Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([NH2:18])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:18][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Sc2ccc(O)cc2)c(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(CO)ccc1Sc1ccc(O)cc1
Temperature: 70 °C
Yield: 65.5 %

Procedure:
To the product from Example 65B (500 mg, 1.82 mmol) in tetrahydrofuran (50 mL) was added a solution of lithium aluminum hydride (1.0M in THF, 1.8 mL, 1.82 mmol) dropwise at room temperature followed by heating the mixture to 70° C. for 4 hours. Water (25 mL) was then carefully added to the solution and the organic layer separated, dried and concentrated under vacuum to provide the title compound (295 mg, 66%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.[C:15]1([C:21]2[CH:22]=[C:23]3[C:29]([NH2:30])=[N:28][NH:27][C:24]3=[N:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Br-:7].[C:15]1([C:21]2[CH:22]=[C:23]3[C:29]([NH:30][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N+:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:14])=[N:28][NH:27][C:24]3=[N:25][CH:26]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1n[nH]c2ncc(-c3ccccc3)cc12
Reactant: c1ccncc1
Reactant: O=C(O)CCCCBr
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CCCC[n+]1ccccc1)Nc1n[nH]c2ncc(-c3ccccc3)cc12
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Oxalyl chloride (0.1 mL, 1.2 mmol) was added to a solution of 5-bromovaleric acid (86 mg, 0.48 mmol) in dichloromethane (10 mL). N,N-Dimethylformamide (1 drop) was added and the mixture was stirred at ambient temperature for 16 hours. The solvent was removed under vacuum, the residue was azeotroped with toluene (3×30 mL) and evaporated to dryness. To this crude acid chloride was added 5-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine (Description 2; 100 mg, 0.48 mmol), pyridine (20 mL). and 4-dimethylaminopyridine (cat). The solution was refluxed at 120° C. for 16 hours then evaporated. The residual material was purified by preparative HPLC on a C18 column, using a gradient elution with 10–90% v/v of acetonitrile (containing 0.01% v/v trifluoroacetic acid) and water (containing 0.1% v/v trifluoroacetic acid) to afford the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C@H:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:7])(=[O:4])=[O:3].[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH3:17][C:18]1[C:19]([N:25]2[CH2:26][CH2:27][N:28]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([C@@H:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH3:7])=[CH:16][CH:15]=3)=[O:14])[CH2:29][CH2:30]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: C[C@H](NS(C)(=O)=O)c1ccc(C(=O)O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc([C@H](C)NS(C)(=O)=O)cc3)CC2)c(C)c1
Yield: 104.4 %

Procedure:
Using (S)-4-(1-methanesulfonylaminoethyl)benzoic acid (146 mg) described in Preparation Example 73 and 1-(3,5-dimethylpyridin-2-yl)piperazine (126 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (261 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([C:19]#[N:20])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Br[CH2:22][CH2:23][CH2:24]Br.C(N(CC)CC)C>C(#N)C>[N:1]1([CH:2]2[CH:11]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10]3[CH:9]=[C:8]([C:19]#[N:20])[CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3]2)[CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Reactant: BrCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc2c(c1)C(Cc1ccccc1)C(N1CCC1)CC2
Temperature: 120 °C

