Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH2:15][CH2:16][CH3:17])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[CH2:18]([NH:21][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([CH2:15][CH2:16][CH3:17])[C:7]=2[N:8]=1)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: C=CCNc1nc(Cl)nc2c(CCC)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(CCC)c2n1
Yield: 56.6 %

Procedure:
189 mg (0.71 mmol) of 4-allylamino-2-chloro-7-propylthieno[3,2-d]pyrimidine and 644 mg (11.3 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 116 mg (yield: 56.9%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:33])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]>>[NH2:31][C:29]([C:28]1[CH:32]=[C:24]([NH:23][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH:25]=[CH:26][C:27]=1[CH3:33])=[O:30]
Reactant: Cc1ccc(N)cc1C(N)=O
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccc(C)c(C(N)=O)c4)cc3)c2)o1

Procedure:
N-(3-Aminocarbonyl-4-methylphenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 5-amino-2-methylbenzamide using method I. LCMS; retention time 3.00 min, MH+ 427.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1>CC#N.CCOC(C)=O>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:2][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 95 °C
Yield: 19.7 %

Procedure:
In a 200 mL round bottom flask, piperidin-4-ol (2.165 g, 21.41 mmol) and K2CO3 (2.96 g, 21.41 mmol) were suspended in MeCN (51.0 mL). Ethyl 4-fluorobenzoate (2.62 mL, 17.84 mmol) was added and the reaction mixture was stirred under reflux (95° C.) for 96 hr. The reaction was cooled to RT, diluted with EtOAc (100 mL) and washed with water (50 mL). Dried organic layer with MgSO4, filtered, and concentrated in vacuo. The product was purified by re-crystallization using EtOAc/hexanes, affording the title compound as a white solid (0.878 g, 19.74% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (t, J=7.07 Hz, 3H) 1.34-1.47 (m, 2H) 1.73-1.85 (m, 2H) 3.03 (ddd, J=13.14, 9.98, 3.16 Hz, 2H) 3.63-3.77 (m, 3H) 4.23 (q, J=7.07 Hz, 2H) 4.72 (d, J=4.04 Hz, 1H) 6.86-7.05 (m, 2H) 7.66-7.85 (m, 2H). ESI-MS: m/z 250.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH:5]([C:7]([O:9]C)=O)[C:4](=O)[CH2:3]1.S(O)(O)(=O)=O.[CH3:17][S:18][C:19](=[NH:21])[NH2:20].[OH-].[K+]>O>[CH3:1][CH:2]1[CH2:3][C:4]2[N:20]=[C:19]([S:18][CH3:17])[NH:21][C:7](=[O:9])[C:5]=2[CH2:6]1
Reactant: COC(=O)C1CC(C)CC1=O
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CSc1nc2c(c(=O)[nH]1)CC(C)C2
Temperature: 0 °C
Yield: 36 %

Procedure:
A solution of methyl 4-methyl-2-oxocyclopentanecarboxylate (0.42 g, 2.69 mmol), 2-methyl-2-thiopseudourea sulfate (1.10 g, 7.9 mmol) and potassium hydroxide (0.50 g, 8.9 mmol) in water (12 mL) was stirred at 25° C. for 30 minutes, and then heated to reflux for 4 hours. The reaction was cooled to 0° C. by adding ice and a precipitate was formed. The solid product was removed by filtration and the filter cake dried to give 6-methyl-2-(methylthio)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (0.19 g, 43% yield) as a white solid. 1H NMR (400 MHz, d6-DMSO): 2.87 (m, 2H), 2.53 (s, 3H), 2.37 (m, 2H), 2.28 (s, 3H), 1.49 (m, 1H), 1.02 (d, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[N:4][N:3]=1.C[Si](C)(C)[C:21]1[O:29][C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[S:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH:22]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC(O)CC>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([NH:37][C:34]3[CH:33]=[CH:32][C:31]([S:30][C:27]4[CH:26]=[CH:25][N:24]=[C:23]5[CH:22]=[CH:21][O:29][C:28]=45)=[CH:36][CH:35]=3)=[N:3][N:4]=2)=[N:13][CH:14]=1
Reactant: Clc1ccc(-c2nnc(Cl)c3ccccc23)nc1
Reactant: C[Si](C)(C)c1cc2nccc(Sc3ccc(N)cc3)c2o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCC(C)O
Product: Clc1ccc(-c2nnc(Nc3ccc(Sc4ccnc5ccoc45)cc3)c3ccccc23)nc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A resealable tube was charged with 1-chloro-4-(5-chloropyridin-2-yl)phthalazine (0.095 g, 0.34 mmol), 4-(2-(trimethylsilyl)furo[3,2-b]pyridin-7-ylthio)benzenamine (0.090 g, 0.29 mmol) and 2-butanol (3.0 mL). The system was flushed with argon, and the tube was sealed. The mixture stirred at 100° C. for 2 h. LC-MS showed starting aniline and hydrolyzed phthalazine, so 90 mg of chlorophthalazine was added and the reaction was stirred for 1 h at 100° C. The reaction was concentrated, re-dissolved in THF, and TBAF (1.0 M in THF) (0.29 ml, 0.29 mmol) was added. The reaction was stirred at 60° C. overnight. The reaction was concentrated and purified via Gilson HPLC (gradient elution 10-90% MeCN:H2O). The clean fractions were partitioned between DCM and saturated sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-2-yl)-N-(4-(furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine as a yellow solid. MS: M+H+=482.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:15]1[C:19](=[O:20])[CH2:18][CH:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]3([CH2:34][OH:35])[CH2:32][CH2:31][C:30](=[O:33])[NH:29]3)=[CH:23][CH:22]=2)[S:16]1(=[O:37])=[O:36])([CH3:14])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[C:11]([N:15]1[C:19](=[O:20])[CH2:18][CH:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]3([CH:34]=[O:35])[CH2:32][CH2:31][C:30](=[O:33])[NH:29]3)=[CH:23][CH:22]=2)[S:16]1(=[O:36])=[O:37])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CC3(CO)CCC(=O)N3)cc2)S1(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)CC(c2ccc(CC3(C=O)CCC(=O)N3)cc2)S1(=O)=O
Temperature: -78 °C
Yield: 28.7 %

