Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[S:22]1[CH:26]=[CH:25][C:24]2[CH:27]=[C:28]([CH2:31][OH:32])[CH:29]=[CH:30][C:23]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[S:22]1[C:23]2[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:2]3[CH:7]=[CH:6][N:5]([C:8]4[CH:9]=[CH:10][C:11]5[N:15]=[C:14]([CH:16]6[CH2:18][CH2:17]6)[N:13]([CH3:19])[C:12]=5[CH:20]=4)[C:4](=[O:21])[CH:3]=3)=[CH:27][C:24]=2[CH:25]=[CH:26]1
Reactant: OCc1ccc2sccc2c1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc5sccc5c4)cc3=O)cc21
Temperature: 100 °C
Yield: 10.5 %

Procedure:
A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), benzo[b]thiophen-5-ylmethanol (110 mg), cesium carbonate (326 mg) and DMF (3 ml) was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (15 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cncc(Br)c1
Product: Nc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 5-bromo-pyridin-3-ylamine (example B.44) (156 mg, 0.9 mmol) according to general procedure II. Obtained as a light brown solid (40 mg, 9%). MS (ISN) 506.1 [(M+OAc)−]; mp 216-217° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([NH:8][CH3:9])[CH:7]=1.[Sn](Cl)Cl.[CH:16](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][N:8]([CH3:16])[C:6]=2[CH:7]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1cnc2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a suspension of (5-bromo-2-nitro-phenyl)-methyl-amine (1.2 g, 5.19 mmol) in ethanol (25 mL) was added tin(II) chloride (1.97 g, 10.39 mmol). The reaction mixture was stirred at 80° C. for 4 h, then it was concentrated in vacuo. To the residue was added toluene (12 mL), trimethyl orthoformate (0.625 mL, 5.71 mmol), and para-toluenesulfonic acid (49 mg, 0.26 mmol). The reaction mixture was stirred at 110° C. for 15 h, then it was concentrated in vacuo and the residue was adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8% methanol/dichloromethane afforded 482 mg of 6-bromo-1-methyl-1H-benzoimidazole as a dark orange solid (44% yield): 1H NMR (DMSO-d6) δ 3.83 (s, 3H), 7.33 (dd, 1H), 7.59 (d, 1H), 7.86 (d, 1H), 8.21 (s, 1H); MS (m/z) 211, 213 [M+H+]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Methyl 2-fluoro-4-hydroxybenzoate (1.4685 g; manufactured by Changzou Fine Chemical Co., Ltd.) and potassium carbonate (3.6-917 g; manufactured by Sigma-Aldrich Co.) were suspended in dehydrated DMF (21 mL; manufactured by Kanto Chemical Co., Inc.), and benzyl bromide (1.22 mL; manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was stirred overnight at 50° C. The reaction solution was cooled to room temperature, and then was poured into water. The mixture was extracted two times with ethyl acetate. The organic layer was washed twice with water and once with brine, and was dried over anhydrous sodium sulfate. Subsequently, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=97:3→77:23). Thus, the title compound (2.2207 g) was obtained.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=O>>[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: Cc1cccc(C)c1C=O
Product: Cc1cccc(C)c1CN1CCN(c2cc(=O)[nH]cn2)CC1

Procedure:
6-[4-(2,6-Dimethyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,6-dimethylbenzaldehyde. Mass spectrum (ES) MH+=299.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1.Br[CH2:19][CH2:20][C:21]1[C:22]([CH3:27])=[N:23][NH:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:19][CH2:20][C:21]2[C:22]([CH3:27])=[N:23][NH:24][C:25]=2[CH3:26])=[CH:8][CH:7]=1
Reactant: Cc1n[nH]c(C)c1CCBr
Reactant: COC(=O)/C=C/c1ccc([C@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc([C@H]2CCCN2CCc2c(C)n[nH]c2C)cc1
Temperature: 85 °C

Procedure:
(E)-3-((R)-4-Pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (697 mg, 3 mmol) and 4-(2-bromo-ethyl)-3,5-dimethyl-1H-pyrazole (734 mg, 3.62 mmol) were dissolved in acetonitrile, potassium carbonate (833 mg, 6 mmol) was added, and the reaction mixture heated under nitrogen at 85° C. for 14 h. Cooled to room temperature, diluted with DCM (20 mL) and filtered through a plug of celite. Wash plug with DCM (30 mL). Filtrate was concentrated to ˜10 mL and columned on silica with EtOAc/hexane. Product elutes with neat EtOAc, and after concentrating gave (E)-3-(4-{(R)-1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester as a tacky, pale yellow solid (804 mg, 2.275 mmol, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:7]([NH:19][C:20]2[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=2)=[O:9])[CH:10]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Cl)ccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cccc(NC(=O)c2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 60 °C

