Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH:25](Br)([CH3:27])[CH3:26]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Reactant: CC(C)Br
Product: CCCCN1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1

Procedure:
The title compound was synthesized by using N-[2-(4-n-butyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 10 and isopropyl bromide according to the same process as in Example 12.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[CH:13][N+:14]([O-])=O)[CH2:11][CH2:10][CH:9]1[C:17]([O:19]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].CO>[CH2:1]([N:8]1[CH:12]2[CH2:11][CH2:10][CH:9]1[C:17](=[O:19])[NH:14][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCC(=C[N+](=O)[O-])N1Cc1ccccc1
Agent: [Pt]
Solvent: CO
Product: O=C1NCC2CCC1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
Methyl 1-benzyl-5-(nitromethylene)-2-pyrrolidinecarboxylate (9.92 g, 35.9 mmol) and 5% platinum on activated carbon (11.25 g) were combined in methanol (100 mL) and shaken for 56 hours at ambient temperature under a hydrogen atmosphere (60 psi). The moisture was filtered and the filtrate concentrated to provide the title compound. MS (DCI/NH3) m/z: 217 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12.[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[S:52](Cl)(=[O:54])=[O:53]>>[CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12)[S:52]([C:48]1[S:47][CH:51]=[CH:50][CH:49]=1)(=[O:54])=[O:53]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Product: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2cccs2)c(OC)c1
Yield: 30.5 %

Procedure:
Thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is prepared as described in Example 211b starting with 0.80 g of (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine and 0.114 g of 2-thiophenesulfonyl chloride instead of the 4-(trifluoromethoxy)benzenesulfonyl chloride used in Example 211b. 0.150 g of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[N:4]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:3]=1.[OH-].[K+:24]>C(O)C>[Cl:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([O-:13])=[O:12])[CH:10]=[C:5]2[N:4]([CH2:14][C:15]2[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=2[Cl:21])[N:3]=1.[K+:24]
Reactant: O=C(O)c1cnc2c(Cl)nn(Cc3c(Cl)cccc3Cl)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1cnc2c(Cl)nn(Cc3c(Cl)cccc3Cl)c2c1

Procedure:
To a solution of the compound [172](27 mg) in ethanol (2.0 mL) was added an aqueous solution of 1N-potassium hydroxide (74 μL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (28 mg) as a white solid.
Reaction SMILES: O[C@@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@H:4]2[CH2:3]1.C(Br)(Br)(Br)[Br:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C>[Br:24][C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@H:4]2[CH2:3]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@H](O)CN12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@@H](Br)CN12
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To a solution of (6S,7aR)-6-Hydroxy-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 33, step f) (900 mg, 2.848 mmol) in acetonitrile (10 ml) was added CBr4 (2.24 g, 8.544 mmol) at room temperature and stirred for 10 min. PPh3 (2.83 g, 8.544 mmol) was added and left stirring for 12 h at room temperature. The mixture was concentrated and the residue was purified through column chromatography over silica (elution with 10% ethyl acetate in hexane) to yield 850 mg (79%) of the title compound as white solid. LC-MS: 381.1 [M+1]+.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[O:27]=[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([NH-:39])=[CH:35][CH:34]=2)[NH:29]1.CCN=C=NCCCN(C)C>CC#N>[C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6](=[O:7])[NH:39][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[NH:29][C:28](=[O:27])[O:32][N:31]=2)=[CH:38][CH:37]=1)(=[O:3])[CH3:2]
Reactant: [NH-]c1ccc(-c2noc(=O)[nH]2)cc1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CC(=O)O[C@@H](C(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.1 %

