Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.O>[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=3)=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1csc2cc(O)ccc12
Reactant: CCCCCC(=O)OCc1nccc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCC(=O)OCc1nccc(Oc2ccc3c(C(=O)OCC)csc3c2)n1
Temperature: 60 °C
Reaction time: 45 h

Procedure:
A suspension of 324 mg (1.33 mMol) hexanoic acid 4-chloro-pyrimidin-2-ylmethyl ester, 313 mg (1.41 mMol) 6-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester (Step 12.3) and 312 mg (1.47 mMol) K3PO4 in 5 ml NMP is stirred for 45 h at 60° C. The reaction mixture is dissolved in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2/ether 59:1→9:1) and crystallization from hexane gives the title compound: m.p.: 51° C.; MS: [M+1]+=429; TLC(CH2Cl2/ether 19:1): Rf=0.28.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl.CCN(CC)CC>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15](=[O:17])[CH3:16])[CH2:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3,3-dimethyl-6-nitroindoline (450 mg) in CH2Cl2 (15 mL) and Et3N (0.6 mL) at −10° C. was added acetyl chloride (180 μL, 2.5 mmol). The mixture was stirred at rt overnight and quenched by addition of sat. aq. NaHCO3, and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column to give a light yellow solid (390 mg, 71% for two steps).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)=[N:24][CH:23]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: Cc1cnc(-c2cc(C=O)ccn2)s1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccnc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with synthesized 2-(5-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 424.03 g/mol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCNCC4)ccc23)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of piperazine (5 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (1 mmol) in DMSO (1 mL) was stirred at 120° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo to obtain 4-(7-piperazin-1-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5](OC)[C:4]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1)[CH3:2].[CH3:22][Mg]Br>O1CCCC1.C(OCC)C>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([CH3:22])[C:4]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1)[CH3:2]
Reactant: CCc1cc(C(F)(F)F)cc(OC)c1C1=NC(C)(C)CO1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C(F)(F)F)cc(C)c1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 50.4 %

Procedure:
To a 0° C. solution of 100 mg (0.332 mmol) 2-(2-ethyl-6-methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (obtained by reaction of 2-(2,6-dimethoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole with ethylmagnesium bromide) in 0.6 ml tetrahydrofuran, was added drop-wise 0.332 ml (0.996 mmol) of a 3M methylmagnesium bromide solution in diethyl ether maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature and stirred for 3.5 hours and then heated in a 70° C. oil bath for 4 days. The mixture was cooled in an ice bath and quenched dropwise with 3 ml saturated ammonium chloride solution. Ethyl acetate was added. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude orange oil (286 mg) was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate (0 to 10%) to provide 50 mg (yield: 50.4%) of the title compound as a light yellow oil. MS (m/e): 286.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.OO.C([O-])(O)=[O:32].[Na+]>CO.OS(O)(=O)=O.CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:21][CH:22]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccccc3)c(C)cc2c1
Yield: 61 %

Procedure:
To a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzaldehyde (8) (2.00 g, 5.43 mmol) in MeOH (40 mL) were added an aqueous solution of, 30-40% by weight, H2O2 (5.0 mL) and a few drops (10-12) of conc. H2SO4. The resultant mixture was stirred for 24 h. Reaction mixture was neutralized with saturated aqueous NaHCO3 and then diluted with EtOAc (200 mL). Reaction mixture was washed with water (2×30 mL), brine (1×30 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (9:1 to 4:1) as an eluent to give 1.180 g (61%) of the title compound (233) as a white foam. The 1H NMR and mass spectral data are consistent with the data reported in Example 41 (Step 1).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[C:12](/[CH3:27])=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:28].CCCCCC>CC(O)C>[NH2:28]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[C:12](/[CH3:27])=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)=[O:6]
Reactant: CC(=O)CC(=O)OCCOC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Reactant: N
Solvent: CCCCCC
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OCCOC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Yield: 80.2 %

