Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]1([CH2:66][CH2:67][NH2:68])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][CH2:66][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: NCCc1ccccc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 2-phenylethanamine (58.0 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (198 mg). LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][CH:7]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][CH2:7]2)=[CH:17][CH:18]=1
Reactant: O=c1c(-c2ccc(F)cc2)coc2ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C1c2ccccc2OCC1c1ccc(F)cc1
Yield: 23.3 %

Procedure:
Prepared according to the general procedure using 4′-fluoroisoflavone (77 mg, 0.319 mmol), ammonium formate (81 mg, 1.28 mmol), methanol (6.4 mL) and 10% Pd/C (81 mg). Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford 46 (18 mg, 23%) as an off-white solid. Analytical data for isoflavanone 46: 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J=9.5 Hz, 1H), 7.53 (app t, J=9 Hz, 1H), 7.29-7.26 (m, 2H), 7.09-7.03 (m, 3H), 4.70-4.62 (m, 2H), 4.02-3.99 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 205.8, 192.2, 191.9, 161.8, 136.4, 130.9, 130.5, 128.0, 122.0, 121.1, 118.1, 116.2, 116.0, 71.6, 51.8; LCMS: Mass calculated for C15H11FO2, [M+H]+, 243. Found 243.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[N:11][CH2:12][C:13](=S)[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:24]([NH:27][NH2:28])(=O)[CH3:25]>C(O)C>[N+:1]([C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[N:11][CH2:12][C:13]3[N:14]([C:24]([CH3:25])=[N:27][N:28]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)NN
Reactant: N#Cc1ccccc1C1=NCC(=S)Nc2cccc([N+](=O)[O-])c21
Solvent: CCO
Product: Cc1nnc2n1-c1cccc([N+](=O)[O-])c1C(c1ccccc1C#N)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6-nitro-1,3-dihydro-5-(o-cyanophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with acetic acid hydrazide and the resulting product heated to 250° C. to give 7-nitro-1-methyl-6-(o-cyanophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[N:9]=[C:10](\[CH2:15][C:16]([O:18]C)=O)/[C:11]([O:13][CH3:14])=[O:12]>CC(N(C)C)=O>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][C:16]2=[O:18]
Reactant: COC(=O)C/C(=N\c1cccc(C)c1F)C(=O)OC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(=O)c2ccc(C)c(F)c2[nH]1
Yield: 42.7 %

Procedure:
Dimethyl(2E)-2-[2-fluoro-3-methylphenyl)imino]butanedioate (7-6, 3.27 g, 12.24 mmol) in DMA (24.47 ml) was heated at 240° C. in the microwave for 5 min. The solvent was evaporated under reduced pressure and the residue triturated with ether to afford a tan solid. The desired product was filtered off and washed with ether till the ether ran colorless affording Methyl 8-fluoro-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (7-7, 1.23 g, 43% yield) as a tan solid, LCMS shows 93% pure, LRMS m/z (M+H)+ 236.1 found, 236.1 required.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH3:33])[NH:28]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]4[CH:29]([CH3:33])[CH2:30][CH2:31][CH2:32][CH:27]4[CH3:26])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCC(C)N1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CC1CCCC(C)N1Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 61.1 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at 70° for 4 hours with 2 g (17 mmol) of 2,6-dimethylpiperidine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there was obtained 0.83 g (61%) of (S)-8-chloro-1-[5-(2,6-dimethylpiperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 233°-236°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[N:20]([CH:21]=2)[CH:19]=[CH:18][S:17]3)=[O:13])[CH2:3]1.[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:28]([C:26]3[N:27]=[C:23]([CH3:22])[S:24][C:25]=3[C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)=[O:29])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[N:20]([CH:21]=2)[CH:19]=[CH:18][S:17]3)=[O:13])[CH2:3]1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3cn4ccsc4n3)[C@H]2C1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cn3ccsc3n2)c1

Procedure:
prepared by reaction of imidazo[2,1-b]thiazole-6-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([N:6](S(C(F)(F)F)(=O)=O)[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([Cl:17])[CH:8]=1)(=[O:5])=[O:4].[OH-].[Na+].CO.O>Cl>[Cl:17][C:9]1[CH:8]=[C:7]([NH:6][S:3]([C:2]([F:26])([F:1])[F:25])(=[O:4])=[O:5])[CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(NS(=O)(=O)C(F)(F)F)cc1Cl