Procedure:
To a solution of compound 70-4 (40 mg) in CH3CN (1 mL) at 0° C. was added 4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl amide (21 mg) followed by EDCI (25 mg). The reaction mixture was warmed to rt and stirred for 72 h. The mixture was concentrated under reduced pressure and placed under high vacuum. The crude material was purified by reverse phase HPLC using a C18 column and a gradient of (89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H) to afford compound 70-5 (30 mg) as a white solid. LC-MS: M+H=522.
Reaction SMILES: C1(SC)C=CC=CC=1.C([O:16][C:17]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][S:48][CH2:47][CH2:46]2)=[CH:38][C:18]=1[C:19]([NH:21][C:22]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:20])C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:16][C:17]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][N:45]2[CH2:46][CH2:47][S:48][CH2:49][CH2:50]2)=[CH:38][C:18]=1[C:19]([NH:21][C:22]1[CH:31]=[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:20]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCSCC2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCSCC2)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
Thioanisole (3.2 mL) and trifluoroacetic acid (10 mL) were added to the obtained methyl 2-(2-(benzyloxy)-5-(2-(thiomorpholin-4-yl)ethoxy)benzamido)-4-phenylbenzoate (0.80 g), followed by stirring at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-0% hexane/ethyl acetate to 100-95% chloroform/methanol] to obtain 0.54 g of methyl 2-(2-hydroxy-5-(2-(thiomorpholin-4-yl)ethoxy)benzamido)-4-phenylbenzoate as a brown solid.
Reaction SMILES: [Na].[Na].[Na].S(C1C=C(P(C2C=CC=C(S(O)(=O)=O)C=2)C2C=CC=C(S(O)(=O)=O)C=2)C=CC=1)(O)(=O)=O.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[C:38]([CH3:45])[CH:37]=1.Br[C:47]1[CH:48]=[CH:49][C:50]([CH2:65][CH3:66])=[C:51]([CH:53]2[C:58](=[O:59])[C:57]([CH3:61])([CH3:60])[O:56][C:55]([CH3:63])([CH3:62])[C:54]2=[O:64])[CH:52]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:47]2[CH:48]=[CH:49][C:50]([CH2:65][CH3:66])=[C:51]([CH:53]3[C:58](=[O:59])[C:57]([CH3:61])([CH3:60])[O:56][C:55]([CH3:63])([CH3:62])[C:54]3=[O:64])[CH:52]=2)=[C:38]([CH3:45])[CH:37]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1ccc(-c2ccc(Cl)cc2C)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 59.1 %

