Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[Cl:13])[NH:6][CH:5]=1)#[N:2].N1[CH2:20][CH2:19][CH2:18][CH2:17]1>CO.[Ni]>[N:2]1([CH2:1][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[C:11]=3[Cl:13])[NH:6][CH:5]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: COc1ccc2[nH]cc(CC#N)c2c1Cl
Agent: [Ni]
Solvent: CO
Product: COc1ccc2[nH]cc(CCN3CCCC3)c2c1Cl

Procedure:
3-Cyanomethyl-4-chloro-5-methoxyindole (2.0 g, 9.1 mmol) was reductively aminated with pyrrolidine (32 ml) in methanol (100 ml) over Raney nickel for 21/2 hours at 30 p.s.i. pressure, at room temperature. After removal of the catalyst, the solvent was removed and the crude mixture purified by chromatography (SiO2 ; CHCl3 /MeOH) to give 3-(2-Pyrrolidinylethyl)-4-chloro-5-methoxyindole (1.26 g) as a solid. Part of this product (250 mg) was dissolved in methanol (10 ml) and treated with a solution of fumaric acid (150 mg) in methanol (5 ml), then ether to give the product as the hemifumarate salt (244 mg), m.p. 217°-8° C.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:12])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[N:14]#[C:15][NH2:16]>>[ClH:1].[CH2:6]([C:5]1[N:12]=[C:15]([NH2:16])[NH:14][CH:4]=1)[CH2:7][CH2:8][CH2:9][C:10]#[CH:11]
Reactant: N#CN
Reactant: C#CCCCCC(N)C(=O)OC
Agent: Cl
Product: C#CCCCCc1c[nH]c(N)n1
Yield: 87 %

Procedure:
2-Amino-oct-7-ynoic acid methyl ester hydrochloride (2.90 g, 14.1 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Hex-5-ynyl-1H-imidazol-2-ylamine hydrochloride (2.45 g, 87%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.43 (s, 1H), δ 2.44 (t, 2H), 2.14 (t, 1H), δ 2.12 (m, 2H), δ 1.64 (m, 2H), δ 1.47 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.3, 127.6, 108.5, 83.4, 68.7, 27.7, 27.1, 23.8, 17.5 ppm; HRMS (ESI) calcd for C9H14N3 (M+) 164.1182. Found 164.1182.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.[ClH:22].O1CCOCC1>O1CCOCC1>[ClH:22].[NH2:8][CH2:9][CH2:10][S:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NCCSc1noc2ccc(F)cc12
Agent: Cl
Solvent: C1COCCO1
Product: NCCSc1noc2ccc(F)cc12
Temperature: 5 °C

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethylthio)-5-fluoro-1,2-benzisoxazole (0.20 g) in dioxane (2 ml) was added 4 N-hydrochloric acid/dioxane solution (0.8 ml) with stirring at 5° C., and the mixture was then stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was recrystallized from ethanol and ethyl acetate, to give the title compound (0.14 g) as a colorless needle.
Reaction SMILES: C[O-].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7]([CH3:15])[N:6]=1.[CH2:16]([O:18]CC)C.O>CO>[CH3:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([O:18][CH3:16])=[N:6][C:7]=1[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Reactant: CCOCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C)c(C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 7 h
Yield: 82.6 %

Procedure:
To a solution of 28% sodium methoxide (1.11 mL) and methanol (5.5 mL) was added dropwise a solution of 2-chloro-5,6-dimethyl-3-nitropyridine (1-013-05) (837 mg) in methanol (6.6 mL) for 5 min at room temperature under nitrogen atmosphere, and the reaction mixture was heated with stirring in oil-bath at 50° C. for 7 h. To the reaction mixture was added diethyl ether and the reaction mixture was poured into water, extracted with twice with diethyl ether, washed once with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5,6-dimethyl-2-methoxy-3-nitropyridine (1-013-06) (675 mg, 82.6%, m.p.: 71-73° C.) as an orange crystal.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][C:10](=[O:27])[C:11]1[C:12](=[C:17]([NH:21]CCCCC)[CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14]>>[CH3:8][O:9][C:10](=[O:27])[C:11]1[C:12](=[C:17]([NH:21][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=Cc1cccs1
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Product: COC(=O)c1cccc(NCc2cccs2)c1C(=O)OC
Yield: 58 %