Procedure:
A mixture of 5-chloro-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 45; 50 mg, 0.19 mmol), methyl (3-aminophenyl)acetate (may be prepared as described in Description 44; 48 mg, 0.29 mmol), EDAC (56 mg, 0.29 mmol), and dichloromethane (3 ml) was heated in the microwave at 60° C. for 40 minutes. DIPEA (53 μl, 0.3 mmol) was added and the mixture was heated at 60° C. in the microwave for another 20 minutes. The reaction mixture was purified by SCX cartridge, eluting with methanol. The fractions were combined and evaporated to give the title compound as an off-white solid. 35 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2F)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NO)c2cc(C(F)(F)F)ccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2noc3ccc(C(F)(F)F)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
A solution of 4-[(2-Fluoro-5-trifluoromethyl-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (4.969 g, 0.013 M) in anhydrous THF (59 mL) was treated with Potassium tert-butoxide (13.4 mL of a 1M solution in THF, 0.0133 M-1.05 eq). The mixture was stirred at ambient temperature for 1 hour and. then heated to 65° C. for 2 hours. The THF was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with H2O (50 mL) and brine (50 mL) respectively. It was then dried over MgSO4, filtered and concentrated to give a solid (5 g) which was purified on silica ˜120 g, (eluting with ethylacetate/heptane (30:70) to give the product as a white solid (2.69 g, 57%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH:27]1([N:30]([CH3:37])[C@@H:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:29][CH2:28]1>>[CH:27]1([N:30]([CH3:37])[C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:21])[CH2:32]2)[CH2:29][CH2:28]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN(C1CC1)[C@@H]1CCCNC1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@@H](N(C)C4CC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N-cyclopropyl-N-methylpiperidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.13-0.61 (m, 4H) 1.38-1.64 (m, 2H) 1.64-2.09 (m, 3H) 2.15-2.41 (m, 3H) 2.43 (s, 3H) 2.55-2.86 (m, 2H) 3.04 (br. s., 1H) 3.49-3.87 (m, 1H) 4.33-4.77 (m, 1H) 7.65 (dd, J=8.08, 1.52 Hz, 1H) 7.72 (s, 1H) 7.81 (d, J=8.08 Hz, 1H) 8.05 (dd, J=8.59, 2.02 Hz, 1H) 8.13 (s, 1H) 8.40 (d, J=7.33 Hz, 1H) 8.53 (d, J=1.77 Hz, 1H); ESI-MS m/z [M+H]+ 457.3.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][CH2:17][CH:18]=O.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[Cl:16][CH2:17][CH2:18][NH:10][C:9]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=CCCl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(NCCCl)cc1OC1CCCC1
Temperature: 15 °C
Yield: 63.4 %

Procedure:
To a solution of 2.15 g (10.4 mmol) 3-cyclopentyloxy-4-methoxyaniline (J. Org. Chem. 2005,70, 1050) in 100 ml methanol were added 2.0 g (14.1 mmol) chloroacetaldehyde solution (55% in water), 3.9 g (62.6 mmol) NaBH3CN and 0.5 ml acetic acid. The reaction was stirred over night at 15° C. and the solvent was subsequently evaporated. The residue was taken up in 120 ml dichloromethane and the organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel (hexane:ethyl acetate 100:1 then 15:1) to give 1.78 g (63.5%) of the desired product as a yellow oil. 1H-NMR (DMSO): 6.70 (d, 1H), 6.28 (s, 1H), 6.06 (d, 1H), 5.43 (m, 1H), 4.69 (m, 1H), 3.68 (m, 2H), 3.60 (m, 3H), 3.32 (m, 2H), 1.83 (m, 2H), 1.69 (m, 4H), 1.55 (m, 2H).
Reaction SMILES: [Si](O[CH2:9][CH2:10][CH2:11][C:12](=[CH2:29])[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[C:18]([F:27])=[CH:17][C:16]=1[F:28])=[O:14])(C(C)(C)C)(C)C.[NH2:30][C:31]([NH2:33])=[S:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC(O)=O.C1COCC1>[F:28][C:16]1[CH:17]=[C:18]([F:27])[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)=[CH:20][C:15]=1[C@@:13]12[O:14][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][S:32][C:31]([NH2:33])=[N:30]2
Reactant: NC(N)=S
Reactant: C=C(CCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(-c2cncnc2)c(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NC1=N[C@]2(c3cc(-c4cncnc4)c(F)cc3F)OCCC[C@@H]2CS1
Temperature: 25 °C
Reaction time: 12 h
Yield: 2.3 %

