Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1.O>CN(C=O)C>[O:1]([C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCC[C@H](O)CC(=O)OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCC[C@@H](CC(=O)OC)O[Si](C)(C)C(C)(C)C
Reaction time: 17 h

Procedure:
12.9 g of methyl (S)-3-hydroxytetradecanoate are dissolved in 50 ml of DMF under argon 9.0 g of t-butyldimethylchlorosilane are added thereto, 8.5 g of imidazole are then added portionwise and the mixture is left to stir for 17 hours. The reaction mixture is poured into 300 ml of water and extracted three times with 50 ml of diethyl ether. The combined organic phases are dried, filtered and evaporated. By distillation at 140°-145° C./0.07 mm there is obtained methyl (S)-3-(t-butyldimethylsiloxy)tetradecanoate as a colourless oil.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:56][CH2:57][CH3:58])=[CH:46][C:47]=3[O:49][CH2:50][C@H:51]3[CH2:55][CH2:54][CH2:53][NH:52]3)[N:42]=[CH:41][N:40]=2)[CH:34]=[CH:35][C:36]=1[F:37].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CS(C)=O>[Cl:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[F:37])[NH:38][C:39]1[C:48]2[C:43](=[CH:44][C:45]([O:56][CH2:57][CH3:58])=[CH:46][C:47]=2[O:49][CH2:50][C@H:51]2[CH2:55][CH2:54][CH2:53][N:52]2[C:1](=[O:5])[CH2:2][OH:3])[N:42]=[CH:41][N:40]=1
Reactant: CCOc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reaction time: 16 h
Yield: 39 %

Procedure:
Glycolic acid (22 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 110 mg) were added sequentially, each in one portion, to a stirred solution of N-(3-chloro-4-fluorophenyl)-7-ethoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (81 mg) and N,N-diisopropylethylamine (68 μl) in DCM (2.5 ml) at room temperature. The reaction mixture was stirred for 16 hours and then concentrated in vacuo to leave a brown residue. The residue was taken up in a 7:2:1 mixture of DMSO:acetonitrile:water, filtered and then purified by reverse phase HPLC. The fractions containing the required product were combined, basified by the addition of potassium carbonate and then extracted with DCM. The organic layer was dried (MgSO4) and then concentrated in vacuo to give the title compound as a white solid (36 mg, 39%); NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.50-3.40 (m, 2H), 2.10-1.85 (m, 4H), 1.40 (t, 3H); Mass spectrum MH+ 475.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-:18][Si](C)(C)C.[Li+].Cl.C(=O)(O)[O-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[ClH:15].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCc2ccccc2)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccccc2)cn1
Temperature: 65 °C
Yield: 98.9 %

Procedure:
To a nitrogen purged solution of mL Pd2(dba)3 (10.19 g, 11.12 mmol), 5-(benzyloxy)-2-chloropyridine (48.87 g, 222.5 mmol), (2-diphenyl)dicyclohexyl-phosphine (7.797 g, 22.25 mmol) and THF (700 mL) was added lithium hexamethyl disilazide (267.0 mL mL, 267.0 mmol). The reaction was heated at 65° C. overnight and cooled to ambient temperature. LM HCl (250 mL) was added and stirred for minutes. Saturated sodium bicarbonate was added slowly. The mixture was extracted several times with CH2Cl2, dried, filtered, and concentrated to give the title compound (52.1 g, 98.94% yield).
Reaction SMILES: [CH3:1][N:2]([S:28]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)(=[O:30])=[O:29])[C:3]1[CH:4]=[C:5]([O:23][C:24]([F:27])([F:26])[F:25])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](OCC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.O1CCCC1.CO.[BH4-].[Li+]>O>[OH:19][CH2:18][CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:4][C:3]=3[N:2]([CH3:1])[S:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)(=[O:30])=[O:29])=[N:16][CH2:15]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a mixture of ethyl {2-[7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (350 mg), tetrahydrofuran (15 mL) and methanol (3 mL) was added lithium borohydride (30 mg), and the mixture was stirred at room temperature for 2 hr. Lithium borohydride (15 mg) was added to the mixture, and the mixture was further stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:1-1:4, volume ratio) to give the title compound (110 mg, yield 34%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 152-153° C.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.C(N(CC)C(C)C)(C)C.[CH2:40]([NH:47][CH2:48][C:49]#[C:50][CH3:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([N:47]([CH2:48][C:49]#[C:50][CH3:51])[C:8](/[N:9]=[C:10]1\[S:11][C:12]([CH3:29])=[CH:13][N:14]\1[C:15]1[CH:28]=[CH:27][C:18]2[O:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[O:22][C:17]=2[CH:16]=1)=[O:30])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CC#CCNCc1ccccc1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCN(Cc1ccccc1)C(=O)/N=c1\sc(C)cn1-c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide (Example 81A, 0.75 mL of 0.14 M in acetonitrile, 58 mg, 0.1 mmol) was added to a 20 mL vial followed by N,N-diisopropylethylamine (0.75 mL of 0.14 M in acetonitrile, 18 mg, 0.13 mmol). Subsequently, N-benzylbut-2-yn-1-amine (0.57 mL of 0.2 M in acetonitrile, 0.11 mmol) was added. The resulting mixture was shaken at room temperature overnight. It was then concentrated in vacuo and the residue was taken up in 1:1 MeOH/DMSO and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method). 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.75 (3H) 2.24 (3H) 4.05 (2H) 4.55 (2H) 7.01-7.10 (1H) 7.17-7.29 (4H) 7.29-7.35 (1H) 7.40-7.54 (1H) 7.58-7.63 (1H) 7.66-7.94 (1H); MS (ESI+) m/z 506 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=O)C.O.[NH2:21][NH2:22].C(O)CCC>O>[F:17][C:14]1[CH:13]=[C:12]2[C:11]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:21][NH:22]2)=[CH:16][CH:15]=1
Reactant: NN
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Solvent: CCCCO
Solvent: O
Product: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Yield: 20.1 %