Procedure:
2-Thiophenecarboxaldehyde (1.12 g, 10 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by preparative HPLC (Symmetry C18, isocratic, 45% acetonitrile/water) to give 0.88 g (58%) of yellow oil: 1H NMR (CDCl3) δ 7.38-7.15 (m, 3H), 7.00-6.93 (m, 2H), 6.87-6.82 (m, 2H), 4.58 (d, J=5.3 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].[F:22][C:23]([F:47])([F:46])[C:24]([F:45])([F:44])[C:25]([F:43])([F:42])[O:26][C:27]([F:41])([C:32]([F:40])([F:39])[O:33][C:34]([F:38])=[C:35]([F:37])[F:36])[C:28]([F:31])([F:30])[F:29]>O1CCCC1>[F:37][C:35]([F:36])([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:34]([F:38])[O:33][C:32]([F:39])([F:40])[C:27]([F:41])([O:26][C:25]([F:42])([F:43])[C:24]([F:44])([F:45])[C:23]([F:22])([F:46])[F:47])[C:28]([F:31])([F:30])[F:29]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
In a dry box, tetrahydrofuran (THF, 1000 mL) and dimethyl 5-hydroxyisophthalate (42.00 g, 0.20 mol) were added to an oven dry round bottom reaction flask equipped with a stirrer and an addition funnel; then potassium t-butoxide (6.16 g, 0.055 mol) was added. 1,1,1,2,2,3,3-Heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2-trifluorovinyloxy)propan-2-yloxy)propane (216 g, 0.50 mol) was then added via the addition funnel forming a reaction. The reaction was allowed to stir at room temperature. After 24 hours the reaction was terminated via the addition of 80 mL of 10% HCl. The reaction was concentrated at reduced pressure, diluted with dichloromethane, washed with 10% HCl (2×100 mL) and then with water (2×100 mL) forming an organic phase and a crude product. The organic phase was dried over anhydrous sodium sulfate and concentrated at reduced pressure. The crude product was purified by column chromatography to give 86.07 g (67.32%) yield of dimethyl 5-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)isophthalate.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29]>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:33]2[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[CH:31][CH:32]=2)[C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(C#N)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 4-cyanophenylboronic acid. The title compound was obtained in 31% yield as yellow foam. MS (m/e): 473.2 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:24])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([O:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>[Pd](Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([CH3:24])[C:5]2[CH:11]=[C:10]([C:36]3[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][CH:37]=3)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([O:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@@H](OCCO)CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2cc3c(C)nc(N)nc3n([C@H]3CC[C@@H](OCCO)CC3)c2=O)cn1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-6-bromo-8-(cis-4-(2-hydroxyethoxy)cyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (50 mg, 0.13 mmol), potassium carbonate (52 mg, 0.38 mmol), and 2-methoxy-5-pyridine boronic acid (38 mg, 0.25 mmol) in 5:1 dimethylformade:water (1.3 mL) was bubbled with argon for 5 minutes. To the mixture was added bis(tripehnylphosphine) palladium (II) chloride (9 mg, 0.13 mmol) and the microwave vial was immediately sealed and the mixture was bubbled again with argon. After heating for 20 min at 100° C. in the microwave, the mixture was concentrated in vacuo. The residue was dissolved in CHCl3 (60 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0-5%) to afford the title compound (50 mg, 93%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[C:17]([S:28][CH3:29])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:30][CH2:31][CH2:32][OH:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]([O:33][CH2:32][CH2:31][NH2:30])[N:18]=[C:17]([S:28][CH3:29])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Reactant: NCCO
Product: CSc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccccc2)c(OCCN)n1

