Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1F)=[O:6])[CH:2]([CH3:4])[CH3:3].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC(=O)c1ccccc1F
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(=O)c1ccccc1N1CCCCC1
Temperature: 120 °C
Yield: 95 %

Procedure:
A mixture of isobutyl-(2-fluoro-phenyl)-ketone 13 (0.928 gm, 5 mmole), piperidine (0.645 gm, 7.82 mole) and potassium carbonate (1.08 gm, 7.82 mmole) in 4 ml of DMF was heated for 4 hrs at 120° C. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and water (30 ml) was added to the reaction mixture and then extracted with ethyl acetate (1×15 ml, 2×7 ml). The combined organic layers were washed with a saturated ammonium chloride solution (2×15 ml) and subsequently dried over sodium sulphate. The solvent was removed under reduced pressure to obtain isobutyl-(2-piperidino-phenyl)-ketone 10 in 95% yield (GC showed 90% Purity). 1HNMR CDCl3, (spectrum 13): 0.92(d, 6H), 1.60(m, 6H), 2.07(m, 1H), 2.95(m, 6H), 7.05(m, 2H). 7.35(m, 2H). IR (spectrum 14) (Neat): 2841, 1657(C═O), 1570, 1435, 1345, 738
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([CH2:32]Br)=[CH:27][C:26]=1[Cl:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:24][C:25]1[C:26]([Cl:34])=[CH:27][C:28]([CH2:32][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:29][C:30]=1[Cl:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: Clc1cc(CBr)cc(Cl)c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2cc(Cl)c(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and 2-benzyloxy-5-bromomethyl-1,3-dichloro-benzene (CAB02118, 1.73 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (2×100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.76 g (78%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)[CH2:14][CH2:13]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1cc(C)cc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1

Procedure:
138.6 mg of the target compound (0.39 mmol, 47.6%) was obtained using 1-(3,5-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=1)=[O:12])[CH2:3][CH2:2]2.[H-].[Na+].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:25]([CH3:27])[CH3:26])[N:14]=1)=[O:12])[CH2:3][CH2:2]2
Reactant: CN1[C@H]2CCC(NC(=O)c3n[nH]c4ccccc34)[C@@H]1CC2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NC2CC[C@H]3CC[C@@H]2N3C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of N-(tropan-4-yl)-1H-indazole-3-carboxamide (2.98 g, 10 mmol) in 75 mL of dimethylformamide under a nitrogen atmosphere was added, in portions, sodium hydride (60% dispersion in mineral oil, 420 mg, 10 mmol). The resulting solution was allowed to stir for about 1 hour at room temperature before adding 2-iodopropane (1.2 mL, 12 mmol). This resulting solution was allowed to stir at room temperature for about 18 hours. The dimethylformamide was evaporated under reduced pressure and the residue was dissolved in about 100 mL of 1N hydrochloric acid. The acidic solution was washed with ethyl acetate and then cooled before making it basic with saturated aqueous sodium carbonate. The basic mixture was extracted 3 times with methylene chloride. The extracts were washed with brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give a viscous oil. The oil was purified by preparative HPLC (gradient methylene chloride:methanol 0-25%, 1% ammonium hydroxide) to give 2.52 g of an oil. Yield: 77%. MS(FD) M+ 326.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=S)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27].C(Cl)CCl>CC#N>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[NH:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:9][C:10]=3[N:15]=2)=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: Nc1ccc(Oc2ccncc2)cc1N
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Solvent: ClCCCl
Solvent: CC#N
Product: FC(F)(F)c1cc(Nc2nc3cc(Oc4ccncc4)ccc3[nH]2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(pyridin-4-yloxy)-benzene-1,2-diamine (0.273 g, 1.36 mmol) in 20 mL CH3CN was added 1-chloro-4-isothiocyanato-2-trifluoromethyl-benzene (prepared similarly to the procedure described in Preparation III, 0.322 g, 1.36 mmol). The reaction was stirred 18 h at RT. The reaction was diluted with 25 mL CH3CN, and then EDC (0.39 g, 2.03 mmol) was added. The reaction was heated at 80° C. for 2.5 h. The reaction was cooled to RT and concentrated in vacuo. The crude mix was dissolved into EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a hexane-EtOAc gradient. The partially pure compound was triturated with CH2Cl2 to yield the title compound. MS (MH+)=405.1; Calc'd 404.78 for C19H12ClF3N4O.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](OCC)=[O:18].COC1C=CC(C(C(=O)C)C#N)=CC=1>>[O:18]=[CH:17][CH:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)[C:15]#[N:16]
Reactant: N#CCc1cccc(Oc2ccccc2)c1
Reactant: CCOC=O
Agent: COc1ccc(C(C#N)C(C)=O)cc1
Product: N#CC(C=O)c1cccc(Oc2ccccc2)c1

