at rt for 10 m. Phenyl chlorothionoformate (0.42 mL, 3.1 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (3×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (8 mL) and treated with NEt3 (1 mL) for 16 h. The solvent was removed under vacuum and the product was washed on a glass frit with 50% CH2Cl2:hexanes to give a white solid (˜36%) 4-benzo[1,3]dioxol-5-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 5)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[N:9]3[C:10](=[N:15][C:16]([CH3:17])=[C:8]3[C:7]1=[O:18])[CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.[C:26](Cl)(=[O:29])[O:27][CH3:28]>C(Cl)Cl>[CH3:17][C:16]1[N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[N:9]2[C:8]=1[C:7](=[O:18])[N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]([O:27][CH3:28])=[O:29]
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCCCn1c(=O)c2c(C)nc3cccc1n32
Yield: 78.9 %

Procedure:
To a solution of 1.22 g (5.0 mmol) of 1-[4-(amino) butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 0.50 ml (6.5 mmol) of methyl chlorocarbonate. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from methylene chloride-methanol-ether to give 1.192 g of the desired compound (78.9%, colorless crystals), m.p.175-176° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([Cl:12])[Cl:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([C@@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([Cl:11])[Cl:12])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:15]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(Cl)Cl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(Cl)Cl

Procedure:
Using the procedure of Step F of Example 9, 3 g of the product of Step B and 2.25 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain after elution with 8-3 and 9-1 mixtures of cyclohexane-ethyl acetate 1.6 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-dichloroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+54°±2° (c=1% in benzene).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15]([O:17][C:18]([CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:23]1([N:22]([CH2:21][CH2:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])[C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C(=O)c1ccc(NC)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitrobenzoic acid chloride and 22.3 g (0.115 mol) of N-(2-ethoxycarbonylethyl)aniline in 300 mL of tetrahydrofuran, 13.1 g (0.13 mol) of triethylamine were added dropwise in 15 minutes, with stirring, at room temperature. After 2 hours stirring, the solvent was distilled off in a water-jet vacuum and the residue was mixed with 700 mL of water with stirring. The mixture was extracted 3 times with 200 mL of dichloromethane, the organic extract was washed twice with 200 mL of 2N hydrochloric acid and twice with 300 mL of water and dried over sodium sulfate. The solvent was then distilled off and the oily product thus obtained was purified by column chromatography (1 kg silica gel; eluant: petroleum ether/ethyl acetate=2:1). Yield: 35.0 g (82% of theory); Rf value: 0.28 (silica gel; dichloromethane/ethanol=50:1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]C)=[C:9]2[C:5]([C:6]3[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:7]=3[NH:8]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:19]=2)[CH:3]=1.C(S(C1C=C(C2C=CC(O)=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([C:6]3[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:7]=3[NH:8]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])[CH:19]=2)[CH:3]=1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(Cl)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Agent: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cc(Cl)c(O)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 246 by using an analogous procedure to that outlined in the preparation of Compound 157. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.33 Hz, 3 H) 2.25 (s, 3 H) 3.41 (q, J=7.58 Hz, 2 H) 4.26 (t, J=6.44 Hz, 2 H) 7.23 (s, 1 H) 7.46 (s, 1 H) 7.87 (t, J=7.71 Hz, 1 H) 8.03 (t, J=7.20 Hz, 2 H) 8.11 (s, 1 H) 8.31 (s, 1 H) 12.27 (br. s., 1 H); [M+H] calc'd for C20H17ClN2O3S, 401.1; found, 401.3.
Reaction SMILES: [F-].C([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])CCCC)CCC.[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[N:6]1[C:11]([C@H:21]2[CH2:20][C@@H:19]2[CH2:23][OH:22])=[CH:12][CH:13]=[C:14]2[CH2:18][CH2:17][CH2:16][C:15]=12
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Agent: [F-]
Product: OC[C@H]1C[C@@H]1c1ccc2c(n1)CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of S-5 (3.19 g, 10.5 mmol) in THF (40 mL) was added tetrabutyl ammonium fluoride solution 1M (10.5 mL, 10.5 mmol). The resulting mixture was stirred 2 hours at room temperature and concentrated. Flash column separation using a 10-100% ethyl acetate/hexane gradient gave S-6 as an oil. (1.44 g, 72%)
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Reactant: [H][H]
Agent: N
Solvent: CO
Solvent: O
Product: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Temperature: 40 °C
Yield: 98.4 %

Procedure:
A solution of 0.13 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid in 20 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.2 g of water wet Raney nickel #30. The solution is heated at 40° C. and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate is washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.13 g of (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro-[5.5]undecane-2-acetic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[N:9][CH:10]=3)[N:16]=2)[CH:19]=1
Reactant: O=C(CBr)c1ccc(-n2ccnc2)nc1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4ccnc4)nc3)cn2c1
Temperature: 100 °C