Procedure:
To a solution of 5-((tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (Preparation 16, 606 mg, 1.448 mmol) in HOAc (7239 μL) was added thiourea (441 mg, 5.79 mmol), and a suspension was formed. The reaction mixture was stirred at rt for 12 h, and a clear yellowish solution was formed. TBAF (2172 μL, 2.172 mmol) in THF was added, and the reaction mixture was stirred at rt for 5 h, followed by heating at 60° C. for 12 h. This crude reaction mixture was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 10% MeOH/90% water/0.1% TFA; B: 90% MeOH/10% water/0.1% TFA) over 12 min to give a mixture of two isomers. This mixture was purified by preparative TLC on silica gel (0.50 mm thickness) eluting with 90% DCM/9% MeOH/1% ammonium hydroxide to give (4aS,8aS)-8a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,6,7,8a-hexahydropyrano[2,3-d][1,3]thiazin-2-amine (13 mg, 0.034 mmol, 2.354% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.22 (s, 1H), 8.91 (d, J=1.4 Hz, 2H), 7.43 (t, J=8.5 Hz, 1H), 7.02 (dd, J=10.8, 10.2 Hz, 1H), 5.0-4.5 (broad s, 2H), 4.00-3.92 (m, 1H), 3.88-3.80 (m, 1H), 2.95 (dd, J=12.6, 4.0 Hz, 1H), 2.81-2.71 (m, 1H), 2.67 (dd, J=12.6, 2.8 Hz, 1H), 2.01-1.83 (m, 2H), 1.75-1.57 (m, 2H). MS (M+H)+: 363.03.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.O.[Sn](Cl)Cl>CCO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2cn3cc(I)ccc3n2)cc1
Yield: 73 %

Procedure:
Prepared as described in the Nitro Reduction section using 6-iodo-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0.45 g, 1.23 mmol) and tin (II) dichloride dihydrate (1.39 g, 6.16 mmol) in EtOH (25 ml) to give the title compound (0.301 g, 73%) as a yellow solid, after work-up and flash chromatography (4:1 EtOAc/DCM).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.CN(C=O)C.[OH-].[K+]>O>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([NH:15][CH2:2][C:3]([NH:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8]([OH:10])=[O:9])=[O:4])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNc1ccc(-c2ccccc2)cc1)Nc1ccccc1C(=O)O

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), para-aminobiphenyl (13.12 g, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. The resulting air-sensitive material was triturated with ethyl acetate (100 mL), filtered, and rinsed with ethyl acetate (2×25 mL) to yield, after drying, 8.18 g (76%) of the title compound as a tan solid; 1H NMR (DMSO-d6) δ 13.4 (broad s, 1H), 12.05 (s, 1H), 8.75 (d, J=8.4, 1H), 7.95 (dd, J=7.4, J=1.2, 1H), 7.60 (td, J=7.2, J=1.2, 1H), 7.54 (d, J=7.6, 2H), 7.45 (d, J=8.8, 2H), 7.37 (t, J=7.6, 2H), 7.22 (t, J=7.6, 1H), 7.13 (t, J=7.6, 1H), 6.69 (d, J=8.4, 2H), 6.7 (broad s, 1H), 3.90 (s, 2H); 13C NMR (DMSO-d6) a 170.74, 169.12, 147.71, 140.60, 140.36, 134.20, 131.14, 128.87, 128.74, 127.28, 125.96, 125.55, 122.69, 119.40, 115.97, 112.85, 48.87; MS (EI, m/z) 328 (M-H2O+).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:25][CH2:26][CH2:27][CH3:28])[N:18]([CH2:19][CH2:20][CH2:21][C:22](=O)[CH3:23])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>CO>[CH3:3][O:2][N:4]=[C:22]([CH2:21][CH2:20][CH2:19][N:18]1[C:14]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=[C:17]1[CH2:25][CH2:26][CH2:27][CH3:28])[CH3:23]
Reactant: CON
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCC(C)=NOC
Reaction time: 8 h
Yield: 99 %

