Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].[NH:18]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:19]([C:28](O)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>>[C:34]([O:33][C:31]([NH:18][C@H:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:28]([N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([N:2]([CH3:17])[CH3:1])=[O:4])[CH2:12][CH2:13]1)=[O:29])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CN(C)C(=O)c1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Product: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1

Procedure:
[2-(4-{(2R)-2-[(tert-Butoxy)carbonylamino]-3-(4-chlorophenyl)propanoyl}piperazinyl)phenyl]-N,N-dimethylcarboxamide was prepared according to the procedure described in Preparation V by using N,N-dimethyl(2-piperazinylphenyl)carboxamide (Step 3) (260 mg, 1.1 mmol), Boc-p-Cl-D-Phe-OH (Peptech Corporation) (370 mg, 1.2 mmol), HOAT (Aldrich) (151 mg, 1.11 mmol), and EDC (Aldrich Chemical Company) (430 mg, 2.2 mmol). The compound was isolated as a crude white foam (480 mg) and used in the next step without further purification. MS (ESI, pos.ion) m/z: 515 (M+H). Calc'd for C27H35ClN4O4: 515.04.
Reaction SMILES: [K].CC(O)(C)C.[CH2:7]([N:14]([CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=O)[CH2:15][CH2:16][CH2:17]C(OCC)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1(C)C(C)=CC=CC=1>[CH2:7]([N:14]1[CH2:15][CH2:16][CH2:17][C:26](=[O:28])[CH2:25][CH2:24][CH2:23]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCN(CCCC(=O)OCC)Cc1ccccc1
Agent: Cl
Agent: [K]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1C
Product: O=C1CCCN(Cc2ccccc2)CCC1

Procedure:
To a stirred boiling slurry made from potassium (1.28 g, 32.8 mmol) and t-BuOH (2.43 g, 32.8 mmol) in xylene (182.5 mL) under N2 was added diethyl 4,4′-(benzylazanediyl)dibutanoate (O2) (5 g, 14.9 mmol) over 5 hrs in xylene (37.25 mL). The mixture was stirred and heated at reflux for 1 hr. After being cooled, the reaction mixture was neutralized with 6N HCl (100 mL) and then was extracted with 6N HCl (3×50 mL). The combined acid solutions were filtered and the filtrate was heated under reflux for 1 hr. After cooling, the mixture was basified with concentrated KOH solution to pH 10 with cooling and extracted with dichloromethane. The combined organics were dried over Na2SO4 and concentrated to give a residue. Another 17 batches were done in parallel. The combined residue from 18 batches was purified together by column (P.E./EtOAc 5:1) to give 1-benzylazocan-5-one (O3). 1H NMR (CDCl3, 400 MHz) δ 7.30-7.33 (m, 2H), 7.21-7.25 (m, 3H), 3.56 (s, 2H), 2.55 (t, J=6.0, 4H), 2.24 (t, J=6.4 Hz, 4H), 1.86-1.91 (m, 4H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]2)=[O:24])[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCCC2)CC1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (20%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1Cl)([O-:21])=[O:20]>CN(C=O)C>[N+:19]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)([O-:21])=[O:20]
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3ccc(Nc4ccc([N+](=O)[O-])cc4[N+](=O)[O-])cc23)CC1
Yield: 53.4 %