Procedure:
Oxalyl chloride (74.3 μL, 0.878 mmol) was stirred in methylene chloride (2.6 mL), and the resulting solution was cooled to −78° C., whereupon dimethyl sulfoxide (142 μL, 2.00 mmol) was added. Then to the mixture, a solution of 2-tert-butyl-5-(4-[2-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methylphenyl)isothiazolidin-3-one 1,1-dioxide (105 mg, 0.266 mmol) in dichloromethane (2.0 mL) was added dropwise, within five minutes. The mixture was stirred for fifteen minutes at −78° C.; after addition of N,N-diisopropylethylamine (695 μL, 3.99 mmol) the mixture was allowed to reach room temperature, and poured into water (1 mL). The aqueous phase was extracted twice with dichloromethane (5 mL) and the combined extracts were evaporated to give the crude aldehyde as a yellow oil. Purification on the preparative LCMS gave the desired aldehyde as a tan solid (30 mg, 30%). 1H NMR (400 MHz, CDCl3): δ 9.60 (s, 1H), 7.38 (m, 2H), 7.25 (m, 2H), 6.70 (s, 1H), 4.76 (m, 1H), 3.17 (m, 1H), 2.92 (m, 1H), 2.30 (m, 2H), 2.18 (m, 2H), 1.65 (s, 9H); LCMS found for C19H25N2O5S (M+H)+: m/z=393
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Br[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28].[H-].[Na+]>>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
To a solution of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) (440 mg, 1.221 mmol) in 3-bromopentane (3196 μL, 25.6 mmol) under nitrogen at rt was added a dispersion of 60% sodium hydride in mineral oil (244 mg, 6.11 mmol). Evolution of gas was observed. The reaction was stirred at room temperature for 10 min and then heated to 120° C. under N2 for 19 h. The reaction mixture was cooled to room temperature and quenched with sat. NH4Cl. The layers were separated and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title compound (375 mg, 71% yield) as a mixture of diastereomers.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:12][S:13]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2)(=[O:15])=[O:14].[Cl:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH:36]1[CH2:38][CH2:37]1)O>ClCCl>[Cl:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH:36]1[CH2:38][CH2:37]1)[C:22]1[C:21]2[C:25](=[C:17]([CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[CH:18]=[CH:19][CH:20]=2)[NH:24][CH:23]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: Cc1ccc(C(O)C2CC2)c(Cl)c1
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cccc23)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
135 mg (0.61 mmol) of indium(III) chloride and 0.07 ml (0.92 mmol) of trifluoroacetic acid were added to 132 mg (0.61 mmol) of the compound from Example 86A and 100 mg (0.51 mmol) of the compound from Example 152A in 5 ml of dichloromethane, and the mixture was stirred at RT overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 29.0 mg (15% of theory) of the title compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].[Br-].[B:23](OC)([O:26]C)[O:24]C>O1CCCC1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[O:13][C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=1[B:23]([OH:26])[OH:24]
Reactant: Fc1ccc(Oc2ccc(C(F)(F)F)cc2Br)c(F)c1
Reactant: COB(OC)OC
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1cc(C(F)(F)F)ccc1Oc1ccc(F)cc1F
Temperature: 45 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a suspension of magnesium (0.083 g, 3.42 mmol) in tetrahydrofuran (1.00 mL) was added 0.5 mL of a solution of Example 275a (1.099 g, 3.11 mmol) in tetrahydrofuran (1.5 mL). The reaction mixture was warmed (about 40-50° C.) until reaction commenced. The remaining solution of starting bromide was added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour. The resulting solution was added dropwise to a solution of trimethyl borate (0.696 mL, 6.23 mmol) in tetrahydrofuran (1.5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 1 hour, quenched with ice water and then neutralized with 2 M HCl. The mixture was extracted with ethyl acetate. The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 10-33% ethyl acetate/hexanes gradient) to provide the title compound (650 mg, 66% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][N:5]2[C:10](Cl)=[C:9]([CH:12]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]([O:15][CH3:16])=[O:14])[C:8]([CH3:22])=[N:7][C:6]=12.[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([CH3:40])=[C:34]2[C:39]=1[O:38][CH2:37][CH2:36][CH2:35]2.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[Br:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][N:5]2[C:10]([C:32]3[C:33]([CH3:40])=[C:34]4[C:39](=[C:30]([F:29])[CH:31]=3)[O:38][CH2:37][CH2:36][CH2:35]4)=[C:9]([CH:12]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]([O:15][CH3:16])=[O:14])[C:8]([CH3:22])=[N:7][C:6]=12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(Br)c(-c3ccccc3)nn2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(Br)c(-c3ccccc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 110 °C
Yield: 9.4 %

