Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cn1

Procedure:
Using the method of Example 81 and using 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.673 g, 3.53 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.2 g, 10.6 mmol), tetrakis(triphenylphosphine)palladium (0.408 g, 0.353 mmol), dimethoxyethane (16 mL) and sodium carbonate (2M, 6.2 mL) gives the title compound. Purify the crude material over silica gel (1/1 hexane in ethyl acetate to 1/3 hexane in ethyl acetate) to yield 0.873 g (61%) of the title compound: mass spectrum (m/z): 408(M+2).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[N:16]2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[CH3:22][C:17]1[C:18]([CH3:21])=[C:19]([CH3:20])[N:15]([CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[N:16]=1
Reactant: Cc1nn(C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c(C)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nn(C[C@H]2CC[C@H](N)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of trans-[4-(3,4,5-trimethyl-pyrazol-1-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (step 2)(215 mg, 0.669 mmol) in methanol (3 mL) at room temp is added a solution of 4M HCl in dioxane (3 mL). The mixture is stirred at room temp for 1 hour and then concentrated in vacuo. The resulting gum is dried under vacuum overnight to afford the title compound which is used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.16 (3H, br s), 4.10 (2H, d), 2.90 (1H, m), 2.29 (3H, s), 2.27 (3H, s), 2.01-1.90 (5H, m including 3H, s), 1.83 (1H, s), 1.54 (2H, m), 1.30 (2H, m), 1.12 (2H, m). (NMR shows contamination with side products and solvents.)
Reaction SMILES: [C:1]([C:3]1[C:4]([O:24]C)=[C:5]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]([F:16])=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]=1[CH3:9])#[N:2].O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([C:3]1[C:4]([OH:24])=[C:5]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:21])[CH3:22])[C:6]([F:16])=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]=1[CH3:9])#[N:2]
Reactant: COc1c(C#N)c(C)c(-c2ccccc2)c(F)c1NC(=O)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C#N)c(O)c(NC(=O)C(C)(C)C)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
N-(5-Cyano-2-fluoro-4-methoxy-6-methylbiphenyl-3-yl)-2,2-dimethylpropionamide (I-237) (200 mg, 0.59 mmol) was dissolved in dichloromethane (5 ml), and under nitrogen atmosphere at −78° C., 1 M borondichloromethane tribromide solution (1.76 ml, 1.76 mmol) was dropwise added. With stirring, the solution was heated up to 0° C., taking 3 hours. At the same temperature, water with ice was gradually dropwise added to it, followed by stirring for 5 minutes. Further, an aqueous saturated sodium hydrogencarbonate solution was added to the solution to make pH=7. The solution was extracted twice with dichloromethane. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=4:1) to obtain the entitled compound (125 mg, 65%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[C:25]([Cl:27])[C:12]([CH2:13][N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[C:11]([Cl:28])[CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[Cl:28][C:11]1[CH:10]=[C:9]([OH:8])[CH:26]=[C:25]([Cl:27])[C:12]=1[CH2:13][N:14]1[CH2:18][CH2:17][C:16]2([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[C:15]1=[O:24]
Reactant: O=C1N(Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCC12CCCCC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1N(Cc2c(Cl)cc(O)cc2Cl)CCC12CCCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Purge with N2 and H2 a mixture of 2-(4-benzyloxy-2,6-dichloro-benzyl)-2-aza-spiro[4.5]decan-1-one (1.18 g, 2.82 mmol) and 20% palladium (II) hydroxide on carbon (0.50 g) in ethyl acetate (100 mL) and stir under a balloon of H2 for 4 hours at room temperature. Add sodium sulfate to the mixture and filter through hyflo. Remove the solvent in vacuo and purify the crude product on silica isocratically with 9:1 chloroform:methyl t-butyl ether on silica gel to affort 0.72 g (78%) of the titled product. Rf=0.18 (9:1 chloroform:methyl t-butyl ether).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cl:14]N1C(=O)CCC1=O>CN(C)C=O>[OH:11][N:10]=[C:9]([Cl:14])[C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:13][CH:12]=1
Reactant: CC(C)Cc1ccc(C=NO)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(Cl)=NO)cc1
Yield: 515.3 %