Procedure:
A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.05 g, 0.207 mmol) and 2,4-dinitrochlorobenzene (0.75 g, 0.373 mmol) in dry DMF (2 mL) was refluxed 2 hours. The solvent was removed in vacuo and the residue was taken up in methylene chloride. The organic phase was washed with saturated sodium bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was recrystallized from ether to give 0.045g (54%) of the title compound: mp 153°-154° C. Analysis calculated for C21H21N5O4 ; C, 61.91; H, 5.20; N, 17.19. Found: C, 61.42; H, 5.10; N, 16.79.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:3]1[OH:19].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl.C(OCC)C>[Si:25]([O:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH:3]1[OH:19])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1CC2=NOCC2C(O)C1O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC2=NOCC2C(O[Si](C)(C)C(C)(C)C)C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
4,5-Dihydroxy-6-(tert-butyldimethylsilyloxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (287 mg) was dissolved in 10 ml of methylene chloride, and 200 mg of imidazole and 226 mg of tert-butyldimethylsilyl chloride were added under ice cooling, followed by stirring the mixture overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 265 mg of 4,6-bis(tert-butyldimethylsilyloxy)-5-hydroxy-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 66%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 6) (20 mg, 0.046 mmol, 1 eq), DIPEA (16 μl, 0.091 mmol, 2 eq) and TBTU (16 mg, 0.05 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 1-amino-4-methylpiperazine (7 mg). The RM was then stirred at rt for 16 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: COc1ccc(CC(=O)Nc2nn3cccnc3c2C(C)(C)C)cc1

Procedure:
The product from Example 105B and 4-methoxyphenylacetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 3.55 (s, 2H), 3.74 (s, 3H), 6.87-6.97 (m, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 7.23-7.26 (m, 2H), 8.47 (dd, J=3.9, 1.9 Hz, 1H), 8.91 (dd, J=7.0, 1.5 Hz, 1H), 9.87 (s, 1H); MS (DCI) m/z 339 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C@@H:14]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[C@H:15]([OH:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:14]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20])[O:25][CH2:10][C:9]1=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](O)[C@@H](CN(Cc1ccccc1)C(=O)CCl)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1OCC(=O)N(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of N-benzyl-N-[(2R,3S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3,4-dichlorophenyl)-3-hydroxybutyl]-2-chloroacetamide (4.13 g) in THF (100 mL) was added sodium tert-butoxide (897 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.52 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[O:32][C:31]([CH3:33])=[N:30][CH:29]=5)=[C:24]([O:34][CH3:35])[CH:23]=4)=[N:20][N:21]=[C:14]23)(=O)=O)=CC=1.[N-:44]=[N+]=[N-].[Na+].O>CS(C)=O>[Cl:43][C:38]1[CH:37]=[C:36]([C:13]2([CH2:12][NH2:44])[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[O:32][C:31]([CH3:33])=[N:30][CH:29]=5)=[C:24]([O:34][CH3:35])[CH:23]=4)=[N:20][N:21]=[C:14]23)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(-c2nnc3n2CCCC3(COS(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(CN)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Temperature: 100 °C
Reaction time: 48 h
Yield: 48.9 %

Procedure:
A mixture of {8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methyl 4-methylbenzenesulfonate (150 mg) and sodium azide (45.8 mg) in DMSO (2 mL) was stirred at 100° C. for 2 days. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was dissolved in THF (2 mL)/water (2 mL), diphenylphosphino-polystyrene (1.99 mmol/g, 236 mg) was added, and the mixture was stirred at 60° C. overnight. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (55.5 mg).
Reaction SMILES: [C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:20]([O:22][C:23](=O)[O:24]CC)[CH3:21]>C1C=CC=CC=1>[OH:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]=1[C:23]([O:22][CH2:20][CH3:21])=[O:24]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCN(c2ccccc2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A solution of 29 g of 2,3-dihydro-1-phenyl-4(1H)-quinolone in 200 ml of benzene was added, dropwise, to a stirred slurry of 7.2 g of sodium hydride in 200 ml of benzene. The slurry was stirred for one hour at room temperature, and then treated with 23.6 g of diethylcarbonate. The resulting suspension was refluxed for five hours, cooled to room temperature, and quenched with 200 ml of water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and evaporated. Purification of the residue by means of high pressure liquid chromatography (silica gel; dichloromethane as the eluent) afforded 22.4 g (59%) of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester. Recrystallization from diethyl ether yielded the analytical sample, m.p. 103°-106° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([CH3:31])[S:19]([C:22]2[CH:26]=[C:25]([C:27](=[O:30])[CH2:28]Br)[S:24][CH:23]=2)(=[O:21])=[O:20])=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([CH3:31])[S:19]([C:22]2[CH:26]=[C:25]([C:27](=[O:30])[CH2:28][N:2]([CH3:3])[CH3:1])[S:24][CH:23]=2)(=[O:21])=[O:20])=[CH:12][CH:11]=1
Reactant: CNC
Reactant: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc(C(=O)CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CC(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1

