Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:12][CH2:13][CH2:14]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH2:1]([O:8][C:9]([N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:12][CH2:13][CH2:14][Br:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CCN(CCCO)C(=O)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: NC(=O)CCN(CCCBr)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of acrylamide (2 g) in ethanol (30 mL) was added 3-amino-1-propanol (3.23 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added tetrahydrofuran (30 mL) and N-(benzyloxycarbonyloxy)-succinimide (14 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=40/1-20/1-5/1) to give 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)-amino]propionamide (3.51 g). To a solution of the obtained 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)amino]propionamide (0.5 g) and carbon tetrabromide (0.65 g) in dichloromethane (5 mL) was added triphenylphosphine (1.03 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/4-dichloromethane/methanol=10/1) to give the title compound (0.41 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[Cl:21][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH:17]([CH2:18][OH:19])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
While under nitrogen, a flame-dried flask was charged with 2-(tert-butoxycarbonyl)-7-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (400 mg, 1.28 mmol) and anhydrous THF (2.5 mL), cooled in an ice-saturated aqueous sodium chloride bath and carefully treated with a solution of borane in THF (1 M, 2.63 mL, 2.63 mmol). The resulting mixture was stirred at 0° C. for ˜1.5 h and then at room temperature overnight. The mixture was then cooled in an ice-water bath, quenched slowly by the dropwise addition of water until most gas evolution ceased, diluted with additional water (15 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and saturated aqueous sodium chloride (10 mL), dried over Na2SO4 and concentrated under reduced. Purification by silica gel chromatography (40 g column, 10-20% ethyl acetate in methylene chloride) gave tert-butyl 7-chloro-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (292 mg, 76%) as a clear gum. 1H NMR (DMSO-d6, 400 MHz) δ 7.29 (m, 1 H), 7.20 (m, 2 H), 4.81 (m, 1 H), 4.64 (d, J=17 Hz, 1 H), 4.20 (bm, 2 H), 3.30 (m, 1 H), 3.12 (m, 1 H), 2.84 (m, 2 H), 1.43 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:28][C:29]1(OCCCCCC)[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:29]3([O:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCCCCOC1(OCCCCCC)CCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCCCCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCC1
Yield: 34.7 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-di-n-hexoxycyclopentane (2.72 g, 10 mmol) in the same manner as the example 20 to give the compound 36 (178 mg, 34.6%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18].O(Cl)[Cl:20].[P+5].C([O-])(O)=O.[Na+].P(Cl)(Cl)(Cl)=O>CCOCC.CCOC(C)=O>[Cl:20][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18]
Reactant: ClOCl
Reactant: N#Cc1c(O)ccn2c(-c3ccccc3)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P+5]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1c(Cl)ccn2c(-c3ccccc3)cnc12
Temperature: 120 °C
Yield: 33 %

