Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][N:27]=1)[CH3:24].O.C(#N)C>CN(C)C=O>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:32][C:30]2[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH2:23][CH3:24])[CH:31]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: CCOc1cc(CBr)ccn1
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOc1cc(CN2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(=O)C2(C)C)ccn1
Reaction time: 0.33 h
Yield: 56.4 %

Procedure:
0.015 g of sodium hydride is added to a solution of 0.175 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 2 ml of anhydrous dimethylformamide, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is maintained at this temperature for 30 minutes. A solution of 0.185 g of 2-ethoxy-4-(bromomethyl)pyridine in 2 ml of anhydrous dimethylformamide is added, followed by addition of ice-cold water after reaction for 10 minutes. The reaction mixture is placed on a cartridge 37 mm in diameter packed with 65 g of octadecyl-grafted 40-60 μm silica conditioned successively with the mixture (water/acetonitrile) (5/95) (v/v) and then with the mixture (water/acetonitrile) (95/5) (v/v). The elution is performed with a mixture (water/acetonitrile) (95/5) (v/v) over 20 minutes, followed by a linear gradient of from 5% to 95% acetonitrile over 60 minutes, at a flow rate of 10 ml/minute. The fractions between 700 and 760 ml are concentrated under reduced pressure. 0.145 g of 5,5-dimethyl-1-(2-ethoxypyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained, the characteristics of which product are as follows:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:15][CH2:14][CH2:13][Br:12]
Reactant: BrCCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrCCCOc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 3.60 g (25 mmol) of 2-naphthol and 6.0 g (30 mmol) of 1,3-dibromopropane in dimethylformamide was added 7.25 g (52.5 mmol) of finely ground anhydrous potassium carbonate. The mixture was stirred vigorously overnight. Solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was further extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, and after filtration, the solvent was removed under reduced pressure. The residue was then chromatographed over silica gel using 10% methylene chloride/hexane as eluent to afford 1.66 g of the title compound, which was homogeneous by thin layer chromatography (5% by volume of ethyl acetate/hexane on silica gel plates).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:15]=[CH:14][C:13]=2[NH2:25])=[N:2]1.C(N(CC)CC)C.[CH3:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39](Cl)=[O:40].C(=O)([O-])O.[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH:15]=[CH:14][C:13]=2[NH:25][C:39]([C:35]2[S:36][CH:37]=[CH:38][C:34]=2[CH3:33])=[O:40])=[N:2]1
Reactant: CN1CCN(c2ccc(N)c(C=Cc3n[nH]c4ccccc34)c2)CC1
Reactant: Cc1ccsc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccsc1C(=O)Nc1ccc(N2CCN(C)CC2)cc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
In a similar manner to Example 2, crude 3-{2-[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (262 mg, 0.72 mmol) obtained in Step 1 was dissolved in ethanol (10 mL) and was reacted with tin (0.26 g, 2.2 mmol) and concentrated hydrochloric acid (1.3 mL) at room temperature to obtain 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methylpiperazine-1-yl)phenylamine. In a similar manner to Example 29, 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methylpiperazin-1-yl)phenylamine (0.10 g, 0.30 mmol) was dissolved in THF (5.0 mL) and the solution was added with triethylamine (0.13 ml, 0.90 mmol) and 3-methylthiophenecarbonyl chloride (0.05 g, 0.31 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained crude product was triturated in ethyl acetate to obtain Compound 228 (0.10 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(N)cc1