Procedure:
24.3 mg (corresponding to 0.0876 mmol) of 5-(2-bromoacetyl)-2-(1H-imidazole-1-yl)pyridine and 19.3 mg (corresponding to 0.0876 mmol) of 2-amino-5-iodopyridine were dissolved in 2.0 mL of acetonitrile. The resulting solution was heated under reflux for 1.5 hours in an oil bath at 100° C. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 2 mL of water and 2 mL of methanol. Then, about 1 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 10 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain crude crystals of 6-iodo-2-[2-(1H-imidazole-1-yl)pyridine-5-yl]imidazo[1,2-a]pyridine. The resulting crude crystals were purified by flash silica gel column chromatography (elution solvent: ethyl acetate/methanol=10/1), to obtain 17.7 mg (corresponding to 0.046 mmol) of 6-iodo-2-[2-(1H-imidazole-1-yl)pyridine-5-yl]imidazo[1,2-a]pyridine (FIG. 3, step 3).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH:24][CH:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([CH2:7][CH2:6][O:5][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH:25]([OH:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=2)[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)OCCN1CCOc2ccccc21
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(O)Cc1ccc(OCCN2CCOc3ccccc32)cc1
Yield: 26.5 %

Procedure:
The title compound (0.14 g, 32%) was prepared as a gummy liquid from 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.36 g, 1.42 mmol), potassium carbonate (0.80 g, 5.8 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (0.3 g, 1.42 mmol) using conditions analogous to that described in preparation 2.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[N:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cnc(C)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)cn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.5 mmol) in N-methyl 2-pyrolidone (0.75 mL) was added powdered potassium hydroxide (0.281 g, 5.0 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.151 g, 1.2 mmol) was added and stirred for further 2 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column−2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as yellow oil (0.05 g, 31% yield). 2,8-Dimethyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.156 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.015 g, 0.000119 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.03 g, 47% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[N:9]2)=[C:4]([O:23][CH3:24])[CH:3]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[CH3:22][O:21][N:19]([CH3:20])[C:17]([C:10]1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[CH:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:3][C:4]=2[O:23][CH3:24])[N:9]=1)=[O:18]
Reactant: c1cn[nH]c1
Reactant: COc1cc(I)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A suspension of 1-(4-iodo-2-methoxyphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (10.7 g, 24 mmol), pyrazole (1.63 g, 24 mmol), Cu2O (0.343 g, 2.4 mmol), salicylaldoxime (1.32 g, 9.6 mmol), and Cs2CO3 (15.6 g, 48 mmol) in CH3CN (100 mL) was refluxed for 4 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt/THF (1/0-0/1) to give the title compound (6.32 g, 68% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.39 (3H, s), 3.73 (3H, s), 3.91 (3H, s), 3.99 (3H, s), 6.53 (1H, dd, J=1.9, 2.3 Hz), 7.27 (1H, dd, J=2.3, 8.7 Hz), 7.58 (1H, d, J=8.7 Hz), 7.61 (1H, d, J=1.9 Hz), 7.77 (1H, d, J=1.5 Hz), 7.84 (1H, s), 7.98 (1H, d, J=2.3 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[C:20]1[O:24][C:23]([CH3:25])=[N:22][CH:21]=1)[C:15]#[N:16]>CN(C=O)C.O>[CH2:3]([O:10][C:18]1[CH:17]=[C:14]([CH:13]=[CH:12][C:19]=1[C:20]1[O:24][C:23]([CH3:25])=[N:22][CH:21]=1)[C:15]#[N:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Cc1ncc(-c2ccc(C#N)cc2F)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc(-c2ccc(C#N)cc2OCc2ccccc2)o1
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
To a mixture of sodium hydride (60%, 2.1 g) in DMF (35 mL) was added benzylalcohol (5.61 g) at 0° C., and the mixture was stirred for 30 min. 3-Fluoro-4-(2-methyl-1,3-oxazol-5-yl)benzonitrile (3.50 g) was added to this reaction mixture at 0° C., and the mixture was stirred at room temperature for 1 hr, and diluted with water. The resultant precipitate was collected by filtration and washed with water to give the title compound (5.20 g).
Reaction SMILES: CC(C)=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].OCCCCCCCCCC[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>C(Cl)(Cl)Cl>[CH2:35]([C:36]([OH:38])=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCCCCCCCCCCCCC(=O)O
Reaction time: 15 h