Procedure:
A solution of 20.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)-piperidine, 60 ml of hydrazine hydrate and 150 ml of n-butanol was refluxed for 48 hrs. The reaction was poured into 11 of water, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. Recrystallization of the residue from isopropanol-water and then from isopropanol yielded 3.3 g (20.1%) of product, mp 214°-216° C.
Reaction SMILES: C(O)(C)(C)C.[CH3:6][O:7][CH2:8][CH:9]([NH2:12])[CH2:10][CH3:11].Cl[C:14]1[C:15]([N+:25]([O-:27])=[O:26])=[C:16]([CH3:24])[C:17]([CH3:23])=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>C(Cl)(Cl)Cl>[CH3:6][O:7][CH2:8][CH:9]([NH:12][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[C:16]([CH3:24])[C:15]=1[N+:25]([O-:27])=[O:26])[CH2:10][CH3:11]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Reactant: CCC(N)COC
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: CCC(COC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
(-)-2-Amino-1-butanol [100 grams, prepared according to D. Pitre and E. B. Grabitz, Chimia 23, 399 (1969)] was added in a dropwise manner to a stirred solution of tert-butanol (800 ml.) containing potassium tert-butoxide (126 grams). After warming this mixture to 70° C. to 80° C. for 2 hours, methyl iodide (175 grams) was added slowly at temperatures below 50° C. The suspension which formed was then stirred with refluxing overnight. After removal of the solid phase by filtration, the filtrate was fractionally distilled to give (-)-1-(methoxymethyl)propylamine contaminated with traces of tert-butanol, boiling point 125° C. to 147° C./760 mm. This amine was then allowed to react with 4-chloro-3,5-di-nitro-o-xylene, as described earlier, to give the desired product as a bright yellow solid with melting point 42.5° to 44° C., [α]D25° =137.6° (c 2.504, chloroform).
Reaction SMILES: [NH2:1][C:2](=[S:15])[CH2:3][N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]([CH3:14])=[N:5]1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=O>>[CH3:14][C:6]1[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([CH2:3][C:2]2[S:15][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[N:1]=2)[N:5]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cc(C)nn1CC(N)=S
Product: CCOC(=O)c1cc(C)nn1Cc1nc(-c2cccc(C(F)(F)F)c2)cs1
Yield: 94.6 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (227 mg, 1.00 mmol) obtained in Example 7b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (283 mg, 1.00 mmol), the title compound (374 mg, 94%) was obtained as a colorless oil.
Reaction SMILES: C(OC1C=C(C=CC=1)CN(C1C=CC(C#N)=CC=1)N1C=NN=C1)C1C=CC=CC=1.[H-].[Na+].[C:32]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][N:41]2[CH:45]=[N:44][N:43]=[CH:42]2)=[CH:36][CH:35]=1)#[N:33].[C:46]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[F:63])[CH2:58]Br)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.CCOC(C)=O>[C:46]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[F:63])[CH2:58][N:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][CH:38]=1)[N:41]1[CH:42]=[N:43][N:44]=[CH:45]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: N#Cc1ccc(N(Cc2cccc(OCc3ccccc3)c2)n2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Yield: 56.1 %