Procedure:
In 8 ml of 2-propanol was dissolved 2.0 g of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl acetoacetate, and ammonia gas was introduced into the resulting solution for 2 hours with ice-cooling. And, the solution was subjected to reaction at room temperature for 15 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 2 ml of 2-propanol and 8 ml of n-hexane, after which the resulting mixture was stirred. The crystals thus precipitated were collected by filtration to obtain 1.6 g (yield 80.2%) of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl 3-aminocrotonate.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)=[C:5](Cl)[N:4]=1.[CH2:20]([OH:22])[CH3:21]>>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)=[C:5]([O:22][CH2:20][CH3:21])[N:4]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: CCO
Agent: [Na]
Product: CCOc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A flask was charged with ethanol (33 ml) and sodium (0.172 g, 7.5 mmol). After all of the sodium had dissolved (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.40 g, 1.5 mmol) from Example 4 was added and the solution was brought to reflux for 0.5 hours. The solution was allowed to cool to room temperature before neutralization with 1.0 N HC1. The solution was then concentrated and the residue partitioned between chloroform and water. The organic layer was dried with MgSO4, filtered and concentrated. The residues were then placed on a silica gel column and eluted with 2% methanol in chloroform to yield a yellow glass (0.28 g, 67.8%).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])C(Cl)=O.[Cl:7][C:8]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].CN(C)C=O>O1CCCC1>[C:1]([Cl:6])([Cl:7])=[O:5].[Cl:7][C:8]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Agent: Cn1cc(-c2ccc(C(=O)O)c(Cl)c2)cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)Cl
Temperature: 35 °C

Procedure:
Oxalyl chloride (0.49 ml) was added to a solution of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid (0.41 g) from Example 114 and dimethylformamide (0.012 ml) in anhydrous tetrahydrofuran (20 ml). The reaction was heated at 35° C. for ten minutes. The resulting solution was evaporated in vacuo to dryness to yield the crude 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid carbonyl chloride. Following co-evaporation with anhydrous methylene chloride, the acid chloride was dissolved in dichloromethane (20 ml) followed by the addition of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (0.888 g) and diisopropylethylamine (1.06 ml). The resulting solution was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water followed by 1N hydrochloric acid. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The dichloromethane was filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography on silica pressure eluting with hexane/ethyl acetate (2/1) to afford 1.4 g of the title compound as a colorless solid m.p. 105-109° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])[CH3:17]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg) in THF (2 mL) at −78° C. was added 3.0 M methylmagnesium bromide in THF (0.144 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[3-(1-hydroxy-ethyl)-pyridin-4-yl]-benzonitrile as a white foam.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:26]>CO.C(O)C>[ClH:26].[ClH:26].[ClH:26].[N:19]1([CH2:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 82.6 %

Procedure:
A suspension of 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide (17.1 g; 47.0 mmoles) [prepared according to published U.K. patent application No. 2,067,987] in 450 mL of methanol was treated with 38 mL of concentrated HCl. The resultant solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave colorless crystals. These were suspended in 200 mL of absolute ethanol, filtered and dried under vacuum to give 16.6 g (82.6%) of the title compound, m.p. 205°-222° C. (dec.). Recrystallization from 50% methanol-ethyl acetate gave an analytical sample, m.p. 206°-216° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O[CH:27](N(C)C)[N:28]([CH3:30])[CH3:29])(C)(C)C>>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH2:17][CH2:16][C:15](=[CH:27][N:28]([CH3:30])[CH3:29])[C:14]2=[O:19])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C1CCCCC1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O

Procedure:
2-(3,5-Bis-trifluoromethyl-phenyl)-cyclohexanone (155, 0.5 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (184 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 366.1 [(M+H)+].
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[Cl-].[NH4+]>ClCCl>[CH3:28][S:29]([O:1][C@@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)(=[O:31])=[O:30]
Reactant: CCOC(=O)[C@@H]1C[C@@H]2C[C@H](O)CC[C@H]2CN1C(=O)OC
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1C[C@@H]2C[C@H](OS(C)(=O)=O)CC[C@H]2CN1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To an ice-cooled solution of ethyl (3S, 4aR, 6R, 8aR) 6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (760 mg, 2.66 mmol) in dry dichloromethane (10 mL) under nitrogen, triethylamine (0.60 mL, 4.3 mmol) and methanesulfonyl chloride (0.33 mL, 4.3 mmol) were added. The resulting mixture was stirred overnight at room temperature and a saturated solution of ammonium chloride was added (10 mL). The layers were separated and the aqueous layer extracted with dichloromethane (10 mL×2). The combined organic phases were washed with 1 N hydrochloric acid (10 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound as an oil (0.965 g, 100%).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([CH3:41])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29](OC3C=CC([N+]([O-])=O)=CC=3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:45][C:46]1([F:52])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([N:49]3[CH2:50][CH2:51][C:46]([F:52])([F:45])[CH2:47][CH2:48]3)=[O:30])[CH2:18]2)[CH3:41])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC1(F)CCNCC1
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCC(F)(F)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
By reaction and purification in the same manner as in the method described in Example 420 and using the compound obtained in Example 362 and 4,4-difluoropiperidine, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9](F)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][SH:35]>O>[Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9]([S:35][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[Cl:27])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: SCc1ccccc1Cl
Reactant: CCOc1nc(F)c2ncccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nc(SCc2ccccc2Cl)c2ncccc2c1Br
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a 5 mL microwave reactor vial was added 5-bromo-6-ethoxy-8-fluoro-1,7-naphthyridine (100 mg, 0.37 mmol), a large excess of K2CO3, followed by DMF (5 mL). (2-chlorophenyl)methanethiol (70 mg, 0.44 mmol) was then added to the mixture, the vessel was capped and heated under microwave irradiation for 20 min at 100° C. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The resultant residue was purified by silica gel to yield 5-bromo-8-(2-chlorobenzylthio)-6-ethoxy-1,7-naphthyridine as a pale yellow solid (100 mg, 0.24 mmol, 66%). 1H NMR (400 MHz, CDCl3): δ ppm 8.74 (d, J=2.64 Hz, 1H), 8.34 (d, J=7.47 Hz, 1H), 7.50-7.68 (m, 2H), 7.35-7.48 (m, 1H), 7.11-7.22 (m, 2H), 4.67 (s, 2H), 4.53 (q, J=7.03 Hz, 2H), 1.41 (t, J=7.03 Hz, 3H). LC/MS m/z 411 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][C:31]=1[F:38])=[O:29])C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][C:31]=1[F:38])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cc(C#N)ccc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cc(C#N)ccc1F
Yield: 71.6 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and 3-(5-cyano-2-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (Example H18) (362 mg, 1.5 mmol) according to the general procedure K. Obtained as a yellow-brown solid (352 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[N:3]=[CH:4][N:5]=1
Reactant: c1nc[nH]n1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(-n2cncn2)ncn1
Yield: 76.5 %