Procedure:
To a solution of 4-isobutylbenzaldehyde oxime (1.0 g, 5.6 mmol) that was obtained in Example 9 (9e) in N,N-dimethylformamide (10 ml) was added N-chlorosuccinimide (0.15 g, 1.1 mmol) with stirring, and furthermore, a small amount of gaseous hydrochloric acid was bubbled into the resulting mixture under stirring, and then the resulting mixture was stirred at room temperature for 10 minutes. After repeating the series of the same procedures described above five times in total, the reaction mixture was poured into ice water (100 ml) and extracted with ether. The extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo to afford the title compound (1.2 g) in a yield of 100% as a yellow oily product.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([Cl:21])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1COCC(=O)N1Cc1ccccc1
Product: O=C(Cl)C1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To (RS)-4-benzyl-5-oxo-morpholine-3-carboxylic acid (2.0 g, 8.51 mmol) in MDC (40 ml) was slowly added oxalyl chloride (1.51 ml, 17.1 mmol). The mixture was stirred for 0.5 h at room temperature and then evaporated to give (RS)-4-benzyl-5-oxomorpholine-3-carbonyl chloride as a brown solid (1.99 g, 92%). Ammonia gas was bubbled steadily through a solution of (RS)-4-benzyl-5-oxomorpholine-3-carbonyl chloride (1.99 g, 7.79 mmol) in MDC (40 ml) at 0° C. for 0.5 h, and then the mixture allowed to warm to room temperature. The solid was collected by filtration, washed with MDC (30 ml) and dried in vacuo at 40° C. to give the title compound as a white solid (2.1 g, 99%). Mass spectrum (API+): Found 235 (MH30 ). C12H14N2O3 requires 234.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH2:23]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:28][CH2:29][NH2:30])[CH2:24][CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][CH2:29][CH2:28][N:27]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:8])=[C:4]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: CCCCN(CCN)CCCC
Reactant: O=C(O)c1ccc(Cl)cc1Nc1ccnc2cc(Cl)ccc12
Product: CCCCN(CCCC)CCNC(=O)c1ccc(Cl)cc1Nc1ccnc2cc(Cl)ccc12

Procedure:
4-Chloro-2-(7-chloro-4-quinolylamino)benzoic acid is converted to the acid chloride which is reacted with 2-(di-n-butylamino)ethylamine as in Example 1 to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6](=O)[CH3:7].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[N:9]=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:18][C:6]=1[CH3:7]
Reactant: COC(=O)CC(NC(=O)c1ccc(Br)cc1)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Cc1nc(-c2ccc(Br)cc2)oc1C
Temperature: 40 °C
Yield: 48.3 %

Procedure:
3-(4-Bromo-benzoylamino)-4-oxo-pentanoic acid methyl ester is dissolved in acetic anhydride (75 mL) and concentrated sulfuric acid is added in 500 uL portions five times over a four hour period. The reaction is monitored by HPLC. The reaction is then heated to 40° C. until the starting material is consumed. The reaction is then concentrated to dryness and purified by column chromatography. This procedure yielded (11.6 g, 37.4 mmol) 48.3% of the desired oxazole.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=2[O:11][C:12]([F:15])([F:14])[CH3:13])[CH2:3][CH2:2]1.[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:16][C:17]1[C:18]([O:10][C:7]2[CH:8]=[N:9][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:5]([O:11][C:12]([F:15])([F:14])[CH3:13])[CH:6]=2)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: CC(F)(F)Oc1cc(O)cnc1C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(OC(C)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A suspension of 6-cyclopropyl-5-(1,1-difluoroethoxy)pyridin-3-ol (Preparation 269, 155 mg, 0.72 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (179 mg, 0.72 mmol) and potassium carbonate (299 mg, 2.16 mmol) in dimethyl sulfoxide (3 mL) was stirred for 4 hours at room temperature. The reaction mixture was diluted with water (40 mL) then extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 5% diethyl ether in heptane to afford the title compound as a white solid (260 mg, 81%).
Reaction SMILES: [CH3:1][C:2](=O)[CH3:3].[NH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]2[N:14]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:15][C:16]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:8]=12.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:13][C:12]1[C:7]([CH2:6][NH:5][CH:2]([CH3:3])[CH3:1])=[C:8]2[C:16]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:15][N:14]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[C:9]2=[CH:10][CH:11]=1
Reactant: CC(C)=O
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4CN)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)NCc1c(Cl)ccc2c1C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)CC2
Reaction time: 8 h
Yield: 60.3 %