Procedure:
A mixture of compound D5 (2.3 g, 9.77 mmol) and phosphorus(V) oxychloride (50 ml) was heated at 120° C. for 5 h. After cooling to room temperature the solvents were evaporated in vacuo. The residue thus obtained was carefully poured into a mixture of crushed ice and NaHCO3 (aqueous sat. solution). Then EtOAc was added and the mixture was stirred for 2 h. until complete hydrolysis of the remaining phosphorus oxychloride had occurred. The organic layer was then separated, washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue that forms a precipitate upon the addition of Et2O. The solid was filtered off and dried in vacuo to yield compound D6 (0.82 g, 33%) as yellow solid.
Reaction SMILES: [Mg].II.[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.CON(C)[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1)=[O:17].[Cl-].[NH4+]>C(OCC)C.C(OCC)(=O)C>[C:27]([O:26][C:24]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([C:16](=[O:17])[CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[F:4])[CH2:19]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccccc1CCl
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Cc2ccccc2F)C1
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
After suspending 334 mg of magnesium in 3 ml of diethyl ether, a catalytic amount of iodine was added, a portion of 1.89 g of 2-fluorobenzyl chloride fleas added dropwise while stirring, and the mixture was heated to initiate the reaction. After adding 10 ml of diethyl ether, the remaining 2-fluorobenzyl chloride was added dropwise to maintain reflux. After stirring the mixture for 15 minutes, approximately 6 ml of the obtained reaction solution was added dropwise to a solution of 1.78 g of N-methoxy-N-methyl-1-(tert-butoxycarbonyl)-3-piperidinecarboxamide [CAS No.189442-78-2] in diethyl ether (20 ml) while cooling on ice, and stirring was continued for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (564 mg, 27% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
Next, 2-biphenyl-4-ylmethyl-succinic acid 4-tert-butyl ester 1-methyl ester (160 mg, 0.451 mmol) is added to trifluoroacetic acid (5 mL). After 10 minutes, the solvent is removed under reduced pressure. Methylene chloride is added and the solvent is removed under reduced pressure to give 2-biphenyl-4-ylmethyl-succinic acid 1-methyl ester. This material is used directly in the subsequent coupling reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2.O=S(Cl)Cl.[CH3:20]O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([O:15][CH3:20])=[O:14])=[CH:7]2
Reactant: CO
Reactant: O=C(O)c1cc2cccc(F)c2c(=O)[nH]1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cccc(F)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (4 g, 19.3 mmol) in MeOH (100 mL) was added SOCl2 (20 mL) at 0° C. The reaction mixture was stirred at RT for 30 minutes and then heated to reflux for 5 hours. The reaction mixture was subsequently concentrated in vacuo. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=1:1-1:2 gradient) to give a second batch of the title compound (3 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.19 (s, 1H), 7.79-7.71 (m, 2H), 7.42-7.38 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](O[Si](C(C)(C)C)(C)C)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[N:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[NH2:32][C:28]1[N:27]=[C:26]2[C:31]([C:9]([C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:25]2)=[CH:30][CH:29]=1
Reactant: Nc1cccc(N)n1
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccc(F)cc1)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-2-t-butyldimethylsiloxy-2-(4-pyridyl)ethanone (16) (3.45 g, 10.0 mmol), 2,6-diaminopyridine (1.09 g, 10.0 mmol), p-toluenesulfonic acid monohydrate (13.3 g, 70.0 mmol), and xylene (140 mL) were warmed to 60° C. under argon (note: all condensation reactions of this type were conducted behind an explosion shield). After 1 h at 60° C., the reaction was warmed to 135° C. for 3 h. After allowing the reaction to cool to 23° C., the top layer of xylene and p-toluenesulfonic acid was decanted from the bottom layer of gummy product residue. The lower product layer was partitioned between saturated bicarbonate (100 mL), and ethyl acetate (250 mL). The ethyl acetate layer was washed with brine (1×100 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by applying flash chromatography (2 liters of ethyl acetate: hexane 7:3 followed by 100% ethyl acetate) to afford the cleanly separated regioisomer (17): Mass Spectrum (CI) 305 (MH+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1) (5.22 g, 20 mmol) in DMF (60 mL) were added K2CO3 (8.3 g, 60 mmol) and 1-fluoro-4-nitrobenzene (2.96 g, 21 mmol). After the resulting mixture was stirred at 100° C. for 24 hr under N2 atmosphere, the reaction mixture was cooled to RT before pouring into water (200 mL). The precipitate was collected, washed with water and dried to provide 3-iodo-1-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (27) (6.8 g, 89%) as light yellow solid. LC-MS (ESI): m/z (M+1) 383.1.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]([Cl:10])([Cl:9])[Cl:8])[C:3](O)=[O:4].S(Cl)([Cl:13])=O>CN(C)C=O>[Cl:1][CH:2]([CH2:6][C:7]([Cl:10])([Cl:9])[Cl:8])[C:3]([Cl:13])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Cl)CC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C(Cl)CC(Cl)(Cl)Cl
Yield: 93.2 %

Procedure:
226 g (1 mol) of 2,4,4,4-tetrachlorobutyric acid [produced according to CA, 63, 13089e (1965)], 600 g of thionyl chloride and 1 ml of N,N-dimethylformamide are heated for 2 hours at 50° C. and for 2 hours at 75° C. After the unreacted thionyl chloride has been evaporated off, the residue is distilled to obtain 227.6 g (93% of theory) of 2,4,4,4-tetrachlorobutyric acid chloride; b.p. 90°-91° C./15 mm Hg.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[C:23]([O:25]CC)=O)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[OH:25][CH:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:29])=[O:28]
Reactant: CCOC(=O)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)C(O)C(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of ethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate (500 mg, 1.26 mmol) obtained in Example 15 in THF (10 mL) was added dropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride (2.0 M THF solution, 1.9 mL, 3.78 mmol) and the mixture was stirred for 30 minutes. After the reaction solution was warmed to room temperature and was stirred at the same temperature for 1 hour, the reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to obtain 194 mg (yield: 38%) of the title compound as a diastereomer mixture. Melting point: 165-166° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:21])[N:8]([CH3:20])[N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1>[CH2:22]([NH:29][C:4]([C:6]1[C:7](=[O:21])[N:8]([CH3:20])[N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH:11]=1)=[O:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(C)c1=O
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2cc(C(=O)NCc3ccccc3)c(=O)n(C)n2)cc1
Yield: 94.2 %

