Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:11]([NH:13][C@@H:14]1[C@@H:21]2[C@@H:17]([CH2:18][NH:19][CH2:20]2)[CH2:16][CH2:15]1)=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C(O)(CC)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:19]1[CH2:20][C@@H:21]2[C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:15][CH2:16][C@@H:17]2[CH2:18]1
Reactant: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)N(C)C(=O)OC(C)(C)C
Reactant: Fc1ccccc1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(c3ccccc3F)C[C@@H]21)N(C)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a microwave vial under nitrogen was added tert-butyl methyl((S)-4-methyl-1-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylamino)-1-oxopentan-2-yl)carbamate from Step 1 (118 mg, 0.334 mmol), 1-bromo-2-fluorobenzene (0.038 mL, 0.350 mmol), potassium phosphate, tribasic (116 mg, 0.668 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.11 mg, 6.68 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS, 12.73 mg, 0.027 mmol) in t-amyl alcohol (1.0 mL). The reaction was heated at 80° C. for 18 hours. The solvent was removed and the solids were washed with 2×2 mL of ethyl acetate. The solvent was removed under a stream of nitrogen. The crude material was applied to a 12 g silica gel cartridge with ether and purified using 1-50% ethyl acetate/hexanes to give tert-butyl(S)-1-((3aR,4S,6aS)-2-(2-fluorophenyl)octahydrocyclopenta[c]pyrrol-4-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.47-8.39 (m, 1H), 7.12 (ddd, J=13.9, 8.0, 1.4, 1H), 7.06 (td, J=7.8, 1.4, 1H), 6.86-6.77 (m, 2H), 5.17 (ddd, J=10.0, 7.5, 1.0, 1H), 4.46-4.35 (m, 1H), 3.65 (d, J=9.4, 1H), 3.30-3.21 (m, 1H), 3.17 (d, J=9.1, 1H), 3.13-3.03 (m, 4H), 2.69-2.57 (m, 2H), 2.11-1.98 (m, 1H), 1.94-1.82 (m, 3H), 1.66-1.55 (m, 2H), 1.48 (s, 9H), 1.39 (dddd, J=21.2, 19.9, 9.7, 4.0, 1H), 0.91 (d, J=6.5, 3H), 0.87 (d, J=6.6, 3H); MS (ESI+) m/z 448 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](Cl)[CH:3]=1.[OH-:12].[K+].C(P(C(C)(C)C)C1(C(C)C)CC(C(C)C)=CC(C(C)C)=C1C1C=CC=CC=1)(C)(C)C.Cl>O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C(C)(C)C)C(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cc(O)cc(Cl)c1
Yield: 67.8 %

Procedure:
To a mixture of 1,3-dichloro-5-nitrobenzene (5.00 g, 26.0 mmol), potassium hydroxide (3.44 g, 52.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (539 mg, 0.52 mmol), and 2-(di-tert-butylphosphino)-2,4,6-triisopropylbiphenyl (885 mg, 2.08 mmol) was added a degassed mixture of dioxane (25 mL) and water (15 mL). The mixture was heated for 30 min to 80° C., then diluted with water/ethyl acetate and acidified with diluted hydrochloric acid. The mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1). The product was then triturated with petroleum ether/tert-butyl methyl ether and collected by suction filtration to yield 3.06 g (66%) of the title compound as yellowish crystals.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=O)[CH2:4][CH3:5])[CH3:2].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=[N:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH2:22])[CH3:2]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: Nc1ccccc1N
Solvent: CCO
Product: CCN(CC)c1ccc(C=Nc2ccccc2N)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.479 g (17.64 mmol) 4-(N,N-Diethylamino)-salicylaldehyde are added at 5° C. in portions to a solution of 1.927 g (17.64 mmol) 1,2-phenylenediamine in 18 ml ethanol, the temperature being kept below 10° C. The resultant dark red suspension is stirred for 8 hours at room temperature and concentrated to dryness in vacuo. The crude product (6.34 g) is resolved by column chromatography (n-hexane/ethyl acetate 65:35). Yield: 1.27 g (26%), golden yellow crystalls.