Procedure:
3-Oxo-2-(3-phenoxyphenyl)propanenitrile was prepared on a 2.39 mmol scale from 3-phenoxyphenylethanenitrile and ethyl formate using the procedure described for the preparation of 2-(4-methoxyphenyl)-3-oxobutanenitrile in Example 17. The product was a viscous orange oil (84% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[CH3:14])[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O1CCOCC1>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[N:3][C:4]([C@@H:13]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][NH:20]3)[CH3:14])=[CH:5]2
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(Cl)n1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(N2CCN(C)CC2)n1
Temperature: 25 °C

Procedure:
To a mixture of (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9H-purin-6-amine 38 (300 mg, 0.84 mmol, 1 eq) in 1,4-dioxane (10 mL) at RT, 1-methylpiperazine (167 mg, 1.68 mmol, 2 eq) was added and the resulting mixture was stirred at reflux for 8 h. The mixture was allowed to cool to RT, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product, (S)—N-(1-(8-chloro-1-(4-methylpiperazin-1-yl)isoquinolin-3-yl)ethyl)-9H-purin-6-amine 46. ESI-MS m/z: 423.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[C:5]([CH3:19])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[C:5]([CH3:19])[C:4]=2[F:20])[CH2:31]1
Reactant: Cc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(N)C2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of 0.50 g (1.60 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.36 g (1.93 mmol) of 3-(t-butoxycarbonyl)aminopyrrolidine, 0.48 g (4.75 mmol) of triethylamine, and 20 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight. The solution was concentrated and the residue was triturated with ether:hexane (1:1) and filtered. The solid was washed with water and hexane. The crude product was suspended in 15 ml of dichloromethane and 1.5 ml of trifluoroacetic acid and was stirred at room temperature for four hours. The solution was concentrated to a gold solid which was suspended in water, made basic (pH 11) with 10% sodium hydroxide, and filtered. The solution was then neutralized (pH 7.10), and the precipitate was filtered and washed with water to give 0.29 g of the title compound, mp 124°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24])[NH:8][C:7](=[O:25])[CH:6]=[CH:5]2.Br[CH2:27][C:28]#[CH:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:29]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:25])[C:28]#[CH:27]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3[nH]c(=O)ccc3cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)ccc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 50.9 %

Procedure:
A stirred solution of 0.6 gram (0.002 mole) of 3-(6-fluoroquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil, 0.5 gram (0.003 mole) of 3-bromopropyne, and 0.5 gram (0.003 mole) of potassium carbonate in 40 mL of N,N-dimethylformamide was stirred at ambient temperature for about 16 hours. The reaction mixture was then subjected to column chromatography on silica gel. Elution was accomplished using 1:1 ethyl acetate-heptane and ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.4 gram of 3-[1-(2-propyn-1-yl)-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil, mp 236°-238° C. The NMR spectrum was consistent with the proposed structure. Other fractions were combined and concentrated under reduced pressure, yielding a small amount of the O-alkylated product, 3-[2-(2-propyn-1-yloxy)-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:15](=[O:16])[C:14]2[CH:13]=[C:12]([Cl:11])[CH:20]=[C:19]([Cl:21])[CH:18]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NC(=O)c2cc(Cl)cc(Cl)c2)cc1
Yield: 83.9 %