Procedure:
4.0 g 4-tert.-butyl-N-(6-chloro-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl) -benzenesulfonamide was reacted with 2-aminoethanol according to Example 4b) to give 1.65 g 4-tert.-butyl-N-[6-(2-aminoethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide. LC-MS: tR=3.75 min, [M−1]−=471.38.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.C(O)(C)C.C(=O)=O.[CH:16]1([N:22]=[C:23]=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1COCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:23]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:24])[CH2:4][CH2:3]1
Reactant: O=C=NC1CCCCC1
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N[C@H]1CC[C@H](NC(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-1,4-diaminocyclohexane (6.15 g, 0.054 mmol) was added in a flame dried Schlenk flask and dissolved in THF (500 mL) under argon atmosphere. The solution was cooled to −40° C. in a cooling bath (isopropyl alcohol/dry ice) and cyclohexyl isocyanate (6.75 g, 0.054 mmol), diluted in THF (100 mL), was added slowly under heavy stirring. The reaction mixture was stirred for 12 h at room temperature. The precipitated white solid was filtered off, suspended in water and acidified to pH 2 (HCl). The emerging clear solution was again filtrated and the filtrate was brought to pH 8 (NaOH) whereupon the trans-1-(4-aminocyclohexyl)-3-cyclohexylurea precipitated as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][S:16][C:10]=2[S:9][CH2:8][CH2:7]1.[Br:17]Br.O>C(O)(=O)C>[Br:17][C:15]1[S:16][C:10]2[S:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: O=C1c2ccsc2SCCN1CCCCCl
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(Br)sc2SCCN1CCCCCl
Temperature: 60 °C

Procedure:
To a solution of 3.0 g of 4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 60 ml of acetic acid was added 1.5 ml of bromine with stirring at 60° C. and the mixture was stirred for 20 minutes at the same temperature. The mixture was poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The resulting crystals were recrystallized from ethanol to give 2.0 g of 7-bromo-4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one as white crystals, melting at 81°-89° C.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].C1(C)C=CC=CC=1.[O:19]1[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20]1>O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:19][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][O:11][C:8]1[CH:9]=[CH:10][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCC(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 388.6 %

Procedure:
The sodium salt of 4-nitrophenol (28.19 g, 0.175 mol) was dissolved in water (50 mL) and toluene (300 mL) and tetrabutylammonium sulfate (6.0 g) was added. 1,2-Epoxydecane (27.3 g, 0.175 mol) was added to this mixture and the reaction was heated at 100° C. for 5 days. The toluene layer was separated and washed with water (4×75 mL), 1N hydrochloric acid (2×75 mL) and water (75 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed. The crude product was purified by silica gel chromatography (2–3% methanol/methylene chloride) to afford 4-(2-hydroxy-1-decyloxy)nitrobenzene as a pale oil (20 g, 0.68 mol, 39% yield).
Reaction SMILES: [ClH:1].[CH:2]([O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])[CH3:3].[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH:2]([O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:7]=1[C:8](=[NH:9])[O:18][CH2:16][CH3:17])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: COc1ccc(C#N)c(OC(C)C)c1
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OC(C)C
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-isopropoxy-4-methoxy-benzonitrile (11.5 g, 60.14 mmol) in anhydrous ethanol (250 mL) cooled to −10° C. After 45 min, hydrogen chloride gas was stopped and the reaction mixture was stirred at room temperature in a closed reaction vessel for 2 weeks. The reaction vessel was cooled to 0° C. before the stopper was removed. Argon gas was passed through the solution to remove excess hydrogen chloride gas. The solvent was evaporated and the residue was triturated in diethyl ether (100 mL) to afford ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride (16.3 g, 99%). It was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]=[C:13]=[O:14])=[C:4]([F:15])[CH:3]=1.[OH-].[Na+].[NH:18]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:19]1[C:20](O)=[O:21]>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([N:12]2[C:20](=[O:21])[CH:19]3[CH2:23][CH2:24][CH2:25][CH2:26][N:18]3[C:13]2=[O:14])=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: O=C(O)C1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: CC(C)Oc1cc(N2C(=O)C3CCCCN3C2=O)c(F)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 17.6 %

Procedure:
A solution of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate (2.3 g) in chlorobenzene (10 ml) was added to a 2% aqueous solution of sodium hydroxide (25 ml) containing pipecolic acid (1.3 g), and the mixture was stirred at room temperature (ca. 20° C.) for 3 hours. After allowed to stand overnight, the precipitated crystals were collected by filtration and washed with ether. The crystals were combined with water (20 ml) and adjusted to pH 2 or less with hydrochloric acid, followed by reflux for 3 hours. After allowed to cool, the mixture was extracted with ether, dried and concentrated. The residue was purified by silica gel chromatography to give 0.6 g of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1,3(2H,8aH)-dione (Compound No. 7). M.P. 60.5°-64.5° C.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1/[CH:23]=[CH:24]/[C:25]([NH:12][C:9]1[CH:10]=[CH:11][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:14])[CH3:13])[N:8]=1)=[O:26]
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1Cl
Product: CC(F)(F)CCCCn1ccc(NC(=O)/C=C/c2cccc(Cl)c2Cl)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(2,3-dichloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.17 min; [M+H]+=401.99.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:31]2[CH2:32][CH2:33][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:29][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(C(C)(C)C)n3)CC2)cc1