Reaction SMILES: [CH3:1][C:2]1([C:5]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:49]([O:53][C:54](=[O:69])[NH:55][CH:56]1[CH:60]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=2)[CH2:59][NH:58][CH2:57]1)([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C.C(OCC)(=O)C>[C:49]([O:53][C:54](=[O:69])[NH:55][CH:56]1[CH:60]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=2)[CH2:59][N:58]([C:13]([CH:10]2[CH2:9][CH2:8][N:7]([C:5]([C:2]3([CH3:1])[CH2:3][CH2:4]3)=[O:6])[CH2:12][CH2:11]2)=[O:15])[CH2:57]1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)NC1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 19 h
Yield: 85.7 %

Procedure:
To a solution of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (4.48 g, 0.02 mol) in DMF (40 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (9.54 g, 0.03 mol). After stirring for 10 min at ambient temperature N,N-diisopropyl ethyl amine (19.82 ml, 0.116 mol) and a solution of rac-(3S,4R)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.39 g, 67% purity, 0.013 mol) in DMF (45 ml) were added and the reaction mixture was stirred for 19 h at this temperature. It was diluted with ethyl acetate (80 mL) and the organic layer was washed with water (80 mL), aqueous sodium carbonate (1M, 40 mL) and brine (40 mL). The aqueous layers were extracted with ethyl acetate (160 mL). the combined organic layers were dried over sodium sulfate and concentrated. Purification by flash chromatography (SiO2, EtOAc/methanol 100:0 to 80:20) afforded 5.84 g (87%) of the title compound as a light brown foam. ES-MS m/e: 524.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14](C)=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nc(C)c(C)s2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1csc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)n1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(4,5-dimethylthiazol-2-yl)-2-naphthalenyl]ethynylbenzoate (Compound 17) (58.0 mg, 0.13 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1M, 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried (Na2O4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.94 (2H, d, J=8.4 Hz), 7.86 (1H, d, J=1.6 Hz), 7.61 (2H, d, J=8.3 Hz), 7.50 (1H, dd, J=1.6, 8.0 Hz), 7.45 (1H, d, J=8.0 Hz), 6.51 (1H, t, J=4.9 Hz), 2.37 (3H, s), 2.36 (2H, d, J=4.6 Hz), 2.32 (3H, s), 1.26 (6H, s).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([N:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[CH2:30][O:31][CH3:32])=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2.C(N(CC)C(C)C)(C)C.C(O)(C(F)(F)F)=O>C(O)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([N:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[CH2:30][O:31][CH3:32])=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: COC[C@H]1CCCN1c1c(C(C)N)cc(Cl)c2cccnc12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H]1CCCN1c1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c2cccnc12

Procedure:
A mixture of 6-bromo-9H-purine (0.0174 g, 0.0876 mmol), 1-{5-chloro-8-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinolin-7-yl]ethanamine (0.014 g, 0.044 mmol), and N,N-diisopropylethylamine (0.01525 mL, 0.0876 mmol) in ethanol (0.1 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the product as a mixture of diastereoisomers (bis-TFA salts). LCMS calculated for C22H25ClN7O(M+H)+: m/z=438.2; found: 438.2.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]=O)=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2:14]/[C:15](/[C:20]#[N:21])=[C:16](\[NH2:19])/[C:17]#[N:18].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:20]([C:15]1[C:16]([C:17]#[N:18])=[N:19][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:12][N:14]=1)#[N:21]
Reactant: CCCc1ccc(C(=O)C=O)cc1
Reactant: N#C/C(N)=C(/N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCc1ccc(-c2cnc(C#N)c(C#N)n2)cc1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
This 4-propylphenylglyoxal (8.0 g, 0.05 mol) and diaminomaleonitrile (5.4 g, 0.05 mol) were dissolved in benzene (50 ml), followed by adding p-toluenesulfonic acid (0.05 g) to the solution, reacting them on heating under reflux for 3 hours, while distilling off water formed, allowing the reaction liquid to cool down to room temperature after completion of the reaction, adding water (50 ml), separating the resulting two layers, twice washing the benzene solution with 5% sodium bicarbonate solution (50 ml), further washing it with water, drying it with anhydrous sodium sulfate, distilling off benzene from the solution, and recrystallizing a remaining solid material from ethanol (10 ml) to obtain the objective product (8.9 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:34]3[CH2:35][CH2:40][CH2:39][CH2:38]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Product: O=C(c1ccc2[nH]c(C(=O)N3CCCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethyl-formamide to give the desired product.
