Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[CH2:17]([O:10][C:9]1[C:2]([Br:1])=[C:3]([CH:6]=[CH:7][C:8]=1[O:11][CH3:12])[CH:4]=[O:5])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1c(OC)ccc(C=O)c1Br
Reaction time: 0.5 h

Procedure:
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (1.68 g) was dissolved in DMF (17 ml), and sodium hydride (0.209 g) was added thereto under ice-cooling, followed by stirring for 30 minutes. Allyl bromide (0.944 ml) was added to the mixture, followed by stirring at 60° C. for one hour. After being allowed to stand for cooling, water was added to the mixture and the precipitated solid was collected by filtration. The obtained crude crystals were recrystallized from isopropanol to give Compound IIe-a (1.30 g, 66%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])=[O:3].[CH3:19][C:20]([CH3:22])=O.N1CCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:18][C:20]([CH3:22])([CH3:19])[CH2:1][C:2]2=[O:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: CC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.8 %

Procedure:
A mixture of 25.0 g (0.103 mole) 2-hydroxy-5-benzyloxyacetophenone, 8 mL (6.0 g, 0.130 mole) acetone and 4 mL (3.7 g, 0.052 mole) pyrrolidine in 100 mL toluene was stirred at room temperature for 4 hours, then refluxed over a Dean-Stark trap for 3 hours. An additional 8 mL (6.0 g, 0.130 mole) acetone and 4 mL (3.7 g, 0.052 mole) pyrrolidine was added and the mixture refluxed for 18 hours. The mixture was concentrated, poured into water, basified to pH 8 with ammonium hydroxide, then extracted with ether. The ether extract was washed successively with 1N KOH, 1N HCl, water and brine, then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes afforded a solid. Recrystallization from ethyl acetate in hexanes afforded a solid. Recrystallization from ethyl acetate in hexanes yielded the title product as a solid 13.6 g (47%), mp 105°-107° C. NMR (CDCl3): δ1.4 (s, 6H); 2.7 (s, 2H); 5.1 (s, 2H).
Reaction SMILES: [C:1]12([CH:7]3[CH2:8][CH2:9][CH:4]1[CH:5]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH:6]13)[CH2:3][CH2:2]2.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C@@H:6]2[C@H:7]3[C:1]4([CH2:3][CH2:2]4)[C@H:4]([CH2:9][CH2:8]3)[C@@H:5]2[C:13]([OH:12])=[O:14])=[O:11])=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)C2C1C1CCC2C12CC2
Reactant: Nc1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H]1[C@H](C(=O)Nc2ccc(Br)cc2)[C@@H]2CC[C@H]1C21CC1

Procedure:
Following General Procedure A, Compound 2 (0.090 g, 0.47 mmol) and 4-bromoaniline (0.080 g, 0.47 mmol) in chloroform (3.0 mL) were converted into the title compound, which was isolated as a white solid.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: NCc1cccc(Cl)c1
Product: CCCCCCCCC#Cc1ccc(CNCc2cccc(Cl)c2)cc1
Yield: 60 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-dec-1-ynylbenzaldehyde and 3-chlorobenzylamine gave the title compound as a colorless oil (60%). 1H NMR (CDCl3, 300 MHz) δ 7.37-7.19 (m, 8H), 3.75 (s, 2H), 3.74 (s, 2H), 2.37 (t, J=7.2 Hz, 2H), 1.64-1.52 (m, 2H), 1.48-1.37 (m, 2H), 1.36-1.19 (m, 8H), 0.91-0.81 (m, 3H). M+(LC/MS(ESI)): 368.4. HPLC (Condition A), Rt: 4.60 min (HPLC purity: 84.1%).
Reaction SMILES: [NH:1]=[C:2]=[NH:3].C(OC(NC(NC(OC(C)(C)C)=O)=S)=O)(C)(C)C.[NH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[CH3:29].C(O)C(N)(CO)CO.C(O)(C(F)(F)F)=O>ClCCCl.ClCCl>[CH3:28][C:25]1[C:24]([CH3:29])=[C:23]([NH:22][C:2]([NH2:3])=[NH:1])[O:27][N:26]=1
Reactant: N=C=N
Reactant: Cc1noc(N)c1C
Agent: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1noc(NC(=N)N)c1C
Temperature: 50 °C
Reaction time: 36 h