Procedure:
To a 2-5 ml microwave tube was added methyl 2-(3-bromo-7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (290 mg, 0.621 mmol), tetrakis(triphenylphosphine)palladium(0) (71.8 mg, 0.062 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.683 mmol), DMF (2 mL) followed by 2M K2CO3 solution (200 μl). The reaction mixture was heated in a microwave reactor at 110° C. for 40 min. The reaction mixture was filtered and the filtrate was purified by silica gel chromatography to afford (35 mg, 9.4%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.90 (dd, J=8.1, 1.4 Hz, 2H), 7.53-7.32 (m, 3H), 6.86 (d, J=10.7 Hz, 1H), 5.02 (s, 1H), 4.48-4.18 (m, 2H), 3.64 (s, 3H), 2.82 (s, 3H), 2.75 (t, J=6.4 Hz, 2H), 2.20-2.12 (m, 2H), 1.84 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:24](=[O:26])[NH2:25])[CH:15]2C)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1>Cl>[O:23]=[C:22]1[C:21]2[C:20]([C:24]([NH2:25])=[O:26])=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][N:14]1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1c2cccc(C(N)=O)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cccc2c1C(=O)N(C1CCNCC1)C2
Yield: 107.5 %

Procedure:
A solution of tert-butyl-4-(4-carbamoyl-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-1-carboxylate (2.7 g, 7.5 mmol) in 4M hydrochloric acid in dioxane (18 mL, 75 mmol) was stirred at 50° C. for 2 hours until HPLC analysis revealed the disappearance of the starting material. The solvent was removed under reduce pressure and the product was dissolved in diethyl ether and filtered to obtain the title compound (2.09 g, 95%) as its hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:29])[C:10](=[O:28])[N:11]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:30].N1CC[O:38]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:29])[C:10](=[O:28])[N:11]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][O:38][CH2:25][CH2:24]3)[C:12]=2[C:16]([N:18]([CH3:19])[CH3:20])=[O:17])[C:7]1=[O:30]
Reactant: C1COCCN1
Reactant: CN(C)C(=O)c1c2c(c(O)c(=O)n1CCN1CCCC1)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1CCN1CCOCC1)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
The title compound was prepared in a manner similar to that described for 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-pyrrolidin-1-ylethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (Example 66), substituting pyrrolidine with morpholine. (ES MS M+1=507)
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:30].C1C([N+]([O-])=O)=CC=C([Cl-][C:41]([O-])=[O:42])C=1.[CH2:44]([NH2:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:41]([NH:49][CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:42])=[C:3]([F:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.7 %

Procedure:
3-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (175 mg, 0.424 mmol) and 4-nitrophenylchloroformate (85 mg, 0424 mmol) were stirred in dichloromethane (2 mL) for 30 minutes. Neopentylamine (110 mg, 1.272 mmol) was added and the reaction stirred at room temperature for 2 hours. The reaction was concentrated under vacuum. The resulting residue was purified by acidic reverse phase HPLC to afford the title compound (26 mg).
Reaction SMILES: C([O:9][C:10]1[N:14]([C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[C:12]([CH:25]([CH3:27])[CH3:26])[C:11]=1Br)(=O)C1C=CC=CC=1.[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[OH:9][C:10]1[N:14]([C:15]([CH3:23])([CH3:24])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:13]=[C:12]([CH:25]([CH3:26])[CH3:27])[C:11]=1[C:36]1[CH:37]=[CH:38][C:33]([C:31]([O:30][CH3:29])=[O:32])=[CH:34][CH:35]=1
Reactant: CC(C)c1nn(C(C)(C)Cc2ccccc2)c(OC(=O)c2ccccc2)c1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2c(C(C)C)nn(C(C)(C)Cc3ccccc3)c2O)cc1
Temperature: 86 °C
Reaction time: 16 h
Yield: 31.1 %