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[N:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=CC=1C.CI>C1COCC1>[CH2:11]([C:10]1[CH:9]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]=1)[CH3:12]
Reactant: Cc1ccc2ccccc2n1
Reactant: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCc1ccc2ccccc2n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 0.40 M solution of diisopropyl amine in THF at −10° C. was added slowly 1.0 equiv of a solution of n-BuLi (2.5 M/hexane). After 10 min, the mixture was cooled to −78° C. and 0.9 equiv of quinaldine was added dropwise. The red/orange solution was then stirred at 0° C. for 1 h. MeI was then added and the reaction was stirred at room temperature for 2 h. The reaction was quenched with aqueous NH4Cl solution, and then extracted with EtOAc. The organic phase was washed with H2O and brine. The solution was then dried (MgSO4), filtered, and evaporated. The crude material was purified by flash chromatography with 1:10 EtOAc:hexanes to give the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([CH:19]=[CH2:20])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]>O1CCOCC1.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH3:20])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C=Cc1cnc(-n2ncc(C(=O)OCC)c2C)c(Cl)c1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2ncc(CC)cc2Cl)c1C
Temperature: 25 °C
Yield: 80.4 %

Procedure:
10% Palladium-carbon (containing ca. 50% water; 281 mg) was added to a solution of 1-(3-chloro-5-vinylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (567 mg) in 1,4-dioxane (19 ml), and stirred under hydrogen atmosphere at room temperature for an hour. The reaction solution was filtered through Celite and the filtrate was concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(3-chloro-5-ethylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (459 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([NH:8][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A mixture of 5-chloro-2-methyl-4-nitrophenylamine (0.560 g, 3.00 mmol) and benzoyl chloride (0.422 g, 3.00 mmol) in toluene (15 mL) was heated under reflux for 1.5 h, and cooled to room temperature. A solid crystallized from the reaction mixture upon cooling, and was isolated by vacuum filtration and dried to provide the title compound as a gray solid (0.276 g, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][C:11](=O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]([NH:22][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:13]=2[CH2:12]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2c1CC(=O)CCC2
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC(NCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (500 mg) and benzylamine (0.29 ml) in the presence of catalytic amounts of p-toluenesulfonic acid monohydrate in toluene (5 ml) was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the solution of the residue in methanol (5 ml) was added sodium borohydride (99 mg) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. After the resulting mixture was evaporated in vacuo, the residue was dissolved into ice-cold water and ethyl acetate. After separation, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 1:1) to give N-benzyl-(4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (660 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:19].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:21][O:20][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:19]
Reactant: COC(CN1C(=O)CCc2ncc(C(F)(F)F)cc21)OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(Cn1c(=O)ccc2ncc(C(F)(F)F)cc21)OC
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of 0.11 g of 1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one in 2 mL of dioxane, 0.16 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone was added, and the mixture was heated under reflux while stirring for 3 hours. Thereto were added water and ethyl acetate, the mixture was adjusted to pH 12 with a 2.0 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with an aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 90 mg of 1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one as a brown solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](B3OC(C)(C)C(C)(C)O3)=[C:6]([O:19][CH3:20])[CH:5]=2)[CH2:3][CH2:2]1.Cl[C:22]1[N:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][N:26]([S:32]([NH:35][C:36]1[S:40][N:39]=[CH:38][N:37]=1)(=[O:34])=[O:33])[CH2:27]2>>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C:22]3[N:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH2:24][CH2:25][N:26]([S:32]([NH:35][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:34])=[O:33])[CH2:27]4)=[C:6]([O:19][CH3:20])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(C2CC2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(ccnc2Cl)C1