Procedure:
To PS-carbodiimide resin (Argonaut Technologies) (1.069 g, 1.71 mmol, 1.6 mmol/g) placed in a 20 mL vial was added anhydrous 1,2-dichloroethane (6.0 mL), N,N′-bis(tert-butoxycarbonyl)thiourea (235 mg, 0.85 mmol) in anhydrous 1,2-dichloroethane (2.0 mL), and 5-amino-3,4-dimethylisoxazole (63.9 mg, 0.57 mmol) solution or dispersion in anhydrous 1,2-dichloroethane (1.0 mL). The reaction mixture was shaken at 50° C. until the reaction completed, typically for 36 hours. The reaction mixture was brought to room temperature and PS-trisamine (317 mg, 1.14 mmol, 3.6 mmol/g) was added. The reaction mixture was shaken at room temperature for 24 hours. The resin was removed by filtration and washed with 1,2-dichloroethane (3.0 mL) and methanol (3.0 mL). The combined organic layers were dried in a Genevac at 40° C. The resultant crude reaction mixture was mixed with TFA in dichloromethane (25% vol., 5.0 mL) and shaken at room temperature for 6 hours followed by evaporation in Genevac 40° C. to give crude xxix-187 (152 mg, 99%).: MS m/z═155 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([F:10])=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:10])=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCc1cc(F)c(OC)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(F)c(O)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 28.5 %

Procedure:
Ethyl 3-(2,5-difluoro-4-methoxyphenyl)propanoate (1.45 g, 5.9 mmol) was dissolved in dichloromethane (50 mL), a 1 M solution of boron tribromide in dichloromethane (7 mL) was added thereto, and the mixture was stirred at 0° C. for 4 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (387 mg, yield 29%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Br:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:43][CH2:44][CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)=[C:37]([N+:40]([O-:42])=[O:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:26]=[CH:27][CH:28]=1.[Cl-].[NH4+]>O1CCCC1>[Br:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:43][CH2:44][CH2:45][CH2:46][OH:47])=[C:37]([N+:40]([O-:42])=[O:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.60 g tetrabutylammonium fluoride-trihydrate are added to 2.50 g of 4-[(3-bromophenyl)amino]-7-[3-(tert. butyldimethylsilyloxy)-propyloxy]-6-nitro-quinazoline in 25 ml of tetrahydrofuran. The reaction mixture is stirred for about 2 hours at ambient temperature. After the cleavage is complete, the reaction mixture is combined with 150 ml of a 2% ammonium chloride solution and cooled in the ice bath. A yellow precipitate is formed which is suction filtered and washed with water. The precipitate, while still damp, is dissolved in methylene chloride/methanol (6:4), dried over sodium sulphate and concentrated by evaporation. The yellow residue is stirred with a little petroleum ether and suction filtered, washed with petroleum ether and dried in vacuo. Yield: 1.29 g (66% of theory) Rf value: 0.63 (silica gel, methylene chloride/methanol=9:1) Mass spectrum (ESI*): m/z=417, 419 [M−H]−
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].[C:36](=[O:47])([O:41][CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])[O:37][CH:38](I)[CH3:39].C(OCC)(=O)C>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O:32][CH:38]([O:37][C:36]([O:41][CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])=[O:47])[CH3:39])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: CCC(C)COC(=O)OC(C)I
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCC(C)COC(=O)OC(C)OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](NC(=O)Cc3csc(N)n3)C(=O)N12
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
In 80 ml of dimethylacetamide is dissolved 5.6 g of potassium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylate, and the solution is cooled to -5° C. With stirring, 4.8 g of 1-iodoethyl 2-methylbutyl carbonate is added at one stroke and stirring is continued for 5 minutes. The reaction mixture is poured into a mixture of 300 ml of ethyl acetate and 200 ml of ice-water and the organic layer is separated. The aqueous layer is extracted with 200 ml of ethyl acetate and these organic layers are combined, water with three 150-ml portions of ice water and three 150-ml portions of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate. The solvent is then distilled off and isopropyl ether is added to the residue. The thus-obtained white powder is collected by filtration, washed with isopropyl ether and dried to give 2.1 g of the title compound.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:35][CH2:34][CH2:33][N:28]1[C:13]2=[N:14][CH:15]=[C:16]([O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]3)[CH:17]=[C:12]2[CH:11]=[C:10]1[C:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]1)=[O:9])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CCO[Si](C)(C)C(C)(C)C)CC1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]methanone (example 13), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane, to give the desired product as a light yellow solid (29%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].[I-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[CH3:12][C:5]1[N:4]([CH2:3][CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)c2ccccc2C1=O
Reaction time: 16 h