Procedure:
A solution of methyl 4-{bis[(trifluoromethyl)sulfonyl]amino}-2-chlorobenzoate (5.9 g, 13.1 mmol), sodium hydroxide (3.12 g, 78.0 mmol), methanol (125 ml) and water (125 ml) was stirred for 2 hours. The solution from concentration to 75 ml by spin evaporation in vacuo and dilution with 100 ml water was extracted with ethyl acetate. The aqueous layer was acidified with 12 N hydrochloric acid and again extracted with ethyl acetate. The organic layer was washed with water and concentrated by spin evaporation in vacuo, with the addition of dichloromethane (3 times) to give a residue that was dissolved in 1 N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with water, and concentrated by spin evaporation in vacuo 2-chloro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid as a solid (3.6 g, 61%). ES-LCMS m/z 304 (M+H).
Reaction SMILES: P(OCC)(OCC)OCC.[NH2:11][C:12]1[C:17]([C:18]#[N:19])=[N:16][C:15]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][N+:13]=1[O-]>O>[NH2:11][C:12]1[C:17]([C:18]#[N:19])=[N:16][C:15]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][N:13]=1
Reactant: N#Cc1nc(-c2ccco2)c[n+]([O-])c1N
Agent: CCOP(OCC)OCC
Solvent: O
Product: N#Cc1nc(-c2ccco2)cnc1N
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
triethyl phosphite (20 mL, 19.20 g, 116 mmol) was heated to 130° C. and 2-amino-3-cyano-5-(furan-2-yl)pyrazine 1-oxide 55 (3.37 g, 13.34 mmol) was added in portions (±20 min). The reaction was stirred for 1 h, cooled down to 70° C., water (40 mL) was added and stirred for 30 min at 70° C. Cooled down with ice bad and the resulting precipitate was collected, washed with water and dried to give 3-amino-6-(furan-2-yl)pyrazine-2-carbonitrile 56 (2.46 g, 99%). NMR (400 MHz, DMSO-d6) 6.64 (m, 1H), 6.99 (d, J=3.5 Hz, 1H), 7.51 (br s, 1H), 7.80 (m, 1H), 8.70 (s, 1H). (m/z)=187 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](F)[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[C:23]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH:24]=1
Reactant: Sc1cccc2cnccc12
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1Sc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 500 mg (3.1 mmol), DMF 10 ml, potassium carbonate 700 mg (5.1 mmol) and 4-chloro-2-fluoronitrobenzene 800 mg (5.0 mmol) was stirred at room temperature for 2 hours, and 5-(5-chloro-2-nitrophenylsulfanyl)isoquinoline 910 mg (92.7%) was obtained.
Reaction SMILES: [Li+].[OH-].[CH3:3][C@H:4]1[C:12]2[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1>O.C1COCC1>[CH3:3][C@H:4]1[C:12]2[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(-c2ncnc3c2[C@H](C)CC3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)O)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A solution of LiOH (64 mg, 2.68 mmol) in H2O (10 mL) was added to a solution of (R)-methyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoate (359 mg, 1.34 mmol) in THF (6 mL) at 0° C. The mixture was allowed to warm up to room temperature and stirred overnight. The volatile solvent was removed in vacuo. The aqueous layer was acidified with 1N HCl to a pH of 3. A solid precipitated, and was collected by filtration, washed with ether, and dried in vacuo to give (R)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid as a solid (306 mg, 90%).
Reaction SMILES: C(O[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH2:12][CH2:13][O:14][CH2:15][CH3:16])C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.Cl>[CH2:15]([O:14][CH2:13][CH2:12][N:11]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]([OH:22])=[C:18]([C:19]#[N:20])[C:17]1=[O:21])[CH3:16]
Reactant: CCOCCN(C(=O)CC#N)c1ccccc1C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCn1c(=O)c(C#N)c(O)c2ccccc21
Temperature: 80 °C

Procedure:
To a stirred solution of 2-[(2-Cyano-acetyl)-(2-ethoxy-ethyl)-amino]-benzoic acid ethyl ester (1 eq, 0.200 g, 0.66 mmole) in dimethylformamide (25 mL) was added potassium carbonate (1.5 eq, 0.136 g , 0.99 mmole) the resulting mixture was heated to 80° C. for 4 hours. Reaction mixture was diluted with 1N HCl aq (25 mL) and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before, drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 1-(2-Ethoxy-ethyl)-4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a pale yellow solid (0.161 g, 95%, LCMS calc M+H 259, obs M+H 259).
Reaction SMILES: [Li]C(CC)C.[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.CN([CH:23]=[O:24])C.O>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:10]=[C:11]([Cl:13])[C:12]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cc(Cl)cc(N2CCOCC2)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Reaction time: 0.5 h