Procedure:
7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (790 mg, 3.03 mmol), 1,3-dibromopropane (0.4 mL, 3.93 mmol) and triethylamine (0.914 mL, 6.56 mmol) were dissolved in acetonitrile (8 mL) and the reaction mixture heated to 120° C. in the microwave for 2 h. The solvent was evaporated in vacuo. Water (30 mL) and ethyl acetate (40 mL) were added. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 346 mg (1.14 mmol, 37.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:23]([CH3:22])[CH2:24][CH2:25][OH:26])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(CCl)N1CCCc2cc(Br)ccc21
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(CCO)CCN1CCCc2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (compound 1, 0.475 g, 1.298 mmol) in acetonitrile (19 mL) and water (1 mL) in a 50 mL pressure vessel fitted with a stir-bar was treated with potassium carbonate (1.793 g, 12.98 mmol) and 2-(methylamino)ethanol (0.975 g, 12.98 mmol) and the sealed vessel stirred at 80° C. overnight. After 18 hours the mixture was partitioned between CH2Cl2 (100 mL) and water (20 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer (pH=12); extracted further with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to a brown residue. Purification on silica gel eluting with 5% 2M NH3 in methanol/95% dichloromethane yielded a pale yellow oil, 2 (341 mg, 84%). 1H-NMR (DMSO-d6) δ 7.06 (dd, 1H, J=8.8, 2.5 Hz), 6.99 (d, 1H, J=2.4 Hz), 6.48 (d, 1H, J=8.8), 4.34 (t, 1H, J=5.3 Hz), 3.44 (q, 2H, J=6.2 Hz), 3.32-3.25 (m, 4H), 2.64 (t, 2H, J=6.2 Hz), 2.47-2.41 (m, 4H), 2.23 (s, 3H), 1.83-1.76 (m, 2H). MS (ESI+): 313/315 (MH+, 100).
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[NH2:19].Cl.Cl.[NH2:26][OH:27]>O>[CH3:15][C:16]1[CH:17]=[C:18]([NH:19][C:3](=[O:5])[CH:2]=[N:26][OH:27])[CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)cc(NC(=O)C=NO)c1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of chloral hydrate (14.1 g, 85.24 mM) and sodium sulfate (88.2g, 7.53 eq.) in 270 mL of water was added a solution of 3,5-dimethylaniline in a solution of concentrated HCl (16 mL) and water (51 mL), whereupon an off-white precipitate formed. The mixture was stirred for 10 min prior to adding an aqueous solution of hydroxylamine hydrochloride (17.4 g, 250 mM) in water (50 mL) and then heated at reflux for 10 min during which time the solids dissolved and a tan precipitate formed. The mixture was cooled and filtered, and the collected solids were air dried to yield the title compound (15.0 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]([OH:13])=[O:12].[H-].[Na+].[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][CH2:17]1>CN(C)C=O>[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:7]([C:11]([OH:13])=[O:12])=[CH:8]2)[CH2:18][CH2:17]1
Reactant: O=C(O)c1c[nH]c2c(Cl)cccc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 134.2 %

Procedure:
To a solution of 7-chloro-1H-indole-3-carboxylic acid (7.5 g, 38.0 mmol) in dimethylformamide (100 ml) at 10° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 3.1 g, 76.0 mmol) portionwise over 10 mins, maintaining the temperature below 15° C. The cooling bath was removed and the suspension stirred for 90 mins. Toluene-4-sulfonic acid tetrahydropyran-4-ylmethylester (14.6 g, 53.0 mmol) was added. The mixture was heated at 50° C. with stirring for 6 h. Dimethylformamide was removed by evaporation and the residue was dissolved in water (500 ml). The emulsion was washed with dichloromethane (2×100 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 1-(tetrahydropyran-4-yl)methyl-7-chloro-1H-indole-3-carboxylic acid (15.0 g, 51.0 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([O:11][CH2:12]COC)[C:8](OCCOC)=[CH:7][C:6]=1[NH2:21])C.N1C=CC=CC=1.[Cl:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35]>C(Cl)Cl>[CH3:1][O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:21][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([CH2:30][Cl:29])[CH:32]=1
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Reactant: O=C(O)c1cccc(CCl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(OC)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
2-Amino-5-methoxy-benzoic acid methyl ester (compound A) (2.2 g) produced by the above process was dissolved in anhydrous methylene chloride (40 ml), pyridine (1.5 ml) and 3-(chloromethyl)benzoyl chloride (compound B) (2.1 ml) was added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 15 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to precipitate crystals. The crude crystals were collected by Kiriyama Rohto and was washed with ether to give 2-(3-chloromethyl-benzoylamino)-5-methoxybenzoic acid methyl ester (3.0 g, yield 75%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9](O)=[O:10])(=[NH:3])[NH2:2].S(Cl)([Cl:17])=O>>[ClH:17].[C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([Cl:17])=[O:10])(=[NH:3])[NH2:2]
Reactant: N=C(N)c1cccc(OCC(=O)O)c1
Reactant: O=S(Cl)Cl
Product: Cl
Product: N=C(N)c1cccc(OCC(=O)Cl)c1

Procedure:
19.4 g of 3-amidinophenoxyacetic acid were heated under reflux, while well stirring, for 2 hours with 70 ml of thionyl chloride. After cooling, filtration with suction and washing with anhydrous diethyl ether, 21 g of 3-amidinophenoxyacetic acid chloride hydrochloride were obtained; decomposition point 149° to 151° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[NH2:8][C:9]1[CH:13]=[CH:12][NH:11][N:10]=1.[F:14][C:15]([F:25])([F:24])[C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([C:15]([F:14])([F:24])[F:25])[NH:8][C:9]3=[N:10][NH:11][CH:12]=[C:13]23)=[CH:2]1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=Cc1ccsc1
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1ccsc1