Procedure:
4-Bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5-yl benzoate (360 mg, 0.82 mmol) in 1,2-dimethoxyethane (4.8 ml) was mixed with 4-(methoxycarbonyl)phenylboronic acid (164 mg, 0.911 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol) and 2 M aqueous sodium carbonate (3.6 ml) and stirred at 86° C. for 16 hours under a nitrogen atmosphere. After completion of the reaction, the 1,2-dimethoxyethane was distilled off under reduced pressure, and the reaction solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was purified by intermediate pressure silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:20 to 1:4) to give 100 mg of the desired product as a pale yellow solid mixture of tautomers.
Reaction SMILES: CO.[NH2-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]([S:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:14]([O:16]C)=O)[CH:9]=[CH:10][C:11]=1[Cl:12].[Cl-].[NH4+]>O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]2[C:14]([OH:16])=[C:20]([C:21]([CH3:22])=[O:23])[CH2:19][S:18]2)[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: COC(=O)C(SCCC(C)=O)c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [NH2-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(=O)C1=C(O)C(c2ccc(Cl)c(Cl)c2)SC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A methanol (500 mL) solution of sodium amide (19.2 g, purity: 90%, 1.5 equivalent amounts based on the starting material) was heated to 40° C., and to this solution, a methanol (200 mL) solution of methyl 2-(3,4-dichlorophenyl)-2-(3-oxobutylthio)acetate (100 g, purity: 95%, 296 mmol) was dropwise added over a period of 12 minutes, followed by stirring at 40° C. for 1 hour. The reaction solution was cooled to 5° C., water (300 mL) was dropwise added over a period of 10 minutes, and then the solvent was distilled off. To the obtained crude product, chloroform and a saturated ammonium chloride aqueous solution were added, followed by liquid separation, and the organic layer was washed with a saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as an oil (59.3 g, yield: 65%).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:4]([C:24]#[N:25])[CH:3]=1.[CH3:26]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:8][C:7]1[C:2]([CH3:26])=[CH:3][C:4]([C:24]#[N:25])=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1Nc1cc(Cl)c(Br)cc1C#N
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C#N)c(N[C@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)cc1Cl
Temperature: 110 °C
Reaction time: 24 h

Procedure:
tert-Butyl {(1S,2S)-2-[(4-bromo-5-chloro-2-cyanophenyl)amino]cyclohexyl}carbamate, trimethyl boroxine and potassium carbonate were suspended in a mixed solvent of 1,4-dioxane (16 ml) and water (4 ml), tetrakis(triphenylphosphine)palladium was added thereto, followed by stirring at 110° C. for 1 day. By post-treating the reaction liquid, tert-butyl {(1S,2S)-2-[(5-chloro-2-cyano-4-methylphenyl)amino]cyclohexyl}carbamate was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1([F:15])[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1.[NH:16]([CH3:18])[CH3:17]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:7][C:8]1([F:15])[CH2:11][CH:10]([C:12]([N:16]([CH3:18])[CH3:17])=[O:13])[CH2:9]1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Oxalyl chloride (21.74 mL, 248 mmol) was added dropwise to a stirred solution of 3,3-difluorocyclobutanecarboxylic acid (26 g, 191 mmol; prepared as described in ref: Elend, D. et al., Syn. Comm., 35:657 (2005)) in CH2Cl2 (500 mL) and DMF (0.5 mL) at 0° C. The reaction mixture was allowed to come to RT and stirred at RT for 1 h prior to being concentrated at RT using a rotary evaporator at ca. 50 mm Hg vacuum. After adding THF (300 mL) to the resulting residue, the stirred solution was cooled 0° C. prior to addition of a 2M solution of Me2NH (478 mL, 955 mmol) in THF. After stirring the reaction mixture at RT for 0.5 h, the mixture was partitioned between ether and 5% aq. Na2CO3. The organic layer was dried over MgSO4 and concentrated in vacuo at RT. After portioning the residue between CH2Cl2 and water, the organic layer was dried over MgSO4 and concentrated in vacuo at RT to give 3,3-difluoro-N,N-dimethylcyclobutanecarboxamide (24 g, 147 mmol, 77% yield) as a brown semi solid, used as such in the next step. 1H NMR (400 MHz, CDCl3) δ ppm 2.82-3.13 (9H, m), 2.62-2.79 (2H, m).