Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[F:4][C:5]([F:41])([F:40])[C:6]1[CH:39]=[CH:38][C:9]([C:10]([NH:12][C:13]2[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]=2)=[O:11])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)(=O)C>[F:40][C:5]([F:4])([F:41])[C:6]1[CH:39]=[CH:38][C:9]([C:10]([NH:12][C:13]2[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: O=C(Nc1nc2ccccc2n1CCCN1CCN(Cc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(Nc1nc2ccccc2n1CCCN1CCNCC1)c1ccc(C(F)(F)F)cc1
Yield: 63.9 %

Procedure:
To a solution composed of 75 ml. ethanol and 1 ml. glacial acetic acid was added 2-(4-trifluoromethylbenzamido)-1-[3-(4-benzyl-1-piperazinyl)-propyl]benzimidazole (500 mg., 0.96 millimole) and 100 mg. of 10% Pd/C catalyst. The mixture was shaken on a Paar apparatus at about 2 atm. pressure of hydrogen and 40° C. for 2.5 hrs. at which time the reaction was complete. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to yield a white solid, which on trituration under acetone yielded 300 mg. (63.9% yield) of 2-(4-trifluoromethylbenzamido)-1-[3-(1-piperazinyl)propyl]benzimidazole, as a white crystalline solid, m.p. 184°-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([O:11]CC=C)=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[CH3:16][CH2:17][CH2:18]CCC.ClCCl>C1C2C(=CC=CC=2)CCC1>[CH3:1][C:2]1[CH:10]=[C:9]([CH2:18][CH:17]=[CH2:16])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15]
Reactant: CCCCCC
Reactant: C=CCOc1ccc(C)c2c1C(=O)CC2
Solvent: ClCCl
Solvent: c1ccc2c(c1)CCCC2
Product: C=CCc1cc(C)c2c(c1O)C(=O)CC2

Procedure:
32 Grams of 4-methyl-7-allyloxy-1-indanone was suspended in 100 ml of tetrahydronaphthalene. The suspension was refluxed by heating for 4 hours under argon gas atmosphere. The reaction mixture was subjected to a silica gel column chromatography (eluent: n-hexane, and dichloromethane: n-hexane=1:2) to obtain 26.8 g of 4-methyl-6-allyl-7-hydroxy-1-indanone.
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=O.[CH2:24]([CH2:26][NH2:27])[OH:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:25][CH2:24][CH2:26][NH:27][CH2:1][C:3]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNCCO)c1
Reaction time: 2 h
Yield: 109.8 %

Procedure:
[3-(2-Formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid (0.12 g, 0.37 mmol), ethanolamine (0.02 mL, 0.37 mmol), and sodium triacetoxyborohydride (0.12 g, 0.56 mmol) were combined in CH2Cl2 (10 mL) and stilled for 2 hours. After work-up, 0.15 g of the desired product was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:23]([CH3:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[CH3:25].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][C:13]2[C:14]([CH3:25])=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][C:23]=2[CH3:24])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C)c(N)c(C)c1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (0.78 g, 4.55 mmol) in CH2Cl2 (15 mL) at room temperature are added ethyl 4-amino-3,5-dimethyl-benzoate (0.878 g, 4.55 mmol) and N,N-diisopropylethylamine (1.98 ml, 11.36 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 3.25 ml, 5.46 mmol) is added via syringe. After 48 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes. After purification, the solid is triturated with 30% ethyl acetate in hexanes and filtered to give the title compound as a white powder (0.907 g, 57.5%). Mass spectrum (m/z): 347.2 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([CH:8]1[CH2:9][N:10]([C:20](=[O:21])[CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: c1ccc(CC2CNC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
A solution of 3-benzylazetidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing the ethyl 1-(3-benzylazetidin-1-yl)-3-phenylpropan-1-one are collected and the solvent is removed in vacuo to give 432 mg of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=[C:7]3[C:6]=2[CH:21]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([C:7]2[N:8]([CH2:9][C:10](=[O:13])[N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]([C:17]([F:20])([F:18])[F:19])=[N:15][N:16]=2)[CH:21]=1
Reactant: CN1C(=O)Cn2c(nnc2C(F)(F)F)-c2cc(Cl)ccc21
Reactant: C1COCCN1
Product: CNc1ccc(Cl)cc1-c1nnc(C(F)(F)F)n1CC(=O)N1CCOCC1