Procedure:
The title compound was prepared by adapting the method for 4-[(3-benzyloxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole using NaH (60% dispersion in oil, 0.20 g, 5.0 mmol), 4-[(4-cyanophenyl)amino]-4H-[1,2,4]triazole (0.926 g, 5.0 mmol) and 3-benzoyloxy-4-fluorobenzyl bromide (1.55 g, 5.0 mmol) in anhydrous DMF (20 mL) to give 4-[(3-benzoyloxy-4-fluorobenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole as a white solid (1.16 g, 56%) after chromatography [SiO2, EtOAc (100%)]; δH (400 MHz, CDCl3) 4.91 (s, 2H), 6.67 (AA′BB′, 2H), 7.07 (ddd, J=8.2, 4.3, 2.0, 1H), 7.18 (dd, J=9.4, 8.6, 1H), 7.24 (dd, J=7.0, 2.3, 1H), 7.49-7.56 (m, 2H), 7.58 (AA′BB′, 2H), 7.62-7.70 (m, 1H), 8.15-8.20 (m, 2H), 8.21 (s, 2H); LRMS (FAB+) m/z (rel. intensity) 414.2 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[N:32]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:35]4[CH2:36][CH2:37][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH2:34]4)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)cc(Cl)c2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)ccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-(5-formyl-1-benzofuran-2-yl)nicotinonitrile (200 mg, 0.47 mmol) in THF (5 mL) and EtOH (2 mL) was added tert-butyl 1-piperazinecarboxylate (262 mg, 1.41 mmol) and acetic acid (54 mg, 0.9 mmol) and the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (398 mg, 1.88 mmol) was added to the reaction mixture and the resulting solution was stirred at room temperature overnight. After the reaction was concentrated, ethyl acetate was added; and the organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane) to give tert-butyl 4-[(2-{4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-cyanopyridin-3-yl}-1-benzofuran-5-yl)methyl]piperazine-1-carboxylate as a yellow solid (203 mg, 73%). HPLC retention time: 9.5 min.(g); MS: 597.4 (M+H); and HRMS: 597.2378.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[C:14]([F:31])[C:13]=1[F:32])[CH2:8][CH2:9][CH3:10].C(OCC)(=[O:35])C.N>C1COCC1>[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][CH:21]([C:24]3([OH:35])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[C:14]([F:31])[C:13]=1[F:32])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(C2CCC(C3CCC(=O)CC3)CC2)c(F)c1F
Reactant: CCOC(C)=O
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCOc1ccc(C2CCC(C3(O)CCCCC3)CC2)c(F)c1F
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (0.62 g) was suspended in THF (200 ml). 4′-(4-Butoxy-2,3-difluorophenyl)-bicyclohexyl-4-one (s-7) (10.0 g) was added dropwise to the suspension in the temperature range of −20° C. to −10° C., and the stirring was continued in this temperature range for 2 hours. After the completion of the reaction had been confirmed by means of GC analysis, ethyl acetate and then a saturated aqueous solution of ammonia were added to the reaction mixture under ice-cooling and deposits were removed by filtration through Celite. The filtrate was extracted with ethyl acetate. The combined organic phase was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by recrystallization from heptane to give 4′-(4-butoxy-2,3-difluorophenyl)-bicyclohexanol (s-22) (8.8 g). The yield based on the compound (s-7) was 87.5%.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>CCO.C(O)(=O)C.O.[Fe]>[NH2:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([Br:1])[C:3]=3[CH3:23])[O:8][C:7](=[O:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc2oc(=O)cc(-c3cccc([N+](=O)[O-])c3)c2c(C)c1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2oc(=O)cc(-c3cccc(N)c3)c2c(C)c1Br
Temperature: 110 °C
Yield: 17.2 %

Procedure:
To a stirred solution of 6-bromo-5,7-dimethyl-4-(3-nitrophenyl)-2H-chromen-2-one (6-3) (15.41 g, 41.18 mmol) in EtOH (100 mL) and acetic acid (40 mL) was added iron (11.50 g, 205.9 mmol) at room temperature. The mixture was heated at 110° C. for 2 h. The reaction mixture was cooled at room temperature and filtrated. To the filtrate was added EtOAc and Na2CO3 (37 g, 0.35 mol) in water (200 mL). After being stirred at room temperature, the mixture was filtrated. Then the filtrated was diluted with EtOAc and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, and concentrated. To the concentrate added CH2Cl2-MeOH (1:9), and the precipitated solid was collected by filtration. The solid was washed with CH2Cl2-MeOH (1:9) and purified by silica gel column chromatography (hexanes:EtOAc=2:1˜1:1) to give the title compound 6-4 (2.44 g, 17% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Li+]>CO.C1COCC1.O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]([O:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:25][CH:26]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(NC/C=C/c2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(NC/C=C/c2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O