Procedure:
2-Propanone (12 mg, 0.20 mmol) was added to a solution of (R)-tert-butyl 4-(aminomethyl)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 0.041 mmol) in DCE (2 mL). The reaction was allowed to stir at room temperature for 15 minutes, at which point Na(OAc)3BH was added. The reaction was allowed to stir overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and concentrated. The residue was purified by column chromatography (15:1, DCM:MeOH) to give (R)-tert-butyl 5-chloro-4-((isopropylamino)methyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (13 mg, 58%) as an oil. LCMS (APCI+) m/z 526/528 [M+H]+; Rt=4.72 min. This material was taken up into DCM (2 mL), and 2N HCl in ether was added (1 mL). The reaction was allowed to stir for 1 hour, at which point it was concentrated to give (R)-N-((5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride salt (13 mg, 59%) as a solid. 1H NMR (D2O, 400 MHz) δ 8.52 (s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.51-4.38 (m, 4H), 4.15 (d, J=9.6 Hz, 1H), 3.71-3.5 (m, 5H), 3.16-2.96 (m, 5H), 2.46-2.18 (m, 3H), 2.06-2.00 (m, 1H), 1.89-1.74 (m, 2H), 1.34-1.32 (m, 6H). LCMS (APCI+) m/z 426/428 [M+H]+; Rt=2.38 min.
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].Cl.[CH2:15](NCC)C>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11]([CH2:15][O:9][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: CCNCC
Reactant: COc1cccc(C(=O)O)c1
Agent: C=O
Agent: Cl
Product: COc1ccc2c(c1)C(=O)OC2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
Formaldehyde 48% v/v (65 ml, 0.86 moles) under stirring, then 3-methoxy-benzoic acid (100 g, 0.66 moles) were added to concentrated HCl (1 l) and the mixture was heated at 100° C. by checking the development of gas for 30 minutes. The cooling of the mixture brought to the formation of a precipitate which was filtered and put aside, while the mixture was washed with water, then with 5% NaOH. The new precipitate was extracted twice with CH2Cl2, the extract was anhydrified, concentrated, joined to the previously filtered solid, and both were dissolved in CH2Cl2 and treated with diethylamine (120 ml, 1.15 moles). After 24 hours it was extracted with 10% HCl and the phases were separated with CH2Cl2. The organic phase was washed with 10% NaOH, decoloured with charcoal, anhydrified and concentrated. The residue was dissolved in CH2Cl2 and treated, under stirring, with 10% HCl for 30 minutes. The organic phase was washed with water, anhydrified and concentrated. The residue was dissolved in CH2Cl2 and treated with 10% NaOH under stirring for 30 minutes. The organic phase was washed with water, dried and concentrated to give a solid which was crystallised from aqueous CH3OH. The filtrate was dried at 50° C. on P2O5, then crystallised again from aqueous CH3OH to give 35.28 g of the title compound (yield: 32%).
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([S:24][CH3:25])=[N:18][C:19]=2[NH2:23])(=O)C1C=CC=CC=1>CN>[OH:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([S:24][CH3:25])=[N:18][C:19]=2[NH2:23]
Reactant: CSc1nc(N)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Agent: CN
Product: CSc1nc(N)c2ncn(COCCO)c2n1

Procedure:
A mixture of 2.20 g (6.12 mmol) of 9-(2-benzoyloxyethoxymethyl)-2-methylthioadenine and 100 ml of 40% aqueous methylamine was heated on a steam bath with occasional agitation for one hour. The solution was cooled and spin evaporated in vacuo. The resultant oil was leached with five 40 ml portions of hot ether to give a solid; yield, 1.31 g (84%), m.p. 174°-176°. Recrystallization from ethanol gave the analytical sample of 9-(2-hydroxyethoxymethyl)-2-methylthioadenine; λmax (ε × 10-3) (10% EtOH in solvent) pH 1-270 (16.7), 291 (sh) (11.9), H2O and pH 13-276 (15.2) nm; nmr (DMSO-d6), 2.49 (3H, S), 3.55 (4H, S), 4.65 (1H, br S), 5.55 (2H, S), 7.31 (2H, S), 8.15 (1H, S) δ.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:7]=2[C:6]=1[C:15](OC)=O.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][C:12]1[CH:11]=[CH:10][C:8]2[S:9][C:5]3[NH:4][C:3]4[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=4[N:1]=[C:15]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[C:6]=3[C:7]=2[CH:13]=1
Reactant: COC(=O)c1c(Nc2ccccc2N)sc2ccc(C)cc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: Cc1ccc2sc3c(c2c1)C(N1CCN(C)CC1)=Nc1ccccc1N3

Procedure:
In the same manner as in Example 1 and using methyl 2-(2-aminoanilino)-5-methylbenzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 2-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[Br:11]Br>C(Cl)(Cl)Cl.C(O)(=O)C.Br>[BrH:1].[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH2:9][Br:11])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cncc(Br)c1
Temperature: 25 °C