Procedure:
A mixture of 17.0 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole, 18.0 parts of potassium phthalimide, and 2.0 parts of potassium iodide in 240 parts of dimethylformamide is heated in a boiling water bath for 3 hours with stirring. Stirring is then continued for 16 hours at room temperature. The resulting brown mixture is diluted with 870 parts of toluene and the toluene solution is washed with several portions of water. The toluene solution is dried over sodium sulfate and the solvent is evaporated to leave a residue which is digested with cold alcohol. The alcohol solution is then cooled and the precipitate which forms is separated by filtration and recrystallized from ethanol to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]phthalimide melting at about 177° C. This compound has the following formula ##STR6##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:15][CH2:14]3)=[C:11]([C:16]([O:18]CC)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]3[CH2:14][CH2:15]3)=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnn(-c2ccc(Br)cc2)c1C1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylate (Intermediate# 31) (423 mg, 1.29 mmol) was dissolved in methanol (20 mL) and treated with 2M aqueous sodium hydroxide solution (3.23 mL, 6.46 mmol). The mixture was stirred at ambient temperature for 24 h and then the methanol was removed by evaporation under reduced pressure. The residue was dissolved in water (50 mL), acidified to pH4 with 2M HCl and extracted with EtOAc (3×25 mL). The combined extracts were washed with water and brine, dried (MgSO4) and evaporated to leave 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylic acid a white solid. (343 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[NH:7][C:8]([C:12]3[CH:13]=[C:14]([S:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:9]2)=[CH:4][C:3]=1[N+:33]([O-:35])=[O:34].[CH3:36]O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[NH:7][C:8]([C:12]3[CH:13]=[C:14]([S:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)(=[O:23])=[O:24])[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][CH2:20][CH2:21][CH3:36])=[N:9]2)=[CH:4][C:3]=1[N+:33]([O-:35])=[O:34]
Reactant: CO
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2cc(Cl)c([N+](=O)[O-])cc2c(=O)[nH]1
Product: CCCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2cc(Cl)c([N+](=O)[O-])cc2c(=O)[nH]1
Yield: 68 %

Procedure:
Prepared using the above method for preparing 1-[[3-(7-chloro-3,4-dihydro-6-nitro-4-oxo-2-quinazolinyl)-4-propoxyphenyl]sulfonyl]-4-methylpiperazine, starting with 2-(2-butoxyphenyl)-7-chloro-6-nitro-4(3H)-quinazoline. Yield: 68%; LRMS [MH+] 536.2; HPLC (YMC S5 ODS 4.6×50 mm column, 4 minute gradient-0% B to 100% B, 4 mL/min flow, solvent A: 10% MeOH-90% H2O-0.2% H3PO4, solvent B: 90% MeOH-10% H2O-0.2% H3PO4) retention time 3.71 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:63])[CH2:55][C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][CH:57]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:63])[CH2:55][C:56]2[CH:57]=[CH:58][C:59]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:60][CH:61]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(Br)cc2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CC(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg) and 4-[2-(4-bromo-phenyl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (132 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-{2-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester was obtained, and further PMB group and BOC group were removed according to the above Deprotection method 2, to obtain the desired compound (D-172) as a colorless powder (5 mg, 3%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[N:7][S@](C(C)(C)C)=O)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH3:20][Mg]Br>ClCCl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C@H:6]([NH2:7])[CH3:20])=[C:4]([C:16]([F:17])([F:18])[F:19])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)N=Cc1ccc(Cl)cc1C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)c1ccc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
To a stirred solution of the crude (S)-N-(4-chloro-2-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (26.8 g, 86.0 mmol) in dichloromethane (290 mL) at −48° C. was added a solution of methyl magnesium bromide (3.0 M in diethyl ether, 63.0 mL, 189.0 mmol) dropwise. The reaction was stirred below −40° C. for 18 h, and the reaction was slowly warmed to 0° C. and quenched with 50% saturated aqueous ammonium chloride solution (100 mL). The phases were separated, and the organic layer was washed with deionized water (50 mL). The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to afford the desired product (14.6 g, 44.5 mmol, 52%).
Reaction SMILES: C([O:5][C:6]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]2[C:7]=1[CH2:8][C:9]([CH3:19])([CH3:18])[C:10](=[O:17])[NH:11]2)C=CC>CN(C)C1C=CC=CC=1.CCCCCC>[OH:5][C:6]1[C:15]([CH:7]([CH3:8])[CH:6]=[CH2:15])=[CH:14][C:13]([CH3:16])=[C:12]2[C:7]=1[CH2:8][C:9]([CH3:18])([CH3:19])[C:10](=[O:17])[NH:11]2
Reactant: CC=CCOc1ccc(C)c2c1CC(C)(C)C(=O)N2
Solvent: CCCCCC
Solvent: CN(C)c1ccccc1
Product: C=CC(C)c1cc(C)c2c(c1O)CC(C)(C)C(=O)N2
Yield: 179.6 %