Procedure:
To a solution (0.6 mL) of 2.0M dimethylamine-tetrahydrofuran diluted with tetrahydrofuran (2 mL), was added dropwise 5-(2-bromoacetyl)thiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide (46 mg) in tetrahydrofuran (1 mL) at room temperature. An aqueous solution of saturated sodium bicarbonate was added, and the solution was extracted with ethyl acetate. After the organic layer was washed with saturated sodium chloride water and dried with anhydrous sodium sulfate, the residuals that were obtained upon removing the solvent by evaporation were purified by silica gel column chromatography (dichloromethane/methanol), and the title compound (16 mg) was obtained as a yellow oily substance.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:9]([C:13]([F:16])([F:15])[F:14])=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].Br[CH2:18][C:19]([NH:21][C:22]1[S:26][C:25]2[CH2:27][CH2:28][CH2:29][CH2:30][C:24]=2[C:23]=1[C:31]([NH2:33])=[O:32])=[O:20].O>CN(C=O)C>[C:31]([C:23]1[C:24]2[CH2:30][CH2:29][CH2:28][CH2:27][C:25]=2[S:26][C:22]=1[NH:21][C:19](=[O:20])[CH2:18][N:11]1[CH:12]=[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])[C:9]([C:13]([F:15])([F:16])[F:14])=[N:10]1)(=[O:32])[NH2:33]
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 120 °C
Yield: 19 %

Procedure:
NaH (60% [w/w] suspension in oil, 10 mg, 0.25 mmol) was added to a solution of ethyl-3-(trifluoromethyl)pyrazole-4-carboxylate (25 mg, 0.056 mmol) in DMF (2 mL). The reaction mixture was stirred at RT for 60 min before the addition of 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide. The reaction mixture was heated at 120° C. for 10 min in the microwave. Water (5 μL) was added and the reaction mixture extracted with EtOAc (3×10 mL). The combined EtOAc layers were washed with water (5×5 mL), brine (5 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to give the crude reaction mixture as a yellow solid (44 mg, 0.01 mmol). Purification by preparative reverse phase HPLC gave the desired product (10 mg, 0.024 mmol, 19%).
Reaction SMILES: CS(OCC[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][O:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47]N)[CH2:42][CH2:41]1>C(N(CC)CC)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:20]2[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:47][CH2:46][N:43]5[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH2:41][CH2:42]5)=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1
Reactant: COCCN1CCN(CCN)CC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3[C@H](c3ccc(F)cc3)C4)cc2)CC1

Procedure:
This was synthesized by using (S)-4-(6-(4-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanamine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=195-198° C.; 1H NMR (CDCl3/DMSO-d6) 400 MHz δ 8.37 (d, J=7.0 Hz, 1H), 8.03, (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.63 (s, 3H), 7.54-7.57 (m, 2H), 7.34-7.37 (d, J=7.0 Hz, 1H) 1H), 8.01 (brs, 1H), 7.69 (d, J=6.6 Hz, 2H), 7.58-7.59 (m, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.12 (d, J=7.0 Hz, 1H), 7.05-7.08 (m, 2H), 7.01, 7.04 (m, 2H), 4.43 (t, J=7.0 Hz, 1H), 3.89-3.91 (m, 7H), 3.39 (s, 5H), 3.28-3.30 (m, 2H), 2.02 (s, 2H). LCMS m/e 538 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[CH:18]=CC(C(C2C=CC(O)=CC=2)(C)C)=C[CH:14]=1>>[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:1]([CH3:4])([CH3:2])[CH2:3][C:13]2([CH3:18])[CH3:14]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21