Procedure:
To a microwave vial is added palladium(II) acetate (3.3 mg, 0.015 mmol), tris(3-sulfophenyl)phosphine trisodium salt (22 mg, 0.038 mmol), 4-chloro-2-methylphenyl boronic acid (0.152 g, 0.89 mmol), 4-(5-bromo-2-ethyl-phenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.208 g, 0.59 mmol) and potassium phosphate (0.625 g, 2.95 mmol). A degassed mixed solution of acetonitrile/distilled water (1.5 ml, 1:1 ratio) is next added (washing-down any solids from the slides of the vial), followed by stirring for 5 minutes and flushing with argon. This mixture is then heated at 160° C. under microwave irradiation for 15 minutes. After cooling to room temperature the reaction mixture is diluted with ethyl acetate (3 ml) and acidified to pH2 with dilute aqueous hydrochloric acid. The organic phase is separated and the aqueous phase is further extracted with ethyl acetate (2×3 ml). All organics are then combined, filtered through a silica plug and evaporated to give a crude product which is dissolved in N,N-dimethylformamide (2.5 ml) and purified by preparative reverse phase HPLC to afford 4-(4′-chloro-4-ethyl-2′-methylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.139 g) as a white powder.
Reaction SMILES: FC1C=CC([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=2)=[O:10])=CC=1O.C([O-])([O-])=O.[Cs+].[Cs+].ClC1C2C(=CC(OC)=C(OC)C=2)N=CN=1>C1COCC1>[C:17]1([N:16]2[C:12]([NH:11][C:9](=[O:10])[NH2:8])=[CH:13][C:14]([C:23]([F:25])([F:26])[F:24])=[N:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1ccc(F)c(O)c1)Nc1cc(C(F)(F)F)nn1-c1ccccc1
Agent: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: NC(=O)Nc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
After a mixture of 1-(4-fluoro-3-hydroxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.22 g, 0.58 mmol) and Cs2CO3 (0.325 g, 1 mmol) in THF (10 mL) was stirred at room temperature for 1 hour, to it was added 4-chloro-6,7-dimethoxyquinazoline (0.13 g, 0.58 mmol). It was stirred at 40° C. for 14 hours. The mixture was quenched by water and extracted with DCM. Extracts were dried over MgSO4 and concentrated. It was purified on a silica gel column using a mixture of EtOAc-hexane as eluent to give 14346,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.064 g, 19% yield). 1H NMR (300 MHz, DMSO-d6) δ 3.99 (s, 3H), 4.00 (s, 3H), 6.87 (s, 1H), 7.24 (m, 1H), 7.36 (t, 1H), 7.42 (s, 1H), 7.59 (m, 6H), 7.67 (dd, 1H), 8.56 (s, 1H), 8.83 (s, 1H), 9.32 (s, 1H); LC-MS (ESI) m/z 569 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:17])[C:10]2[C:5](=[CH:6][C:7]([OH:14])=[C:8]([N+:11]([O-])=O)[CH:9]=2)[C:4]([F:16])([F:15])[O:3]1.C(O)(=O)C>[Fe].O>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([F:16])([F:15])[O:3][C:2]2([F:1])[F:17])=[CH:6][C:7]=1[OH:14]
Reactant: O=[N+]([O-])c1cc2c(cc1O)C(F)(F)OC2(F)F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A mixture of 6.8 g of 1,1,3,3-tetrafluoro-5-hydroxy-6-nitro-1,3-dihydroisobenzofuran and 20 ml of acetic acid was added dropwise to a mixture, which was heated to 80° C., of 7.8 g of electrolytic iron, 20 ml of acetic acid and 20 ml of water, and then the reaction mixture was stirred for one hour. The mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated sodium chloride solution, and dried over magnesium sulfate. Activated carbon was added, followed by filtration through Celite™. The filtrates were concentrated under reduced pressure to give 4.43 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH:11]=O)[CH:8]=1)([O-:3])=[O:2].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.O>CC#N.C(Cl)Cl.CC(O)=O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=CCCn1cc([N+](=O)[O-])cn1
Reactant: c1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cnn(CCCN2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(4-nitro-1H-pyrazol-1-yl)propanal (722 mg, 4.27 mmol) in MeCN (7.0 mL) and DCM (5.0 mL), indoline (0.48 mL, 4.27 mmol) was added, followed by STAB (1.36 g, 6.40 mmol) and one drop of AcOH. The resulting yellow suspension was stirred at rt for 1 h 15 min, then water and DCM was added and the org. layer was separated. The aq. layer was extracted with DCM and the combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 1-(3-(4-nitro-1H-pyrazol-1-yl)propyl)indoline as a yellow oil which was used without further purification in the next step. LC-MS conditions B: tR=0.76 min, [M+H]+=273.06.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])([O-:5])=[O:4].Br[CH2:20][CH2:21][CH3:22].C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[O:10])[C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH2:21][CH3:22]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
50% Sodium hydride 4 g (160 mmol) in mineral oil was suspended, under nitrogen atmosphere, in 250 ml of anhydrous dimethylformamide. A solution of 15 g (69 mmol) of 2-(3-nitrobenzoyl)pyrrole, prepared, for example, as described in Preparation 3A, in 50 ml of anhydrous dimethylformamide was added thereto, at room temperature, in a dropwise fashion and under stirring. The resulting mixture was stirred for 12 additional hours and then a solution of 18 ml (197 mmol) of 1-bromopropane in 50 ml of dry dimethylformamide was added. The reaction mixture was stirred for 18 hours further and thereafter poured into 1000 ml of ethyl acetate, washed with water (5×500 ml), dried and evaporated in vacuo. Purification of the residue by column chromatography on 500 g of silica gel, using hexane-ethyl acetate (90:10) as eluant provided 17.61 g (98%) of 1-propyl-2-(3'-nitrobenzoyl)pyrrole, the title compound, as an oil.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]([CH3:15])([C:11]([O:13]C)=[O:12])[CH2:7][CH2:6]1.Cl>CO>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]([CH3:15])([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(C)CCC(CO)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C(=O)O)CCC(CO)CC1
Yield: 60.1 %