Procedure:
4 g (0.02 mol) of 5-bromo-3-acetyl-pyridine are dissolved in 50 ml of chloroform, 5 drops of glacial acetic acid/hydrobromic acid (35%) are added and the mixture is heated to boiling. To this boiling solution, 3.2 g (0.02 mol) of bromine in 30 ml of chloroform are added dropwise over a period of 5 hours with stirring. After cooling to ambient temperature the yellow solid product is suction filtered.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:26][CH2:25][CH2:24][C@H:14]2[C:15]([N:17]2[CH2:23][CH2:22][CH2:21][C@H:18]2[CH2:19][OH:20])=[O:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([CH2:10][C:11]([N:13]2[CH2:26][CH2:25][CH2:24][C@H:14]2[C:15]([N:17]2[CH2:23][CH2:22][CH2:21][C@H:18]2[CH:19]=[O:20])=[O:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C([C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21)N1CCC[C@H]1CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
0.53 g of 1-[1-(2-indenylacetyl)-L-prolyl]-L-prolinol prepared in Preparation Example 41 and 0.76 g of triethylamine were dissoved in 6 ml of dimethylsulfoxide. To the solution was added 1.19 g of sulfur trioxide-pyridine complex and the mixture was stirred for one hour at room temperature. The reaction mixture to which 10 ml of ice-water was added was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, water, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to produce 0.29 g of 1-[1-(2-indenylacetyl)-L-prolyl]-L-prolinal as a colorless oil (yield: 55%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH2:21][CH:22]3[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]3)[C:16]([CH3:30])=[CH:15][N:14]=2)(=O)=O)=CC=1.[SH:31][C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:29][C:25]1([CH3:28])[O:24][CH2:23][CH:22]([CH2:21][O:20][C:17]2[C:16]([CH3:30])=[CH:15][N:14]=[C:13]([CH2:12][S:31][C:32]3[NH:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[N:33]=3)[C:18]=2[CH3:19])[CH2:27][O:26]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCc2ncc(C)c(OCC3COC(C)(C)OC3)c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a mixture of (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl 4-methylbenzenesulfonate (457 mg, 1.05 mmol), 2-mercaptobenzimidazole (158 mg, 1.05 mmol), and tetrahydrofuran (5 ml), triethylamine (0.293 ml, 2.1 mmol) was added and the mixture was stirred at room temperature for 15 hours and 30 minutes. To the reaction mixture, toluene and a diluted aqueous sodium hydroxide solution were added and the organic layer was taken out. The aqueous layer was extracted again with toluene. The organic layers were combined and washed with a saturated saline solution, dried over sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in n-heptane/ethyl acetate (1/1) and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (419 mg, 96.5%) as a colorless viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of t-butyl 2-(3-nitrophenyl)-2-methyl-propionate (3.6 g) in ethanol (100 mL), 10% palladium carbon (400 mg) was added, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane=1:5), whereby tert-butyl 2-(3-aminophenyl)-2-methylpropionate (2.87 g) was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[F:18])#[N:11].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:18][C:17]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]=[O:9])[N:7]=2)=[CH:13][C:12]=1[C:10]#[N:11]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: O=Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cccc(C=O)n2)ccc1F
Temperature: 80 °C

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 3-cyano-4-fluorophenylboronic acid (0.887 g, 5.38 mmol), 2M cesium carbonate (8.1 mL, 16.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled, concentrated and partitioned between water and CH2Cl2. The organic layer was concentrated and purified by chromatography (30% ethyl acetate:hexanes) to provide 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile. To a solution of 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile (0.500 g, 2.21 mmol) in methanol (20 mL) at ambient temperature was added D-valinol (0.25 mL, 2.2 mmol), acetic acid (0.50 mL, 8.8 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated, and the residue partitioned between ether and 1M NaOH. The organic layer was concentrated and purified by chromatography to provide 362 mg (52%) of the title compound. MS (DCI+) m/z 314 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.62 (dd, J=6.3, 2.3 Hz, 1H), 8.52 (ddd, J=8.9, 5.3, 2.4 Hz, 1H), 7.97-7.84 (m, 2H), 7.66 (t, J=9.0 Hz, 1H), 7.49 (dd, J=7.4, 1.1 Hz, 1H), 3.92 (d, J=3.6 Hz, 2H), 3.52-3.43 (m, 1H), 2.40-2.22 (m, 2H), 1.93-1.76 (m, 1H), 0.89 (dd, J=9.5, 6.9 Hz, 6H).