Procedure:
172.5 g (1.15 mol) of 4-tert.-butylphenol, 57.5 g (0.25 mol) of 2,2-bis-(4-hydroxyphenyl)-propane and 10 g of an acid-activated fuller's earth were heated with stirring in an autoclave for 6 hours to approximately 200° C. The hot reaction mixture is then filtered off from the catalyst under suction and the resulting 221.3 g reaction mixture subjected to fractional distillation in vacuo, giving 25.2 g (52 % of the theoretical) of 5-hydroxy-1,1,3,3-tetramethyl indane.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C:15]1([CH3:41])[NH:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=2[F:40])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:40][C:29]1[CH:30]=[C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:33][C:28]=1[CH:26]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][C:15]([CH3:41])([CH3:14])[N:27]1[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: COC(=O)/C=C/c1ccc(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (1.259 g, 5.62 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-fluorophenyl)acrylate (racemate) (850 mg, 2.25 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.467 ml, 8.42 mmol) in 1,4-dioxane (5 ml). The mixture was heated at 60° C. for 4 hours, then stirred at ambient temperature for 12 hours. The mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was extracted with ethyl acetate (2×25 ml) and the extracts combined with the organic layer. The combined extracts were evaporated under vacuum. The residue was purified by flash silica chromatography, elution solvent 10% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (mixture of diastereoisomers) (600 mg, 59.0%). m/z: ES+ [M+H]+ 453.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][OH:15])[C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].Br[CH2:17][CH2:18][CH2:19][N:20]1C(=O)C2=CC=CC=C2C1=O>>[NH2:20][CH2:19][CH2:18][CH2:17][NH:1][C@H:2]([CH2:14][OH:15])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[OH:4]
Reactant: N[C@@H](CO)[C@@H](O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: NCCCN[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1
Yield: 66.7 %

Procedure:
By using (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (3.0 g) and N-(3-bromopropyl)phthalimide (4.53 g) as starting materials, the title compound (2.54 g) was obtained in the same manner as that of Reference Example 139.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([F:4])[CH3:3].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[F:4][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:42]=2)=[O:19])[N:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([F:1])[CH3:3]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(F)F)nn4-c4cccnc4)c3)c2cc1OC
Yield: 62.8 %

Procedure:
Following the procedure in Example 115C, phenyl 3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (27 mg, 0.078 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (26 mg, 0.086 mmol) (prepared as described in Example 113A) to afford 1-(3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (27 mg, 0.049 mmol, 63%). 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.82-8.78 (m, 2H), 8.70 (d, 1H), 8.54 (s, 1H), 8.04 (d, 1H), 7.65-7.61 (m, 2H), 7.54-7.51 (m, 2H), 7.19 (d, 1H), 6.93 (d, 1H), 6.69 (s, 1H), 3.99 (s, 6H), 2.00 (t, 3H); LC-MS (ESI) m/z 548 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:12][CH:13]([CH3:14])[N:9]3[C:10]=2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]3)=[CH:4][C:3]=1[F:19].[O:20]=[C:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>CN(C)P(=O)(N(C)C)N(C)C>[O:20]=[C:21]1[NH:22][CH2:23][CH2:24][N:25]([C:2]2[C:11]3[CH2:12][CH:13]([CH3:14])[N:9]4[C:10]=3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]4)=[CH:4][C:3]=2[F:19])[CH2:26]1
Reactant: CC1Cc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: O=C1CNCCN1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1Cc2c(N3CCNC(=O)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 32.6 %

Procedure:
A mixture of 6 g of 9-chloro-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid, 8.6 g of 2-oxo-piperazine and 60 ml of hexamethylphosphoric triamide was reacted at 140°-150° C. on an oil bath for 6 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off and to the residue was added ethyl acetate to form crystals, which then were collected by filtration. The crystals thus obtained were recrystallized twice each from dimethylformamide to give 2.4 g of 9-(3-oxo-1-piperazinyl)-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid. m.p. not lower than 300° C., white rhombic crystals.