Procedure:
The title compound was prepared from thiophene-3-aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:9]([N:8]([C@@H:16]([C@@H:17]([OH:18])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCBr
Reactant: C[C@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCC[C@H](O)[C@@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 26 (445 mg, 1.76 mmol) and 1-bromopentadecane (1.28 g, 4.39 mmol), alcohol 80 was obtained as a colorless oil (422 mg, 52% yield).
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O=P(Cl)(Cl)[Cl:23]>>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[N:12][C:13]2[C:14]([C:4]=1[Cl:23])=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=2)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
A 20 mL microwave vial was charged with 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester (1.711 g, 5.0 mmol) and POCl3 (phosphoryl chloride, 10.0 mL, 16.8 g, 109 mmol). The vial was capped and the mixture was microwave heated stepwise up to 180° C. (watching the pressure) over 5 min and then kept at 180° C. for 30 min Excess POCl3 was evaporated and the residue partitioned between CH2Cl2 (40 mL) and 2 N NaOH (aq) (40 mL). The aqueous layer was extracted with CH2Cl2 (2×40 mL). The organic layers were combined, dried with Na2CO3 and evaporated. The residue was purified on column (silica gel, CH2Cl2 as eluent). Pure fractions were pooled, evaporated and the residue dried under vacuum to give 0.821 g (52%) of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. MS (ESI+) m/z 314, 316 (MH+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.[Cl:19]N1C(=O)CCC1=O.O>C(#N)C>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:4]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1CNc2ccc(Cl)cc2C1
Reaction time: 6 h
Yield: 32.9 %

Procedure:
To a solution of 1A (28.3 g, 114 mmol) in acetonitrile (240 mL) at RT was added dropwise a solution of N-chlorosuccinimide (15.22 g, 114 mmol) in acetonitrile (240 mL). After addition, the reaction mixture was stirred for 6 h, then water (500 mL) added. The mixture was extracted with EtOAc (2×500 mL). The combined organics were washed with brine, dried Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc/hexane 1:5 to give the title compound (10.6 g, 58% yield) as a white solid.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.[CH2:12]([N:14]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1)[C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1SCC)[CH3:13].C(=O)(O)[O-].[Na+].[S:45]([O-:49])([O-])(=[O:47])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([N:14]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][N:31]=1)[C:15](=[O:29])[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][C:21]=1[S:45]([CH2:2][CH3:3])(=[O:49])=[O:47])[CH3:13]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1cc(C(F)(F)F)ccc1C(=O)N(CC)c1ccc(C(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)c1ccc(C(F)(F)F)cc1S(=O)(=O)CC)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.27 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.20 g of N-ethyl-2-ethylsulfanyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide and 5 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.26 g of N-ethyl-2-ethylsulfonyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 5).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[CH3:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 4 of Example 60, from 3.15 g (9.77 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 80 mL of 1:1 methanol-water mixture and 0.28 g (11.7 mmol) of lithium hydroxide with a work-up consisting only of thorough evaporation of solvents.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCC[CH2:16]1.CC(C)([O-])C.[K+].IC>C(OC)(C)(C)C>[CH3:16][N:11]1[CH:12]=[CH:13][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH2:9][C:10]1=[O:14]
Reactant: O=C1CC=C(c2ccccc2)C=CN1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: COC(C)(C)C
Product: CN1C=CC(c2ccccc2)=CCC1=O
Temperature: -30 °C
Yield: 100 %

Procedure:
The 5-phenyl-1,3-dihydro-azepin-2-one (168.5 g, 911.3 mmol) is combined with tetrahydrofuran (1300 mL) and the solution cooled to about −30° C. Potassium tertiary-butoxide (107.4 g, 956.9 mmol) is added in one portion. Exotherm is observed warming the reaction contents to −12° C. Upon subsiding of the exotherm, the contents are allowed to re-cool to −25° C. and iodomethane (113.5 mL, 1.823 moL) is added providing a slight exotherm. The reaction contents are allowed to warm to room temperature and stirred. After 10 hours the reaction mixture is diluted with methyl tertiary-butyl ether (1300 mL) and extracted with saturated ammonium chloride solution (2×250 mL), water, and saturated aqueous sodium chloride solution. The combined aqueous layers are back extracted with methyl tertiary-butyl ether (200 mL). The methyl tertiary-butyl ether extracts are combined, dried over MgSO4 and filtered. The solution is concentrated via rotary evaporation to provide the title compound (185 g, 100%) as a brown powdery residue. The material is used directly, without purification, in the next step.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14](O)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[P:29](Cl)(OC1C=CC=CC=1)([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14]([PH:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)OCCOC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCOC(=O)[C@H]([PH](=O)Oc1ccccc1)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Yield: 78 %