Procedure:
4.8 g. (0.0152 mole) of 10-chloro-7-methyl-3-(trifluoromethyl)-5H-s-triazolo[4,3-d][1,4]benzodiazepin-6(7H)-one from example 1a are dissolved in 40 ml. of morpholine and the resulting solution is refluxed for 3 days. The morpholine is removed under vacuum, 3N aqueous NaOH is added, and the mixture is extracted with benzene. The benzene solution is dried over Na2SO4, decanted from drying agent, and the solvent removed under vacuum to yield a gum. This gum is chromatographed on silica gel plates with chloroform/ethyl acetate, 6:4. The largest band is isolated, extracted with chloroform, the chloroform is evaporated, and the residue is recrystallized from ethanol to yield 3-[5-chloro-2-(methylamino)phenyl]-4-[2-oxo-2-(4-morpholinyl)ethyl]-5-(trifluoromethyl)-1,2,4-triazole; m.p. 152°-153°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29](O)=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:44][C:45]1[CH:46]=[CH:47][C:48]([S:51]([NH2:54])(=[O:53])=[O:52])=[CH:49][CH:50]=1.CCCCCCC=CCCC>O1CCCC1>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH:54][S:51]([C:48]3[CH:49]=[CH:50][C:45]([CH3:44])=[CH:46][CH:47]=3)(=[O:52])=[O:53])=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N(CCCCOCC(=O)O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CCCC=CCCCCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)COCCCCN(c2cnc(-c3ccccc3)c(-c3ccccc3)n2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To a solution of 500 mg of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid obtained in Example 42 in 5 ml of anhydrous tetrahydrofuran, 214 mg of 1,1′-carbonyldiimidazole was added and, after stirring at room temperature for 30 minutes, the mixture was heated at reflux for 30 minutes. After air-cooling to room temperature, 206 mg of p-toluenesulfonamide was added. After stirring for 10 minutes, 0.18 ml of 1,8-diazabicyclo[5.4.0.]undec-7-ene was added dropwise. After stirring at room temperature overnight, almost all of the solvent was evaporated under reduced pressure. The residue was combined with water and then neutralized with 1N hydrochloric acid. The reaction solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 460 mg of the desired compound.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:8][C:9]([NH:17][C:20](=[O:21])[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[Cl:18])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(Cl)C(=O)Cl
Reactant: CC(C)(N)c1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(NC(=O)C(Cl)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Into a 200 ml four-necked flask, there were charged toluene (100 ml), α,α-dimethylbenzylamine (9 g) and pyridine (5.8 g), and α-chloro-tert-butylacetyl chloride (11.3 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. The reaction mixture was washed with water to remove pyridine hydrochloride. After the toluene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 15.8 g of N-(α,α-dimethylbenzyl)-α-chloro-tert-butylacetamide. M.P., 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([CH2:21][O:22][CH2:23][CH3:24])[CH:10]=[C:11]([C:16]([O:18]CC)=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2>O.C(O)C.[OH-].[K+]>[Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([CH2:21][O:22][CH2:23][CH3:24])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOCn1cc(C(=O)OCC)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Temperature: 20 °C
Yield: 72 %

Procedure:
A suspension of 6 g of 8-chloro-3-ethoxycarbonyl-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 120 cm3 of water, 120 cm3 of ethanol and 47.5 cm3 of 2N aqueous potassium hydroxide solution is heated, with stirring, at a temperature close to 75° C. for 2 hours and a half. A small amount of insoluble matter is removed by filtering at the same temperature. After cooling to about 20° C., 6 cm3 of acetic acid are added to the filtrate. The precipitate obtained is drained, washed with 3 times 20 cm3 of water and recrystallized from 60 cm3 of dimethylformamide. 4 g of 8-chloro-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid which decomposes at 285° C.
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=[O:18].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O.O>[N:19]([CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=[O:18])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(SC)c2c1CCC(N=[N+]=[N-])C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
Ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (5.24 g) was suspended in N,N-dimethylformamide (80 ml); a solution of sodium azide (1.95 g) in water (12 ml) was added at 0° C. After the reaction mixture was stirred at room temperature for 4 hours, it was poured over water (50 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9 to 1:2, v/v) to yield ethyl 5-azido-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (3.77 g, 80.7%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 163-164° C. (decomposed).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][CH:39]=[C:38]3[CH:44]=O)[CH2:28][CH2:27]1>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:44]/[C:38]3[C:37]4[C:41](=[CH:42][CH:43]=[C:35]([O:34][CH2:33][CH2:32][N:29]5[CH2:30][CH2:31][O:26][CH2:27][CH2:28]5)[CH:36]=4)[NH:40][CH:39]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccc(OCCN3CCOCC3)cc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(OCCN5CCOCC5)cc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.067 g, 0.19 mmol) obtained in Example A16, Step 1 in methanol (5.0 mL) was added with 5-(2-morpholinoethoxy)-1H-indole-3-carboxaldehyde (0.044 g, 0.16 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl (Z)-4-[(6-hydroxy-2-{[5-(2-morpholinoethoxy)-1H-indol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.076 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (276 mg, 1.08 mmol) [Prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (317 mg, 0.95 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (612 mg, 1.31 mmol) in Chloroform (14 mL). DIEA (940 μL, 5.38 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=537 (M+H)+.
Reaction SMILES: CP(C1C=CC(N)=C(S(C(C)C)(=O)=O)C=1)(C)=O.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([P:41]([CH3:44])([CH3:43])=[O:42])=[CH:37][C:36]=2[S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])[C:31]([Cl:51])=[CH:30][N:29]=1.[N:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[N:58]1[CH2:63][CH2:62][N:61]([C:64]2[S:68][C:67]([NH2:69])=[N:66][N:65]=2)[CH2:60][CH2:59]1>>[Cl:51][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([P:41]([CH3:44])([CH3:43])=[O:42])=[CH:37][C:36]=2[S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])=[N:33][C:28]([NH:69][C:67]2[S:68][C:64]([N:61]3[CH2:60][CH2:59][N:58]([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][N:52]=4)[CH2:63][CH2:62]3)=[N:65][N:66]=2)=[N:29][CH:30]=1
Reactant: Nc1nnc(N2CCN(c3ccccn3)CC2)s1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)s2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine. 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine is then reacted with 5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-thiadiazol-2-amine according to the procedure described in Example 32.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[CH:23]([CH2:26][CH3:27])[CH2:24][N:25]=[C:20]2[C@H:19]([NH2:28])[CH2:18][CH2:17]1.[O:29]=[C:30]1[NH:38][C:33]2=[N:34][CH:35]=[CH:36][CH:37]=[C:32]2[N:31]1[CH:39]1[CH2:44][CH2:43][N:42]([C:45](Cl)=[O:46])[CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[CH:23]([CH2:26][CH3:27])[CH2:24][N:25]=[C:20]2[C@H:19]([NH:28][C:45]([N:42]2[CH2:41][CH2:40][CH:39]([N:31]3[C:32]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:38][C:30]3=[O:29])[CH2:44][CH2:43]2)=[O:46])[CH2:18][CH2:17]1
Reactant: CCC1CN=C2[C@H](N)CC[C@@H](c3cccc(F)c3F)CN21
Reactant: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CN=C2[C@H](NC(=O)N3CCC(n4c(=O)[nH]c5ncccc54)CC3)CC[C@@H](c3cccc(F)c3F)CN21
Reaction time: 18 h
Yield: 42.5 %