Procedure:
Methoxylamine hydrochloride (0.59 g, 21 mmol, 1.5 eq) was added to a solution of 5-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one (1.54 g, 4.73 mmol, 1 eq) in methanol (20 mL) and stirred overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with dichloromethane (2×25 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a yellow solid. The material was subjected to HPFC (silica gel, eluting with 0-25% CMA in chloroform), triturated with hot acetonitrile, filtered, and dried at 100° C. under vacuum for 24 hours to afford 1.66 g of 5-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one O-methyloxime as a white powder with an E/Z ratio of 80:20, mp 132-134° C. Anal. calcd for C19H26N6O: C, 64.38; H, 7.39; N, 23.71. Found: C, 64.19; H, 7.42; N, 23.76.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][OH:10])([CH3:8])[CH2:3]1.[H-].[Na+].F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][O:10][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])([CH3:8])[CH2:3]1
Reactant: N#Cc1cccc(F)c1
Reactant: CN1CCCC(C)(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC(C)(COc2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (1,3-dimethylpiperidin-3-yl)methanol (0.50 g, 3.5 mmol) in dry DMF (10 mL) at room temperature, 60% sodium hydride in oil (0.28 g, 7.0 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes and 3-fluoro benzonitrile (0.44 g, 3.7 mmol) was added. Due to excessive foaming the reaction mixture was diluted with dry DMF to 15 mL. The reaction mixture was then stirred at room temperature over night and quenched with water. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient with EtOAc:MeOH:TEA (1:0.1:0.05) in EtOAc, which gave the product as a colorless oil. Yield: 0.53 g (59%). 1H NMR (400 MHz, CD3OD) δ 7.41 (t, 1H, J=8.11 Hz), 7.20-7.27 (m, 3H), 3.89 (d, 1H, J=8.89 Hz), 3.82 (d, 1H, J=8.89 Hz), 2.21-2.51 (m, 3H), 2.19 (s, 3H), 2.12 (m, 1H), 1.54-1.67 (m, 3H), 1.21-1.30 (m, 1H), 1.07 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.F[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1.[CH3:16][S-:17].[Na+]>CO>[CH3:15][C:8]1[CH:7]=[C:6]([S:17][CH3:16])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: C[S-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CSc1ccc(C(=O)O)c(C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (2 mL, 27.4 mmol) was added dropwise to a solution of 4-fluoro-2-methyl-benzoic acid (1.25 g, 8.11 mmol) in methanol (10 mL). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and methyl 4-fluoro-2-methylbenzoate was used in the next step without further purification. Methyl 4-fluoro-2-methylbenzoate was dissolved in DMF (5 mL) and sodium thiomethoxide (1.1 g, 15.7 mmol) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was then partitioned between 1M hydrochloric acid and ethyl acetate. The layers were separated and the organic layer was washed with 1M hydrochloric acid, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 2-methyl-4-(methylthio)benzoic acid which was carried to the next step without further purification. 2-Methyl-4-(methylthio)benzoic acid was suspended in acetic acid (10 mL) and hydrogen peroxide (5 mL of 30% w/w) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was concentrated in vacuo, then partitioned between 0.2 M HCl (25 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (50 mL). The combined organics washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The resulting solid was rinsed with ether (2×10 mL) and dried in vacuo to give 2-methyl-4-methylsulfonyl-benzoic acid (0.87 g, 50%) as a white solid. ESI-MS m/z calc. 214.0. found 215.5 (M+1)+; Retention time: 0.48 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.99 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 3.25 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C[O-].[Na+].C(O[C:15](=[C:18]([C:21]#[N:22])[C:19]#[N:20])[CH2:16][CH3:17])C>C(O)C>[CH:2]1([N:7]2[C:21]([NH2:22])=[C:18]([C:19]#[N:20])[C:15]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(CC)=C(C#N)C#N
Reactant: NNC1CCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1nn(C2CCCC2)c(N)c1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
Cyclopentylhydrazine hydrochloride (20.9 g, 0.1 moles), 97% sodium methoxide (5.6 g, 0.1 moles) and ethanol (100 ml) were combined and stirred at room temperature under argon for 2.5 hours. (1-Ethoxypropylidene)malononitrile was added to the reaction mixture and the mixture was refluxed for 21 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was treated with water (150 ml) and the obtained precipitate was collected by filtration, washed with water and dried in a vacuum oven for 24 hours to afford 14.2 g (70%) of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carbonitrile as a brown powder, m.p. 171°-173° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:7])[CH2:5][CH3:6].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH:4]([CH2:5][CH3:6])[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CCC(O)CCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC(CCCl)O[Si](C)(C)C(C)(C)C

Procedure:
Using the procedure of Example 6A substituting 1-chloro-3-pentanol (50 g, 0.41 moles), tert-butyldimethylsilyl chloride (71, 0.47 moles), imidazole (32.6 g, 0.48 moles), and dimethylformamide (150 ml), there is obtained (3-chloro-1-ethylpropoxy)(1,1-dimethylethyl)dimethylsilane. The crude product is fractionally distilled under vacuum leaving a clear, colorless oil (78 g, 0.33 moles), BP 48° C./0.1 mm.