Procedure:
Following the general procedure for phosphorylation of Description 23, (ethoxycarbonyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-hydroxy-butanoate (32) (0.43 g, 1.0 mmol) dissolved in 10 mL of anhydrous dichloromethane (DCM) was reacted with 0.58 mL (0.67 g, 2.5 mmol) of diphenyl chlorophosphate [(PhO)2POCl] in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) (0.12 g, 1.0 mmol) and triethylamine (TEA) (0.35 mL, 0.25 g, 2.5 mmol). The reaction was monitored by TLC. After aqueous work-up, the crude material was further purified by silica gel column chromatography using ethyl acetate (EtOAc) as eluent to provide 0.43 g (65% yield) of the title compound (51a) as a colorless oil. Rf=0.45 (EtOAc). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.09-1.10 (2s, 3H), 1.12-1.13 (2s, 3H), 1.26-1.32 (m, 3H), 1.45-1.52 (2d, J=5.6, 5.6 Hz, 3H), 1.86-1.87 (2s, 3H), 2.01-2.06 (m, 2H), 3.15-3.17 (m, 2H), 3.39-3.34 (m, 2H), 3.98-4.05 (m, 2H), 4.15-4.22 (m, 3H), 4.87-4.91 (2d, J=7.6, 7.6 Hz, 1H), 6.30-6.34 (br. m, 1H), 6.81-6.83 (m, 1H), 7.18-7.26 (m, 6H), 7.33-7.38 (m, 4H) ppm. MS (ESI) m/z 660.11 (M+H)+, 681.94 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.O.Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6]1([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:12]
Reactant: COc1cccc2c1CCC2=O
Reactant: BrCCCCCBr
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc2c1CC1(CCCCC1)C2=O

Procedure:
A solution of 20 g 4-methoxyindan-1-one and 24 g 1,5-dibromopentane in 150 ml benzene is added quickly dropwise to a solution of potassium tert.-butylate (produced from 9.7 g potassium and excess tert.-butanol) in 200 ml benzene at 80°. The mixture is refluxed for 4 hours, treated with 50 ml water and 200 ml 2 N hydrochloric acid, and extracted with benzene. Chromatography on silicagel of the benzene phase gives 4'-methoxy-spiro(cyclohexane-1,2'-indan)-1'-one. M.Pt. 94°-96°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]([C:19]([OH:21])=O)[CH2:10][CH2:9]1.C[N:23](CC1C=CC(N)=CC=1)C1CCOCC1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=N>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]([C:19]([NH2:23])=[O:21])[CH2:10][CH2:9]1
Reactant: Cc1ncsc1CN1CCC(C(=O)O)=Cc2ccccc21
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CN(C)CCCN=C=N
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncsc1CN1CCC(C(N)=O)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
A catalytic amount of N,N-dimethyl-4-aminopyridine was added to a solution of 7-butoxyethoxyphenyl)-1-[(4-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (150 mg), 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (88 mg) and 1-hydroxybenzotriazole (96 mg) in DMF (15 ml), followed by addition of 1-ethyl-3-(3-dimethylaminopropylcarbodiimide (137 mg). The mixture was stirred under nitrogen atmosphere at room temperature overnight. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:3) to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-tetrahydropyran-5-yl)amino]methyl]phenyl]-1-[(4-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 81) (7 mg) as yellow amorphous.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=[S:20])[C:7]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[C:6]=2[O:5]1.[CH3:21][NH:22][CH3:23]>>[ClH:1].[CH3:21][N:22]([CH3:23])[CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=[S:20])[C:7]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[C:6]=2[O:5]1
Reactant: CNC
Reactant: CN1CC(CCCl)Oc2c(ccc3cccnc23)C1=S
Product: CN(C)CCC1CN(C)C(=S)c2ccc3cccnc3c2O1
Product: Cl

Procedure:
Following the procedure of Example 31, 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.