Procedure:
Add sec-BuLi (1.4M in cyclohexane, 5.44 mL) in a dropwise manner to a solution of 4-(3,5-Dichloro-phenyl)-morpholine (Tetrahedron (2001), 57(36), 7657-7664, 1.60 g, 6.93 mmol) in dry THF (20 mL) under N2 at −78° C. Allow to stir for 30 min. Slowly add DMF (2.68 mL, 34.7 mmol) to the cold solution. Upon disappearance of the starting material by TLC, warm the reaction to 0° C. Quench the reaction by addition of H2O (15 mL) and extract the mixture with EtOAc (150 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Triturate the resulting solid with Et2O to yield the title compound. Evaporate the filtrate to yield another crop of the title compound as a yellow solid: 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 3.46-3.54 (m, 4H) 3.85-3.93 (m, 4H) 7.06 (s, 2H) 10.44 (s, 1H); MS (m/z) 260.0 (M+1).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:14][C:15]([C:18]1[CH:23]=[C:22]([SH:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])[CH3:16]>C(#N)C>[CH3:28][C:25]([C:20]1[CH:21]=[C:22]([S:24][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:23]=[C:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[C:19]=1[OH:29])([CH3:26])[CH3:27]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
Methyl acrylate (1.1 g, 12.6 mmol) and triethylamine (0.5 mL, 0.4 mmol) are sequentially added to a room temperature solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.0 g, 12.6 mmol) in acetonitrile (6 mL). The reaction is stirred for 1.5 hours and then evaporated under high vacuum to give 3.7 g (90%) of the crude product. A small portion is chromatographed on a silica column with ethyl acetate/hexane (1/9) to afford an analytically pure sample of methyl 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoate, mp 64.0°-66.0° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)(=[O:21])[CH3:20]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([O:17][CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OCCCCBr
Reactant: CCCCOc1c(O)c2cccc(O)c2oc1=O
Product: CCCCOc1c(O)c2cccc(OCCCCOC(C)=O)c2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-butoxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 4-bromobutyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-butoxy-4-hydroxy-8-(4-acetoxybutoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[N:19]1[CH:21]=[CH:22][CH:23]=[C:18]1[C:17]2=[O:24])=O>C(O)(=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:10]([C:12]3[C:20]4[N:19]5[CH:21]=[CH:22][CH:23]=[C:18]5[C:17](=[O:24])[C:16]=4[CH:15]=[CH:14][CH:13]=3)[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)ccc1NC(=O)c1cccc2c1-n1cccc1C2=O
Solvent: CC(=O)O
Product: O=C1c2cccc(-c3nc4ccc(F)cc4[nH]3)c2-n2cccc21
Yield: 33.6 %

Procedure:
In a 250 ml round-bottomed flask, a mixture of 375 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid (2-amino-4-fluorophenyl)amide obtained according to the preceding stage, in 40 ml of glacial acetic acid, is refluxed for 3 hours. The reaction medium is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (0 to 30% by volume) in dichloromethane. 119 mg of 5-(6-fluoro-1H-benzimidazol-2-yl)pyrrolo[1,2-a]indol-9-one are obtained in the form of a yellowish solid, the characteristics of which are the following:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[CH3:38][O:39]C1C=CC(B(O)O)=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:6]=[CH:7][C:2]([O:39][CH3:38])=[CH:3][CH:4]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)cc1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-methoxyphenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=527, obsd.=527).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>CO>[ClH:19].[CH3:18][O:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COCCOC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCOC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methoxyethoxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 81, 114 mg, 0.44 mmol) in methanol (3 mL) was added 4M HCl in dioxane (550 μL, 2.20 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude residue dissolved in water (10 mL). The aqueous solution was extracted with ethyl acetate (2×10 mL) then concentrated in vacuo. Purification by trituration in ethyl acetate gave the title compound as the hydrochloride salt. δH (CD3OD): 3.74–3.67 (1H, m), 3.64 (2H, m), 3.56 (2H, m), 3.40–2.39 (7H, m), 2.11–1.96 (2H, m), 1.93–1.83 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].O>C(Cl)Cl>[C:16]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9])(=[O:19])[CH:17]=[CH2:18]
Reactant: Cc1ccc(O)c(N)c1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)Nc1cc(C)ccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-4-methylphenol (5 g, 40.6 mmol) and pyridine (5 ml, 62 mmol) in methylene chloride (70 ml) was added dropwise a solution of acryloyl chloride (4 ml, 50 mmol) in methylene chloride (30 ml) under ice-cooling. The reaction mixture was stirred at 0° C. for 2 hours. To the reaction mixture was added water, and the mixture was stirred at room temperature for 30 minutes, extracted with methylene chloride, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and thus obtained brown oil was purified by column chromatography on silica gel to give a pale yellow prismatic crystals. Yield 1.55 g (22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:12][CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCCCO)c1cc(F)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
The 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-pentanol (115 mg, 0.307 mmol) obtained in Example 29, t-butyl N-methylsulfonylcarbamate (120 mg, 0.614 mmol), and triphenylphosphine (163 mg, 0.614 mmol) were dissolved in tetrahydrofuran (3 ml). At room temperature, diisopropyl azodicarboxylate (120 μl, 0.614 mmol) was added to the resulting solution. After stirring the resulting mixture for 18 hours at room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated, whereby the title compound (168 mg, 0.304 mmol, 99%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[C:49]([NH:52][CH2:53][CH2:54][NH2:55])(=[O:51])[CH3:50].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[C:49]([NH:52][CH2:53][CH2:54][NH:55][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)(=[O:51])[CH3:50]
Reactant: CC(=O)NCCN
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCNC(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and N-acetylethylenediamine (0.048 ml, 0.501 mmol). The mixture was stirred for 2 h at rt then to the mixture was added sodium triacetoxyborohydride (0.177 g, 0.835 mmol). The mixture was stirred at rt for 3 days then was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude material was used in the next step with no additional purification. LCMS: m/e 685.4 (M+H)+, 3.86 min (method 6).