Procedure:
50 ml of 3N aqueous sodium hydroxide solution was added to a solution of 4.5 g of methyl 4-hydroxymethyl-1-methyl-1-cyclohexanecarboxylate (Example 42) in 100 ml of methanol. The solution was reacted for 2 hours, while it was refluxed. After reaction, 2N hydrochloric acid was added to the reaction solution, acidifying the solution. The solution was extracted five times with 50 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 50 g of silica gel. From the fraction eluted with hexane and ethyl acetate=1:1, the solvent was removed in vacuo, yielding 2.5 g of 4-hydroxymethyl-1-methyl-1-cyclohexanecarboxylic acid as a pale yellow oily, which had the following physiochemical properties:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]#[CH:16])[CH:12]=[CH:11][C:10]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu]I>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]#[C:16][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:10]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(F)c(NC(=O)OC(C)(C)C)c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(C#Cc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 1-(tert-butoxycarbonylamino)-5-ethynyl -2-fluorobenzene (0.11 g), iodobenzene (0.1 g), tetrakis -(triphenylphosphine)palladium(0) (16 mg) and copper (I) iodide (5 mg) in N,N-diisopropylamine (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-(tert -butoxycarbonylamino)-2-fluoro-5-phenylethynylbenzene (0.14 g). This material was dissolved in ethyl acetate (3 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 1-(tert-butoxycarbonylamino)-2-fluoro -5-(2-phenylethyl)benzene (0.11 g). To this material was added hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =8/1 -5/1) to give the title compound (53 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(Cl)Cl.CN(C=O)C>[OH:47][CH2:46][C:45]([NH:44][C:28]([C:25]1[CH:24]=[N:23][C:22]([C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[N:27][CH:26]=1)=[O:29])([CH3:49])[CH3:48]
Reactant: CC(C)(N)CO
Reactant: COc1cccc(C2(c3ncc(C(=O)O)cn3)CCN(Cc3ccccc3)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C2(c3ncc(C(=O)NC(C)(C)CO)cn3)CCN(Cc3ccccc3)CC2)c1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a stirring solution of 2-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid (375 mg, 0.93 mmol) in 10 mL of CH2Cl2 at room temperature was added oxalyl chloride (0.11 mL, 0.12 mmol) and 0.01 mL DMF. After 1 hour, triethyl amine (0.52 mL, 3.72 mmol) and 2-amino-2-methyl-propan-1-ol (0.13 mL, 1.39 mmol) was added and the resulting mixture stirred for 60 minutes. The reaction was quenched by the addition of NaOH and poured into CH2Cl2. The layers were separated, the aqueous layer was extracted with CH2Cl2 (3×20 mL), and the combined organic layers were dried, filtered and concentrated to yield 350 mg of the desired product. 1HNMR (400 MHz, CDCl3) δ 8.98 (s, 2H), 7.28-7.21 (comp, 5H), 7.15 (t, 1H), 6.94-6.91 (comp, 2H), 6.65 (d, 1H), 6.29 (br s, 1H), 3.73 (s, 3H), 3.65 (s, 2H), 3.38 (s, 2H), 2.98-2.96 (comp, 2H), 2.85-2.76 (comp, 2H), 2.33-2.21 (comp, 2H), 2.11-2.08 (comp, 2H), 1.39 (s, 6H); MS (M+1) 475.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21](Br)[C:20]=2[CH3:30])=[CH:12][CH:11]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:20]=2[CH3:30])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(C(=O)Nc3ccccc3N)cc2)c(C)c(Br)c1OC
Product: COc1cc(C(=O)NCc2ccc(C(=O)Nc3ccccc3N)cc2)c(C)c(-c2ccccc2)c1OC
Yield: 56.5 %

Procedure:
The procedure of Example 76 was repeated except for using N-(2-aminophenyl)-4-((3-bromo-4,5-dimethoxy-2-methylbenzamido)methyl)-benzamide (50 mg, 0.10 mmol) instead of the compound 1a, and phenyl boronic acid (18 mg, 0.15 mmol) to obtain the title compound (28 mg, 56%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>O1CCCC1>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[N:25]([CH:22]([CH3:24])[CH3:23])[C:26]2=[O:27])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)N1CC1c1cccc(Br)c1
Reactant: CC(C)N=C=O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1

Procedure:
In analogy to example 1, step 2,1-benzenesulfonyl-2-(3-bromo-phenyl)-aziridine (example 5, step 1) was reacted with sodium iodide and isopropyl isocyanate in tetrahydrofuran to give 1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=C[CH:2]=1.[N:21]1C=CC=C(B(O)O)C=1>>[N:21]1[CH:4]=[CH:5][CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1cccnc1
Product: O=C1NCCc2c(-c3cccnc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-pyridylboronic acid (153 mg, 1.24 mmol) were coupled to yield 2-pyridin-3-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 75 mg (25%) as a light brown solid: m.p. 260.5-262.0° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.07 (m, 2H), 3.40 (m, 2H), 7.25 (app t, J=7.8 Hz, 1H), 7.57 (m, 2H), 7.71 (dd, J=7.5, 0.9 Hz, 1H), 8.05 (m, 1H), 8.12 (br t, 1H), 8.59 (m, 1H), 8.88 (m, 1H), 11.75 (br s, 1H). MS (FAB, MH+) 264. Anal. (C16H13N3O.0.2 H2O) C, H, N.