Procedure:
To a suspension of 4-amino-phenyl acetic acid (5 g, 33 mmol) in methanol (20 mL) was added concentrated sulfuric acid (2 mL) dropwise. The reaction mixture was stirred at reflux for 1.5 h, then concentrated in vacuo. The residue was partitioned between 1 M aqueous potassium carbonate and diethyl ether. The organic layer was washed with 1 M aqueous potassium carbonate, water, then dried over sodium sulfate and filtered. The filtrate was concentrated and dried in vacuo to give 4.65 g of the product as a dark yellow oil. 1H NMR 500 MHz (DMSO) δ 3.43 (s, 2H), 3.57 (s, 3H), 4.97 (s, 2H), 6.49 (d, 2H), 6.88 (d, 2H); MS (m/z) 166 [M+H+]+.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4](=[O:16])[NH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][C:4]2[C:5]3[CH2:11][CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[C:6]=3[N:1]=[CH:2][N:3]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=c1[nH]cnc2c1CCCc1ccccc1-2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ncnc3c2CCCc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 118B (154 mg, 0.72 mmol), p-toluenesulfonyl chloride (278 mg, 1.44 mmol), DMAP (17 mg, 0.14 mmol) in CH2Cl2 (20 mL) was treated with triethylamine (0.25 mL, 1.8 mmol) and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with 40% EtOAc/hexanes to provide the title compound. 1H NMR (CDCl3) δ 2.18-2.40 (m, 4H), 2.48 (d, 3H), 2.51-2.58 (m, 2H), 7.25-7.29 (m, 1H), 7.35-7.45 (m, 4H), 7.66-7.73 (m, J=17.63 Hz, 1H), 8.07 (dd, J=15.60, 8.48 Hz, 2H), 8.85 (d, J=8.48 Hz, 1H). MS (M+H)+ m/z 367
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][C:10]=3[CH:20]=2)=[CH:2]1.[OH-].[Na+]>C1COCC1.CO>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=3[CH:20]=2)=[CH:2]1
Reactant: COC(=O)C1=Cc2cc(-c3ccsc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(-c3ccsc3)ccc2OCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
In THF (24 ml) and methanol (6 ml) was dissolved methyl 7-(3-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (610 mg), and to the mixture was added 1N sodium hydroxide (12 ml). The mixture was stirred at room temperature for 3 hours. Under reduced pressure, the organic solvent was removed, and to the residue was added ethyl acetate. The mixture was extracted with water, and to the aqueous layer was added 6N hydrochloric acid to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7-(3-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (500 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[CH:4]1)[CH3:2].Cl.C(N(CC)CC)C.[N-:24]=[N+:25]=[N-:26].[Na+]>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[NH:26][N:25]=[N:24][N:15]=2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1cc(-c2nnn[nH]2)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 45.2 %

Procedure:
A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in toluene (30 mL) is treated with triethylamine hydrochloride (1.03 g, 7.50 mmol) and sodium azide (0.49 g, 7.50 mmol) and is heated at reflux for 16 h. After cooling to room temperature, the reaction mixture is diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer is then washed with additional NaHCO3 (2×). The combined aqueous phases are acidified to pH 2 with 6N HCl. The resultant thick precipitate is extracted with hot EtOAc (3×) and the combined organic phases are washed with saturated NaCl and dried and concentrated to give 0.55 g (45%) of 1-ethyl-6-methoxy-3-(1H-tetrazol-5-yl)-1H-indole as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16].[CH3:48][C:49]1([CH3:56])[CH2:54][C:53](=[O:55])[O:52][C:50]1=[O:51]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:37])([CH3:38])[C@@H:26]([O:39][C:53](=[O:55])[CH2:54][C:49]([CH3:56])([CH3:48])[C:50]([OH:52])=[O:51])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 46.8 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1S,3R)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 8, 0.250 g, 0.385 mmol) 2,2-Dimethylsuccinic anhydride (0.26 ml, 2.31 mmol) and DMAP (0.094 g, 0.77 mmol) in pyridine (10 ml) were added at room temperature then the reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with EtOAc, the organic layer was washed with water, 1N HCl, water, brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200, elution 35% EtOAc in hexane) to afford the title compound as a off white solid. Wt: 0.140 g: Yield: 46.8%; 1H NMR. (300 MHz, CDCl3): δ 5.95 (d, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.52-4.43 (m, 1H), 4.19-4.09 (m, 1H), 3.82-3.40 (m, 8H), 3.17-3.04 (m, 1H), 2.92-1.82 (m, 1H), 2.71-2.29 (m, 6H), 2.00-1.91 (m, 3H), 1.80-1.09 (m, 28H), 1.00-0.77 (m, 21H); Mass: [M+1]+ 779 (100%), [M+Na]+ 801 (15%); IR (KBr, cm−1): 3419, 2952, 2867, 1757, 1733, 1729, 1638, 1631, 1460, 1452, 1376, 1243, 1180, 1117, 1067, 978, 879, 775; M.R: 248.7° C.-252.6° C.; HPLC: 87.7%
Reaction SMILES: [C:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15]C(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>O.C(OCC)(=O)C>[C:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:15])=[O:11])=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)(C)C)nc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a mixed liquid of 2163 mg of 6-tert-butoxynicotinic acid and 32 ml of acetone were added 2297 mg of potassium carbonate and 0.97 ml of methyl iodide, followed by stirring at 35° C. overnight. Ethyl acetate and water were added thereto to carry out liquid separation, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.191 g of methyl 6-tert-butoxynicotinate.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:2].[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][S:12][C:11](=[NH:10])[NH2:13])[CH:5]=1
Reactant: NC(N)=S
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1cccnc1
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
A solution of 3-chloromethylpyridine hydrochloride (100 g) in ethanol (310 cc), at 60° C. is added dropwise and in the course of 15 minutes to a suspension of thiourea (55 g) in boiling ethanol (310 cc). The reaction mixture is stirred for 1 hour 45 minutes at the boil and then cooled to 30° C. After decantation, the supernatant solution is discarded. Ethanol (400 cc) is added to the remaining gummy solid and the mixture is stirred for 63 hours at a temperature of about 20° C. The resulting crystals are filtered off, washed twice with ethanol (60 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Pyrid-3-yl-methyl)isothiourea monohydrochloride (100 g), melting at 220° C. is thus obtained.
Reaction SMILES: [F:1][C:2]([P:8]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])(=[O:14])[O:9][CH2:10][CH2:11][CH2:12][Br:13])([F:7])[C:3]([F:6])([F:5])[F:4].[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[F:7][C:2]([P:8]([C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])(=[O:9])[O-:14])([F:1])[C:3]([F:6])([F:5])[F:4].[Br:13][CH2:12][CH2:11][CH2:10][N+:25]1[CH:26]=[CH:27][N:23]([CH3:22])[CH:24]=1
Reactant: O=P(OCCCBr)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: Cn1ccnc1
Product: Cn1cc[n+](CCCBr)c1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
3-Bromopropyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH2—CH2CH2Br, (4.710 g; 11.1 mmol) is slowly added dropwise to cooled (0° C.) N-methylimidazole (0.907 g; 11.0 mmol) (exothermic) in a 50 ml glass flask. It The colourless, more highly viscous and slightly cloudy reaction mixture is stirred at 0° C. for 1 h and at room temperature for 3 h and purified in vacuo (10−3 mbar) at room temperature. 1-(3-Bromopropyl)-3-methylimidazolium bis(pentafluoroethyl)phosphinate, [BrCH2CH2CH2MIM][(C2F5)2P(O)O], (5.286 g; 10.5 mmol) can be isolated as colourless, highly viscous and slightly cloudy liquid in a yield of 95% and a purity of 90%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C(O)(=[O:12])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:6][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: C=Cc1cccc(F)c1
Reactant: CC(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 111.5 %