Procedure:
A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), 1H-1,2,4-triazole (1.381 g, 20.00 mmol), and cesium carbonate (13.03 g, 40.0 mmol) was stirred in DMF (25 mL) at room temperature for 16 h. The reaction was diluted with 100 mL water and extracted with EtOAc. The combined organic extracts were concentrated and purified by flash chromatography on a 160 g silica gel cartridge with 25 to 50% EtOAc in hexane to yield 4-chloro-6-(1H-1,2,4-triazol-1-yl)pyrimidine (2.78 g, 38% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.21 (1H, s), 8.87 (1H, s), 8.15 (1H, s), 7.91 (1H, s). LCMS: RT=0.68 min, MH+=182.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH2:12]>ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 97 %

Procedure:
To a 0° C. solution of the 4-chlorobenzoyl chloride (4.50 g) in dichloromethane (10 mL) was added an 8M solution of methylamine in ethanol dropwise. The solution was stirred for 16 h and then evaporated to dryness. The residue was diluted with saturated sodium bicarbonate solution (10 mL) and extracted three times with ethyl acetate (3×20 mL), the organics washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo to afford the sub-title compound as a white solid (4.33 g; 97%). 1H NMR (400 MHz, CDCl3) δ 3.00 (3H, s), 7.40 (1H, br) 7.40 (1H, d), 7.70 (1H, d) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][Cl:29].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH2:27][CH2:28][Cl:29])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCl)c2ccccc12
Yield: 58.3 %

Procedure:
N-tert-butyloxycarbonyl-4-amino-1-naphthol (2.0 g, 7.72 mmol), potassium carbonate (5.34 g, 38.6 mmol) and 1-bromo-2-chloroethane (1.28 ml, 15.4 mmol) are heated to 80° C. in anhydrous acetonitrile (40 ml) under a nitrogen atmosphere for 1 day. The mixture is poured into ethyl acetate (250 ml) and washed with water (500 ml). The aqueous layer is re-extracted with ethyl acetate (2×100 ml), the organic layers combined and dried over anhydrous sodium sulfate. The organic layers are evaporated to dryness and the residue purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexanes to give [4-(2-chloro-ethoxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester (1.448 g).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[CH3:10]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH3:10])=[O:4]
Reactant: CO
Reactant: C=CCC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)C(=O)OC

Procedure:
2,2-Dimethyl-4-pentenoic acid (15 g, 0.117 mol) was mixed with 70 mL anhydrous methanol and 50 mL toluene. Concentrated sulfuric acid (0.1 mL) was added. The solution was refluxed for 24 h. Solvents were then removed. The crude product was distilled under reduced pressure to gave 6 g pure product. 1H NMR (CDCl3): δ 1.28 (s, 6H, —CMe2-); 2.37 (d, 2H, CH2═CHCH2—); 3.77 (s, 3H, —CO2Me); 5.15 (m, 2H, CH2═CH—); 5.84 (m, 1H, CH2═CH—).