Procedure:
In Example 3, acetone solution of 12-hydroxydodecanoic acid was replaced by 16-hydroxy hexadecanoic acid (100 mg) dissolved in chloroform (10 ml) and reaction time was set for 15 hours. 72 mg of 1,16-hexadecane dicarboxylic acid was produced.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[O:34])=[C:4]([F:44])[CH:3]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[O:34])=[C:4]([F:44])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (314 mg, 0.505 mmol) and anisole (273 mg, 2.52 mmol) was treated with TFA (3.0 mL, 51.9 mmol) and stirred at RT for 2.5 h. The mixture was concentrated to near-dryness, treated with EtOAc and satd. NaHCO3 and the resulting solid collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (233 mg, 92% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.24 (m, 2H), 8.40 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.97 (m, 1H), 7.73 (s, 1H), 7.54 (d, J=11.0 Hz, 1H), 7.27 (m, 1H), 7.02 (m, 1H), 6.80 (m, 1H), 6.23 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 502.2 [M+H]+.
Reaction SMILES: C(ON=O)(C)(C)C.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10](N)[CH:9]=1.B(F)(F)[F:20].CCOCC>C1C(Cl)=CC=C(Cl)C=1>[F:20][C:10]1[CH:9]=[N:8][C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: FB(F)F
Reactant: Nc1cnc2ccccc2c1
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: Clc1ccc(Cl)cc1
Product: Fc1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Tert-butylnitrite (4.6 ml, 38.7 mmol) was added dropwise over 15 min to a solution of quinolin-3-amine (4.61 g, 32.0 mmol) and borontrifluoride-etherate (6 ml, 47.3 mmol) in dichlorobenzene (100 ml). The solution was heated to 100° C. After stirring for 1 h, the solution was cooled to ambient temperature and the dichlorobenzene was decanted leaving 3-fluoroquinoline as a black residue. Method [8] retention time 3.28 min by HPLC (M+ 148).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][O:14][CH3:15])[CH:3]=1.CS(C)=O.[CH2:20]([S-:22])[CH3:21].[Na+]>O>[CH2:20]([S:22][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][O:14][CH3:15])[CH:3]=1)[CH3:21]
Reactant: CC[S-]
Reactant: COCOc1cc(F)ccc1C(=O)OC
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1ccc(C(=O)OC)c(OCOC)c1
Reaction time: 19 h

Procedure:
To a solution of methyl 4-fluoro-2-(methoxymethoxy)-benzoate (10.6 g, 50 mmol) and DMSO (20 mL), under nitrogen, was added sodium ethanethiolate (5.8 g, 55 mmol) in portions. The exothermic reaction was stirred for 19 h, diluted with water, and extracted with ethyl acetate. The organic layer was concentrated; and the residue was dissolved in ether, filtered through diatomaceus earth, and concentrated to give intermediate methyl 4-(ethylthio)-2-(methoxymethoxy)benzoate.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][Mg]Cl)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)=[CH:14][CH:13]=1
Reactant: Fc1ccc(C[Mg]Cl)cc1
Reactant: O=C1CCC2CCC(=O)N12
Product: O=C(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Yield: 104.9 %

Procedure:
Analogous to the procedure described for Example 1A, Step A, tetrahydro-pyrrolizine-3,5-dione (1.41 g, 10.1 mmol) was reacted with 4-fluorobenzylmagnesium chloride (0.25M in Et2O, 50 mL, 12.5 mmol) over 5 h. Purification by medium pressure chromatography (2% MeOH in CH2Cl2) provided 5-[4-(4-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.64 g). 1H NMR (CDCl3) δ7.18 (m, 2H), 7.03 (m, 2H), 6.34 (m, 1H), 3.70 (s, 2H), 3.62 (m, 1H), 2.54 (t, 2H), 2.34–2.15 (m, 3H), 1.82–1.61 (m, 3H).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>C1COCC1.O>[CH:1]1([C:18]2([OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:11][C:10]3[C:19]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: O=c1c2ccccc2sc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C2CC2)c2ccccc2Sc2ccccc21

Procedure:
A solution of cyclopropylmagnesium bromide in dry THF (prepared from cyclopropylbromide (18.2 g, 0.15 mol), magnesium turnings (2.9 g, 0.12 mol) and dry THF (80 ml)) was placed under an atmosphere of nitrogen. A solution of thioxanthen-9-one (12.7 g, 0.06 mol) in dry THF (70 ml) was added dropwise and when addition was complete the mixture was heated at reflux for 20 minutes. The reaction mixture was cooled on an ice-bath and saturated ammonium chloride (70 ml) was carefully added. The mixture was diluted with water (100 ml) and extracted with diethyl ether (2×100 ml). The combined organic extracts were washed with water, dried (Na2SO4) and the solvent was evaporated in vacuo to give 25.2 g of crude 9-cyclopropyl-9H-thioxanthen-9-ol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][NH:17][CH2:18]3)[CH2:13]2)[CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:36][C:37]1[CH:38]=[CH:39][C:40]([N:46]2[N:50]=[CH:49][CH:48]=[N:47]2)=[C:41]([CH:45]=1)[C:42](O)=[O:43].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:36][C:37]1[CH:38]=[CH:39][C:40]([N:46]2[N:50]=[CH:49][CH:48]=[N:47]2)=[C:41]([C:42]([N:17]2[CH2:16][CH2:15][C@@H:14]3[C@@H:19]([N:12]([C:4]4[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=4)[CH2:13]3)[CH2:18]2)=[O:43])[CH:45]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(C(F)(F)F)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(6-methyl-2-trifluoromethyl-pyrimidin-4-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 9) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C21H19F4N7O, 461.422; m/z found 462.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.09-7.71 (m, 2H), 7.55-6.50 (m, 3H), 6.14 (d, J=81.2, 1H), 4.76-3.62 (m, 6H), 3.50-2.85 (m, 2H), 2.78-1.92 (m, 5H).