Procedure:
To a solution of m-fluorostyrene (5.00 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 mL) and H2O (78 mL) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to RT. After 4 hours, 2N NaOH (60 mL) was added and the reaction was left to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.30 g of the title compound as a slightly tinted oil which was used without further purification.
Reaction SMILES: O=[C:2]1[NH:19][CH2:18][CH2:17][S:16][CH2:15][CH2:14][S:13][CH2:12][CH2:11][NH:10][C:9](=O)[CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3]1.B#B.O>O1CCCC1>[O:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][S:16][CH2:17][CH2:18][NH:19][CH2:2][CH2:3]1
Reactant: O=C1COCCOCC(=O)NCCSCCSCCN1
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: C1COCCOCCNCCSCCSCCN1

Procedure:
A solution of 7 g. of the cyclic diamide obtained in Example 28 in 100 ml. anhydrous tetrahydrofurane is added slowly to 50 ml. of a freshly prepared solution (1.5 M) of diborane in anhydrous tetrahydrofuran under nitrogen atmosphere and at a temperature of 0°C. The mixture is then heated to reflux for two hours. The excess reagent is destroyed by adding 10 ml. of water and the solution is evaporated to dryness on a rotatary evaporator under vacuum. 100 ml. 6N hydrochloric acid are added to the residue and the mixture is refluxed for two hours; a clear solution is obtained. This solution is then evaporated to dryness under vacuum. The residue is dissolved in 30 ml. water and the solution is pressed through a column of an anion exchange resin (Dowex 1, Trade Mark). The column is washed with water until there is no basic reaction. The combined water solutions obtained are evaporated to dryness under vacuum on a water bath (80°C - 100°C). The residue is recrystallized.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:12]1)=O)C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[Pd]>[C:28]1([C:20]2[NH:21][C:22]3[C:27]([C:19]=2[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(c1c(-c2ccccc2)[nH]c2ccccc12)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: O=C(c1c(-c2ccccc2)[nH]c2ccccc12)C1CCCNC1
Yield: 93.2 %