Procedure:
The title compound was synthesized by hydrolyzing ethyl 2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]-phenyl}propionate obtained in Example 12 (4 g, 8.95 mmol) in methanol-THF-water (45:4:9, 58 mL) using lithium hydroxide (563 mg, 13.42 mmol) following the same procedure as described in the Example 14 (1.2 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=[O:16])[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[N:22]1([CH2:28][CH2:29]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:9]3[C:15](=[O:16])[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: ClCCN1CCCCC1
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Product: CN1C(=O)c2c(c3ccc(Cl)cc3n2CCN2CCCCC2)Oc2ccccc21

Procedure:
In the same way as described in example 19, 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepin-6(5H)-one was alkylated with piperidinoethyl chloride. The crude solid base was recrystallized from acetonitrile, mp. 160°-2°.
Reaction SMILES: CC1C2C(=O)CCCC=2N=CN=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[NH2:22][C:23]1[N:32]=[C:31]([CH3:33])[C:30]2[C:29](=[O:34])[CH2:28][CH:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3C3C=CC=CC=3)[CH2:26][C:25]=2[N:24]=1>>[NH2:22][C:23]1[N:32]=[C:31]([CH3:33])[C:30]2[C:29](=[O:34])[CH2:28][CH:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)[CH2:26][C:25]=2[N:24]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccccc1)C2
Agent: Cc1ncnc2c1C(=O)CCC2
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccncc1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-bromo-phenyl), 4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/i) and pyridin-4-yl-boronic acid, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 5/a stage 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[CH:13]=3)=[N:10][N:9]([C:22](=[O:25])[CH2:23][CH3:24])[CH:8]([CH3:26])[CH2:7][C:6]=2[CH:27]=1.O.NN>CO.ClCCl.[Ni]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:5]3[CH:4]=[C:3]([Cl:28])[C:2]([Cl:1])=[CH:27][C:6]=3[CH2:7][CH:8]([CH3:26])[N:9]([C:22](=[O:25])[CH2:23][CH3:24])[N:10]=2)=[CH:13][C:14]=1[CH3:21]
Reactant: CCC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)c(Cl)cc2CC1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)c(Cl)cc2CC1C
Reaction time: 0.75 h
Yield: 51 %

Procedure:
4.2 g (10 mmoles) of (±)-4,5-dihydro-7,8-dichloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3-propionyl-3H-2,3-benzodiazepine are dissolved in a mixture of 40 cm3 of methanol and 40 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from acetonitrile. Thus, 1.99 g (56%) of the title compound are obtained in the form of pale yellow solids melting at 106–108° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[CH2:6][CH:5]2[NH:15][CH:4]12)[CH3:2].[BrH:18].C(OCC)(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(O)C>[BrH:18].[NH2:15][CH:4]1[C:3]([CH2:16][CH3:17])([CH2:1][CH3:2])[C:12]2[CH:11]=[C:10]([OH:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]1[Br:18]
Reactant: CCC1(CC)c2cc(OC)ccc2CC2NC21
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC1(CC)c2cc(O)ccc2CC(Br)C1N
Temperature: 100 °C
Yield: 62.5 %

Procedure:
To a flask was added 7,7-diethyl-5-methoxy-1a,2,7,7a-tetrahydro-1H-1-aza-cyclopropa[b]naphthalene (268 g, 1.16 mol) and hydrogen bromide (1.97 L, 17.38 mol), followed by tetra-N-butylammonium bromide (38 g, 0.12 mol). The reaction mixture was heated at 100° C. overnight with stirring, cooled to room temperature and then poured into stirred ethyl acetate (2.5 L). The product was isolated by filtration, the filter cake was washed with ethyl acetate (2×200 mL) and dried to yield crude product (370 g) as a purplish solid. The crude product was suspended in ethanol (1.50 L) then heated at 80° C. for 30 min. The resulting slurry was cooled to room temperature over 1 h, and filtered. The flask and filter cake with were washed with ethanol (2×100 mL) and then with ethyl acetate (100 mL) and dried overnight to yield the title compound (275 g, ˜96% purity).