Procedure:
In xylene, 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one and benzylamine were reacted at 140° C. for 1 hour. Post-treatments were conducted as in Example 68, whereby the title compound was obtained in a yield of 94.2%.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1>C(O)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[C:4]1[CH2:3][C:2]([CH3:28])([CH3:1])[CH2:7][CH:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:5]=1
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccncc2N)=CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (1 eq) in acetic acid (0.1 M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.10 eq) was added. The reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. The organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (89%). LC/MS (m/z): MH+=348.3, Rt=0.79.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16].C(N(CC)CC)C>O1CCCC1>[F:22][C:19]1[CH:18]=[C:14]2[C:13](=[CH:21][CH:20]=1)[N:12]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])[NH:17][C:15]2=[O:16]
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cc(F)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1-c1nc2ccc(F)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
o-Anisoyl chloride (15.7 g, 92 mmol) was added dropwise to a solution of 2-amino-5-fluorobenzamide (13.0 g, 84 mmol) and triethylamine (16 mL, 110 mmol) in tetrahydrofuran (100 mL) cooled in an ice bath. Immediately a precipitate started forming. Stirring of the solution was continued for 5 hours at room temperature. The formed precipitate was collected by filtration and was washed twice with diethyl ether and dried at 50° C. in vacuo. The dried solid was suspended in 2 N aqueous sodium hydroxide solution (250 mL) and heated at reflux until a clear solution was obtained (3 hours). The reaction mixture was cooled to room temperature and filtered. The filtrate was acidified to pH<1 with concentrated aqueous HCl. The formed precipitate was collected by filtration and washed twice with water, twice with methanol, and twice with diethyl ether. The solid was dried in an oven at 45° C. to yield 6-fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one (18.2 g, 80%) as a white solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:30])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.ClC1C=CC(OCC(N2C3C=CC=CC=3CN3C(C(NCC4C=NC=CC=4)=O)=CC=C3C2)=O)=CC=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:30])=[C:23]([CH3:29])[CH:24]=1
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1cccnc1
Agent: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Product: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)NCc3cccnc3)n2Cc2ccccc21

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step C (0.34 mmol), and 3-aminomethylpyridine (0.71 mmol), in a manner similar to the synthesis of 10-[(4-chlorophenoxy)acetyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 179 (0.126 g; 74%), m.p. 168° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:22])([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)[C:9]([O-])=[O:10].Cl.C(OCC)(=O)C>C1COCC1>[F:7][C:8]([F:22])([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)[CH2:9][OH:10]
Reactant: CCCc1ccc(CC(F)(F)C(=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1ccc(CC(F)(F)CO)cc1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 0.8 g of lithium aluminum hydride and 50 ml of THF were added, and the resultant mixture was cooled to −10° C. Thereto, 3.9 g of 2,2-difluoro-3-(4-propylphenyl)propanoate (e-26) dissolved in 10 ml of THF was added dropwise in a temperature range of −10° C. to 0° C. Then, the resultant mixture was heated to 25° C. and stirred for 1 hour. Subsequently, 100 ml of 1 N HCl aqueous solution and 200 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, and then the resultant solution was dried over anhydrous magnesium sulfate. The resultant solution was concentrated under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=5:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 1.6 g of 2,2-difluoro-3-(4-propylphenyl)propan-1-ol (e-27) was obtained. A yield based on compound (e-26) was 50.4%.
Reaction SMILES: O1C2(CCC(C3C4C(=CC=CC=4)NC=3)CC2)OCC1.[O:20]1[C:24]2([CH2:29][CH2:28][C:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]#[N:40])[CH:37]=4)[NH:32][CH:31]=3)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>>[O:23]1[C:24]2([CH2:29][CH2:28][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]#[N:40])[CH:37]=4)[NH:32][CH:31]=3)[CH2:26][CH2:25]2)[O:20][CH2:21][CH2:22]1
Reactant: N#Cc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Agent: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Product: N#Cc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Yield: 94.8 %

Procedure:
This compound was prepared in the manner described above for intermediate 2a by replacing 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1H-indole (54.6 g)) to afford 52.12 g (95%) of the title compound as a white solid in 95% (52.12 g) yield as a white solid: mp 153-155° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH2:15][O:16][CH:17]3[CH2:20][N:19]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][NH:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH2:15][O:16][CH:17]4[CH2:20][N:19]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]4)[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CCl)cc3)c2C(F)(F)F)C1
Reactant: NCC1CC1
Product: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CNCC4CC4)cc3)c2C(F)(F)F)C1
Yield: 98 %

Procedure:
The benzyl chloride (195) (34 mg, 0.075 mmol) and cyclopropylmethylamine (1 mL, 12 mmol) were heated to 50° C. for 18 h. The reaction mixture was cooled, excess amine was removed under reduced pressure and the residue partitioned between ethyl acetate and sodium hydroxide (1M). The organic phase was washed with water (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered and the solvent removed under reduced pressure to afford the crude product. Purification by SCX-2 cartridge afforded the title compound (197) as a colourless gum (36 mg, 98% yield).