Product: COc1cc(C2CC2)ccc1-c1nccc2c1CCN(S(=O)(=O)Nc1ncns1)C2

Procedure:
The title compound was prepared in a manner analogous to Example 1, except that 2-(4-cyclopropyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate W) was used in place of (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid and 5-chloro-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2,6-naphthyridine-2(1H)-sulfonamide (Intermediate V) was used in place of 5-bromo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide. [M+H]+=444.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.35 (d, J=5.0 Hz, 1H), 8.12-8.17 (m, 1H), 7.10 (d, J=5.1 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.74 (d, J=7.7 Hz, 1H), 4.28-4.43 (m, 2H), 3.76 (s, 3H), 3.43-3.56 (m, 1H), 2.79-3.22 (br. m, 2H), 2.38-2.52 (br. m, 1H), 1.94-2.02 (m, 1H), 0.93-1.03 (m, 2H), 0.71-0.81 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][CH:9]([F:13])[C:10](O)=[O:11].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C>[F:8][CH:9]([F:13])[C:10]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:11]
Reactant: Nc1ccccn1
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)F
Temperature: 25 °C
Reaction time: 61 h
Yield: 14 %

Procedure:
2-aminopyridine in an amount of 400 mg (4.26 mmol) was dissolved in 10 mL of anhydrous dichloromethane, following which 322 μL (490 mg, 5.11 mmol) of difluoroacetic acid, 982 mg (5.10 mmol) of EDC-HCl and 622 mg (5.11 mmol) of DMAP were added, and the mixture was stirred at room temperature for 61 hours. Following solution completion, the reaction mixture was diluted with dichloromethane, washed once with water and twice with 1% aqueous HCl, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, giving 102 mg of 2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide (yield, 14%).
Reaction SMILES: [BH4-].[Na+].C1COCC1.C(O)(C(F)(F)F)=O.[BH4-].[Na+].C(O)(C(F)(F)F)=O.[C:24]1([C@@H:30]([NH:32][C:33]2[CH2:34][N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36][CH2:37][C:38]=2[C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[C:24]1([C@@H:30]([NH:32][C@@H:33]2[CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:34]2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C[C@@H]1N[C@@H](C)c1ccccc1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a 100 L reactor charged with NaBH4 (1.16 kg, 30.5 mol, 2.0 equiv) and anhydrous THF (60 L) under nitrogen was added TFA (10.5 kg, 92 mol, 6.0 equiv) slowly over 30 min while maintaining temperature at 0˜5° C. The mixture was then cooled to −45° C. In a separation reactor, crude product 3-3 was dissolved in anhydrous acetonitrile (30 L), which was added slowly to the above solution of NaBH4/TFA while maintaining the internal temperature between −45˜−30° C. The mixture was stirred at −45° C. for 1 h, after which time, HPLC indicated complete consumption of compound 3-3. The mixture was slowly diluted with ice water (50 kg) and the mixture was then warmed to 10° C. The product was extracted with EtOAc (2×40 L) and the combined organic layers were washed with saturated NaHCO3 solution (20 L). pH of the aqueous was ˜8. The organic layers were dried (Na2SO4) and concentrated in vacuo to nearly dryness to afford a residue which was further azeotroped with MeOH (10 L×3) to remove excess EtOAc. In the end, a 10 L solution of crude 3-4 in MeOH was obtained, which was used directly in the subsequent step without further purification. ESI-MS (M+H-1)+: 377.2. 1H NMR (400 MHz, CD3OD) δ: 7.31-7.22 (m, 5H), 4.20 (q, 2H), 4.11-3.86 (m, 3H), 3.15 (s, 1H), 3.00-2.90 (m, 2H), 2.64 (d, 2H), 1.87-1.85 (m, 1H), 1.68 (s, 1H), 1.50-1.25 (m, 15H).