Procedure:
A solution of 11.6 g (26.5 mmol) of 3-(2-phenyl-1H-indol-3-ylcarbonyl)piperidine-1-carboxylic acid benzyl ester and 6.4 g (79.5 mmol) of 1,4-cyclohexadiene in ethanol under an atmosphere of nitrogen was charged with 1 g of 10% palladium on carbon. The mixture was heated under reflux for 2 hr, after which it was cooled and filtered to remove the catalyst, and the filtrate evaporated in vacuo to afford 7.5 g (24.7 mmol; 93%) of (2-phenyl-1H-indol-3-yl)piperidin-3-ylmethanone as a clear oil. δH (360 MHz; CDCl3) 1.02-1.15 (1H, m, aliphatic), 1.51-1.70 (2H, m, aliphatics), 1.73-1.84 (2H, m, aliphatics), 2.51-2.62 (1H, m, aliphatic), 2.78-2.89 (3H, m, aliphatics), 2.92-3.02 (1H, m, aliphatic), 7.22-7.28 (2H, m, aromatics), 7.36-7.47 (3H, m, aromatics), 7.50-7.56 (2H, m, aromatics), 8.21-8.27 (1H, m, aromatic), 10.46 (1H, br s, NH); m/z (ES+) 305 (M++H, 100%).
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[C:13]([NH2:14])=[C:12]([Cl:15])[N:11]=[CH:10][N:9]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([OH:23])[CH2:18]1>C1COCC1>[Cl:15][C:12]1[C:13]([NH2:14])=[C:8]([O:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([CH3:16])[CH2:18]2)[N:9]=[CH:10][N:11]=1
Reactant: CN1CCC[C@@H](O)C1
Reactant: Nc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H](Oc2ncnc(Cl)c2N)C1
Temperature: 70 °C

Procedure:
Sodium t-butoxide (586.0 mg, 6.098 mmol) was added to a solution of 4,6-dichloropyrimidin-5-amine (500 mg, 3.049 mmol) and (3R)-1-methylpiperidin-3-ol (351.2 mg, 3.049 mmol) in THF (25.00 mL) at RT. The reaction mixture was heated at 70° C. overnight. The reaction mixture was quenched with 1 mL water and concentrated in vacuo. The residue was extracted with DCM and the combined organic extract were dried and concentrated in vacuo to afford (R)-4-chloro-6-((1-methylpiperidin-3-yl)oxy)pyrimidin-5-amine which was used in next step without further purification.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27](Cl)=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:25][C:24]=2[CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27]([S:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:25][C:24]=2[CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Sc1ccccc1
Temperature: 60 °C
Yield: 83.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--0.39 ml, 2.5 mmol) was added to a mixture of ethyl 6-(benzyloxy)-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 8, 800 mg, 2.3 mmol) and thiophenol (0.47 ml, 4.6 mmol) in dimethylformamide (4 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 6 hours and then partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using a mixture of 20% dichloromethane and 80% hexane, then 50% dichloromethane and 50% hexane as eluant. The isolated product was crystallised from diisopropyl ether and hexane to give the title compound as a colourless solid (810 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1([CH3:28])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2.CC(CC)=[O:31]>[Cu]>[C:8]1([N:7]([CH:18]2[CH:19]=[CH:20][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:15]([CH3:28])([CH3:14])[C:16]=3[C:17]2=[O:31])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CC1(C)c2ccccc2-c2ccccc21
Reactant: CCC(C)=O
Agent: [Cu]
Product: CC1(C)C2=C(C=CC(N(c3ccccc3)c3ccccc3)C2=O)c2ccccc21
Reaction time: 8 h
Yield: 79 %

Procedure:
16.9 g of diphenylamine, 50.0 g of 9,9-dimethylfluorene, 10.0 g of potassium carbonate anhydride and 3.0 g of copper powder were added to 70 ml of o-dichlorobenze, followed by stirring for 8 hours at 180°-185° C. After the reaction, the reaction mixture was cooled and subjected to filtration. The filtrate was concentrated under reduced pressure to obtain a solid. An appropriate amount of methylethylketone was added to the solid to obtain a crystal. The crystal was recovered by filtration and purified by silica gel column chromatography (eluent: toluene/hexane) to obtain 28.2 g of 2-(N,N-diphenyl)amino-9,9-dimethylfluorenone (Yield: 79%; melting point: 144.2°-145.1° C.).