Procedure:
Triethylamine (17 μL, 0.124 mmol) was added to a solution of the (6S,9R)-6-(2,3-difluorophenyl)-3-ethyl-2,5,6,7,8,9-hexahydro-3H-imidazo[1,2-a]azepin-9-amine (13 mg, 0.035 mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl chloride (15 mg, 0.053 mmol) in dichloromethane (1 mL). After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by reverse phase HPLC(C-18, 95% water/acetonitrile 30% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (8 mg). MS 538.2710 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])[CH:18]=1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 12.1 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (0.350 g, 2.4 mmol), 5-methyl-2-nitro-benzenesulfonyl chloride (Intermediate 449) (0.86 g, 3.6 mmol), pyridine (1 ml) DMAP (cat) and DCM (5 ml) gave the title compound (100 mg, 12%) after purification by column chromatography with n-hexane/EtOAc (10:90) as the eluent. The structure was confirmed by 1H NMR.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[O:12])[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)Cl.CN([CH:30]=[O:31])C>[Au]>[C:19]([N:16]1[CH2:15][CH2:14][CH:13]([C:11]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[NH:1][C:2]([CH:30]=[O:31])=[CH:3][C:4]2=3)=[O:12])[CH2:18][CH2:17]1)(=[O:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]ccc32)CC1
Agent: [Au]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]c(C=O)cc32)CC1

Procedure:
1-[4-(5,6,7,8-Tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-piperidin-1-yl]-ethanone (1.1 g) was formylated with POCl3 (186 μL, 1.2 eq.) and DMF using standard Vilsmierer condition to give 240 mg of 4-(1-acetyl-piperidine-4-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde as a gold colored solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=2[CH3:31])=[CH:19][CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:25]3[CH:26]=[N:27][C:22]([O:21][C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:33][CH:32]=4)=[C:23]([CH3:31])[CH:24]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1Oc1ccc(F)cc1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1ccc(F)cc1
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (120 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (100 mg, 0.36 mmol, Step-1 of Intermediate-1) and 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (120 mg, 0.43 mmol, Amine-39, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: OC1C=CC(CC(CC2C=CC(O)=CC=2)=O)=CC=1.BrCCBr.BrCCC1C=C(C(=O)C)C=[CH:28][C:27]=1[O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][C:37]=1CCBr.[CH:48]([NH2:51])([CH3:50])[CH3:49]>>[C:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][CH2:27][CH2:28][NH:51][CH:48]([CH3:50])[CH3:49])=[CH:41][CH:40]=1)(=[O:44])[CH3:43]
Reactant: CC(C)N
Reactant: CC(=O)c1ccc(Oc2ccc(C(C)=O)cc2CCBr)c(CCBr)c1
Agent: O=C(Cc1ccc(O)cc1)Cc1ccc(O)cc1
Solvent: BrCCBr
Product: CC(=O)c1ccc(OCCNC(C)C)cc1

Procedure:
4-Hydroxyphenylmethyl ketone is reacted with 1,2-dibromoethane in the presence of base. The product of that reaction, 2-bromoethyl-4-acetylphenyl ether is then reacted with isopropylamine as in Preparation 26 to give the title compound.