Procedure:
62 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (50 mg, 0.195 mmol), 1-(4-methoxyphenyl)piperazine (49 mg, 0.186 mmol), DIPEA (49 mL, 0.279 mmol) and NaBH(OAc)3 (118 mg, 0.558 mmol).
Reaction SMILES: [N:1]1([C:7]([O:9][CH:10](Cl)[CH3:11])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[C:15]([F:54])=[C:16]([C@@H:20]2[C@:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:23]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:22][C@H:21]2[C:40]([NH:42][C:43]2[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][C:44]=2[O:52][CH3:53])=[O:41])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:1]1([C:7]([O:9][CH:10]([O:49][C:47](=[O:48])[C:46]2[CH:50]=[CH:51][C:43]([NH:42][C:40]([C@H:21]3[C@H:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[C:15]=4[F:54])[C@:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[F:34])([C:25]#[N:26])[C@H:23]([CH2:35][C:36]([CH3:38])([CH3:39])[CH3:37])[NH:22]3)=[O:41])=[C:44]([O:52][CH3:53])[CH:45]=2)[CH3:11])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(Cl)OC(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(=O)N2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 74.2 %

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (2.64 g, 2 mL, 18.5 mmol) was reacted with morpholine (1.69 g, 1.7 mL, 19.4 mmol) and pyridine (1.68 g, 1.72 mL, 21.2 mmol) in methylene chloride (25 mL) at room temperature overnight to give the crude product, 1-chloroethyl morpholine-4-carboxylate. A portion of 1-chloroethyl morpholine-4-carboxylate (670.1 mg, 3.46 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.5 mg, 0.325 mmol) in the presence of cesium carbonate (1.094 g, 3.36 mmol) in dimethylformamide (7 mL) overnight to give, 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl morpholine-4-carboxylate as an off-white solid (186.5 mg, 74% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O7: [(M+H)+]: 773, found: 773
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([F:21])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: F[B-](F)(F)F
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Temperature: 75 °C
Reaction time: 60 h
Yield: 22.8 %

Procedure:
A solution of (S)-N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75° C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[N:19][C:20]([Cl:26])=[CH:21][CH:22]=2)[N:17]=1>O>[Cl:26][C:20]1[N:19]=[C:18]2[C:23]([CH:24]=[CH:25][C:16]([NH:15][C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[N:17]2)=[CH:22][CH:21]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Solvent: O
Product: CCCCOc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1
Yield: 35.2 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-butoxybenzoic acid (15.5 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product produced by precipitation in water (approximately 18 g; m.p. 140° C.) is purified by chromatography on a column 40 mm in diameter charged with silica (200 g; 0.063-0.2 mm), using methylene chloride as eluant and collecting 60-cc fractions. After concentration to dryness of fractions 8 to 12 at 40° C. under reduced pressure (4 kPa), N-(7-chloro-1,8-naphthyridin-2-yl)-4-butoxybenzamide (6.2 g) is produced, m.p. 197° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH2:15][O:16][S:18]([CH3:17])(=[O:20])=[O:19])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(Br)cc(COS(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
To a DCM (20 mL) solution of tert-butyl 3-bromo-5-(hydroxymethyl)benzoate (1.2 g, 4.2 mmol) was added methanesulfonyl chloride (0.62 g, 5.5 mmol) and triethylamine (1.2 mL, 8.4 mmol) at 0° C. The mixture was allowed to stir for 16 hours. TLC showed clean conversion. The reaction was diluted with DCM (100 mL), washed with 0.1 N HCl (100 mL) and brine, dried over sodium sulfate, and concentrated to afford tert-butyl 3-bromo-5-{[(methylsulfonyl)oxy]methyl}benzoate as a light yellow oil, which was used without further purification.