Procedure:
Reaction of 4-aminoacetophenone (76 mg, 0.56 mmol) in THF (6 mL) with 3,5-dichlorobenzoyl chloride (145 mg, 0.69 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-3,5-dichloro-benzamide (145 mg, 0.47 mmol, 84% yield) as a white powder after washing by dichloromethane.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][C:30]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])[CH2:31][OH:32]>>[CH3:33][C:30]([CH:34]1[CH2:35][CH2:36][N:37]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:38][CH2:39]1)([CH3:29])[CH2:31][OH:32]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)(CO)C1CCNCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure E for amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-methyl-2-(piperidin-4-yl)propan-1-ol were reacted to give 339. LCMS: M+H+=519.3
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.[F:23][CH:24]([F:40])[O:25][C:26]1[C:31]2[N:32]=[C:33]([CH2:35][CH3:36])[O:34][C:30]=2[C:29]([C:37](O)=[O:38])=[CH:28][CH:27]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:37]([C:29]2[C:30]3[O:34][C:33]([CH2:35][CH3:36])=[N:32][C:31]=3[C:26]([O:25][CH:24]([F:23])[F:40])=[CH:27][CH:28]=2)=[O:38])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
para-Nitrophenol (0.95 g), 4-dimethylaminopyridine (80 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.4 g) were added to a stirred suspension of 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (1.6 g) in dry dichloromethane (60 ml) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 18 hours. Water (20 ml) was added and the aqueous layer extracted with dichloromethane (400 ml). The organic layer was washed with water (80 ml), separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 1:4 ethyl acetate/heptane to 1:1:2 ethyl acetate/dichloromethane/heptane afforded the title compound as a pale yellow solid (1.9 g)
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(COC)OC.[F-].[Cs+]>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.CO>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[CH:4]=[N:3][C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:7][N:6]=1
Reactant: Clc1cnc(-c2ccco2)cn1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: c1coc(-c2cnc(-c3ccncc3)cn2)c1
Yield: 57.9 %

Procedure:
At room temperature, 2-chloro-5-(furan-2-yl)pyrazine (N. Sato, J. Heterocyclic Chem., 19, 407(1982)) (1.00 g) and (pyridin-4-yl)boronic acid (1.09 g) were suspended in a mixed solvent of dimethoxyethane (50 ml) and methanol (50 ml), followed by the successive addition of tetrakis(triphenylphosphine)palladium (O) (640 mg) and cesium fluoride (5.55 g). The resulting mixture was heated under reflux for 16 hours. After cooling, the reaction mixture was concentrated. Dichloromethane and water were added to the concentrate to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, treated with activated carbon and filtered through Celite. After the filtrate was concentrated to about 5 ml, petroleum ether (50 ml) was added to the concentrate. Yellow crystalline powder thus precipitated was collected by filtration and dried, whereby the title compound (716 mg, 58%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][CH:32](O)[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH:32]([CH3:33])[CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)O
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: CC(C)OC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Yield: 66 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and propan-2-ol according to Method E (yellow solid, 145 mg, 0.313 mmol, 66% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (d, J=8.1 Hz, 1H), 7.89-7.94 (m, 2H), 7.46 (d, J=8.9 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.03 (dd, J=8.9, 2.1 Hz, 1H), 5.22-5.32 (m, 1H), 4.63 (dd, J=9.7, 5.4 Hz, 1H), 3.44-3.54 (m, 1H), 3.08-3.16 (m, 1H), 2.86-2.98 (m, 1, 2.25-2.36 (m, 1H), 2.07-2.19 (m, 1H), 1.88-2.03 (m, 1H), 1.73-1.83 (m, 1H), 1.42-1.66 (m, 5H), 1.39 (d, J=6.4 Hz, 6H), 1.20-1.37 (m, 2H). ES-HRMS m/z calc. for C27H29ClN3O2 (M+H) 462.1943, found 462.1897.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:20][CH3:21])(=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].O>CN(C=O)C>[CH3:21][O:20][C:10](=[O:19])[CH2:11][CH:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.6 %