Procedure:
A solution of 5-(2-butenyloxy)-3,3,8-trimethyl-3,4-dihydrocarbostyril (1.9 g, 7.3 mmol) in N,N-dimethylaniline (5 ml) was stirred at 210° C. for 7 hours in the stream of argon gas. After spontaneous cooling, the reaction mixture was diluted with hexane, and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from ethyl acetate-hexane to obtain 1.7 g of the title compound as colorless needles (89.3%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]2[C:20]3[C:25]([CH:26]=[CH:27][C:12]1=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=O)(C)(C)C.OC1C=CC(N2C(=O)CC(=O)NC3C4CCCCC=4C=CC2=3)=CC=1.FC(F)(F)C(O)=O.BrC1C=C(S(OC2C=CC(N3C(=O)CC(=O)NC4C5CCCCC=5C=CC3=4)=CC=2)(=O)=O)C=CC=1>C(=O)([O-])O.[Na+].ClCCl>[NH2:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]2[C:20]3[C:25]([CH:26]=[CH:27][C:12]1=2)=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)CC(=O)Nc2c1ccc1ccccc21
Agent: O=C([O-])O
Agent: O=C1CC(=O)N(c2ccc(O)cc2)c2ccc3c(c2N1)CCCC3
Agent: O=C1CC(=O)N(c2ccc(OS(=O)(=O)c3cccc(Br)c3)cc2)c2ccc3c(c2N1)CCCC3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN1C(=O)CC(=O)Nc2c1ccc1ccccc21

Procedure:
5-[2-(tert-Butoxycarbonyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (10 mg, 0.027 mol) obtained in Example 72, (3) was treated with trifluoroacetic acid in the same manner as that of Example 72, (4) to give a solution of 5-(2-aminoethyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione in saturated aqueous sodium hydrogencarbonate and dichloromethane. This solution was added with 2-chlorobenzylsulfonyl chloride (7 mg, 0.03 mol) with stirring under ice cooling, and the mixture was stirred for 1 hour under ice cooling, and then at room temperature for 2 hours. This reaction mixture was added with water, and the dichloromethane layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate/hexane to obtain the title compound (7 mg, yield 56%) as pale brown crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]([F:35])([F:34])[S:18][C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=[CH:23][CH:24]=1.S(Cl)(Cl)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([N:25]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:18][C:17]([F:35])([F:16])[F:34])[CH:20]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)CNc1cccc(SC(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(SC(F)(F)F)c2)c1
Yield: 16.1 %

Procedure:
Using a procedure similar to that described in Example 17, but starting with 2-[(3-methylphenyl)ureido]acetic acid (2.08 g), tert-butyl 2-[(3-trifluoromethylthiophenyl)amino]acetate (3.07 g) and sulphinyl chloride (1.3 g), and after recrystallisation in diisopropyl ether, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-(3-trifluoromethylthiophenyl)acetamido}acetate (0.8 g), m.p. 112° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:16]([CH2:17][C:5]2=1)[CH2:15][CH2:14][CH2:13]3.ClC1C=CC2NC3CCN4C(C=3C=2C=1)CCC4.Br[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.C(N(CC)CC)C>CCO.CCOC(C)=O>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][N:7]2[C:8]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=3[C:11]3[CH:12]4[N:16]([CH2:17][CH2:5][C:6]2=3)[CH2:15][CH2:14][CH2:13]4)=[CH:39][CH:40]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: Clc1ccc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: Clc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(CCn2c3c(c4cc(Cl)ccc42)C2CCCN2CC3)cc1

Procedure:
A mixture of 7-chloro-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole and 10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (non-separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and 1-(2-bromoethyl)-4-fluorobenzene (577 mg, 2.84 mmol, 1.4 equiv) were heated at 95° C. with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6 mL of EtOH for 18 h. The mixture was brought to RT followed by dilution with EtOAc (40 mL), washed with water (2×10 mL), and once with brine, then dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography over 230-400-mesh silica gel using a gradient of MeOH in EtOAc (0 to 50%). The product was further purified by reverse phase HPLC.