Procedure:
To a solution of indole (2.88 g, 25 mmol) and methyl trans-cinnamate (3.98 g, 25 mmol) in anhydrous DMF (50 mL) was added a suspension of 60% NaH (0.29 g, 7 mmol) at room temperature. The reaction mixture was allowed to stir for 6 hours at room temperature. The reaction mixture was poured into water (300 mL) and product was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water (5×200 ml), dried over Na2SO4 and evaporated under vacuum. Purification by chromatography (SiO2, benzene-hexane, 1:9) afforded 1.51 g (22% yield) of 3-indol-1-yl-3-phenyl-propionic acid methyl ester as a white powder: MS 280 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=[O:12])[CH2:7][CH:6]([CH2:14][CH2:15][OH:16])[CH2:5]2.[N:17]#[C:18][NH2:19].[CH]Cl.[OH-].[Na+]>>[NH2:19][C:18]1[N:17]=[N+:11]([O-:12])[C:10]2[CH:9]=[C:8]3[C:4]([CH2:5][CH:6]([CH2:14][CH2:15][OH:16])[CH2:7]3)=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CC(CCO)C2
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)CC(CCO)C3
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A mixture of nitroaniline 156 (17.6 g, 79 mmol) and cyanamide (19.8 g, 471 mmol) were melted together at 60° C. and cHCl (35 mL) was added dropwise. The solution was heated to 100° C., stirred for 1 h, cooled to ca. 50° C. and the mixture made strongly basic with 7.5 M NaOH solution. The mixture was heated to 100° C. for 3 h, cooled to 20° C. and diluted with ice/water. The resulting precipitate was filtered, washed with H2O (100 mL) and Et2O (30 mL), and dried to give 1-oxide 157 (18.4 g, 94%) as a yellow-green solid: mp 230-235° C.; 1H NMR [(CD3)2SO] δ 7.92 (s, 1H, H-9), 7.33 (s, 1H, H-5), 7.11 (br s, 2H, NH2), 4.45 (br s, 1H, OH), 3.49 (t, J=6.6 Hz, 2H, CH2O), 3.06-3.15 (m, 2H, H-6, H-8), 2.59-2.69 (m, 2H, H-6, H-8), 2.49-2.54 (m, 1H, H-7), 1.63 (q, J=6.6 Hz, 2H, CH2); HRMS calcd for C12H14N4O2 (M+) m/z 246.1117, found 246.1115.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].[C:23](NC1C=C(Cl)N=C(C(OC)=O)C=1Cl)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22])(=[O:25])[CH3:24]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl

Procedure:
Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate is produced from a 4-chloro-2-fluoro-3-substituted-phenylboronic acid derivative, such as PBA. As shown in the reaction scheme below, the methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (Compound 1) is produced by reacting PBA (Compound 2) with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate (Compound 3) to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (Compound 4), which is deacetylated to produce Compound 1:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[S:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:16][C:14]1[O:13][N:12]=[C:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH:15]=1
Reactant: CCOC(=O)c1csc(-c2cc(C)on2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2nc(C(=O)O)cs2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
A mixture of 2-(5-methyl-isoxazol-3-yl)-thiazole-4-carboxylic acid ethyl ester (0.24 g, 1.0 mmol) and lithium hydroxide monohydrate (84 mg, 2.0 mmol) was dissolved in THF/H2O (2/1, 9 mL). The resulting reaction was allowed to stir at room temperature for about 15 hours, then acidified using 20% aqueous HCl. The solvent was removed by lyophilization to provide 2-(5-methyl-isoxazol-3-yl)-thiazole-4-carboxylic acid (21 mg).