Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]=1[N+:25]([O-:27])=[O:26].[CH:28]1([C@@H:31]([NH2:34])[CH2:32][CH3:33])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:34][C@H:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][CH3:33])[C:12]=1[N+:25]([O-:27])=[O:26]
Reactant: COc1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Reactant: CC[C@H](N)C1CC1
Product: CC[C@H](Nc1nccc(-c2cc(F)c(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 11.3 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.3 g, 0.70 mmol) and (S)-1-cyclopropyl-propylamine (0.28 g, 2.09 mmol) were treated substantially as described in Part C of Example 19a to produce 30 mg (12%) of crude (S)-[4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:3]1.[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26]>>[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:21]\[C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:12]=1[CH2:11][CH2:10][CH2:9][N:4]1[CH2:5][CH:6]([CH3:8])[NH:7][CH:2]([CH3:1])[CH2:3]1)(=[O:27])=[O:26]
Reactant: CC1CN(CCCc2c(C=O)[nH]c3c2CCCC3)CC(C)N1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CC(C)NC(C)C1)CCCC3)C(=O)N2
Yield: 60.4 %

Procedure:
3-[3-(3,5-Dimethyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (67 mg, 0.22 mmol) was condensed with 5-methylaminosulfonyloxindole (50 mg, 0.22 mmol) following the procedure used in Example 1 to provide (68 mg, 60% yield) of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].CN(C)C(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]1[N:41]=[C:40]([CH3:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>O>[CH3:42][C:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[C:32]([CH2:31][N:4]2[C:5](=[O:16])[C:6]3[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:17])[N:41]=1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: Cc1nc(CCl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
3-Methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (10 gm) and N,N-dimethylacetamide (150 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (9.3 gm) and 2-(chloromethyl)-4-methylquinazoline (6.8 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 90° C. and maintained the temperature for 8 hours. The reaction mixture was cooled to 30° C. and water (450 mL) was added and the mixture was stirred for 1 hour at 30° C. The solid formed was collected by filtration and washed with water (150 mL). The wet cake was charged into 500 mL round bottomed flask and toluene (220 mL) was added and the mixture was heated to reflux temperature and maintained for 1 hour. The mixture was cooled to 10° C. and maintained for 2 hours. The solid was collected by filtration and washed with toluene (50 mL). The solid was dried in oven under vacuum at 80° C. to get 10.8 gm of the title compound. Purity by HPLC: 99.59%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.CC1(C)N([O])C(C)(C)CCC1.[O-:24]Cl.[Na+].Cl>O.CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:24])=[O:11])[CH2:7][C:6]=2[CH:12]=1
Reactant: OCC1Cc2cc(Cl)ccc2O1
Reactant: [O-]Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)C1Cc2cc(Cl)ccc2O1
Temperature: 0 °C
Yield: 74 %

Procedure:
To a solution of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol (2 g, 11 mmol), KHCO3 (4.32 g, 43 mmol, 4 eq) and TEMPO (20 mg, 0.13 mmol, 0.1 eq) in water (8 ml) and CH3CN (18 ml) was added NaOCl (20 ml, aq. 15%, ˜4 eq) dropwise with stirring at 0° C. and stirred for 1 hour. The mixture was diluted with water (200 ml) and adjusted to pH˜4 with hydrogen chloride (2N). After extraction with ethyl acetate (3×200 ml), the organic layers were combined, washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum. The crude material was purified by silica gel chromatography using 1% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid as a yellow solid (1.6 g, 74%). 1H NMR (300 MHz, CDCl3): δ 7.05-7.22 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.20-5.30 (m, 1H), 3.56-3.65 (m, 1H), 3.33-3.45 (m, 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:32])([F:31])[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([N:23]3[CH2:28][CH2:27][CH:26]([O:29][NH2:30])[CH2:25][CH2:24]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][O:29][CH:26]2[CH2:27][CH2:28][N:23]([C:20]3([C:17]4[CH:18]=[CH:19][C:14]([O:13][C:12]([F:11])([F:31])[F:32])=[CH:15][CH:16]=4)[CH2:21][CH2:22]3)[CH2:24][CH2:25]2)=[O:10])=[CH:4][CH:3]=1
Reactant: NOC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(NOC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
4-Fluorophenyl isocyanate (0.062 ml, 0.546 mmol) was added to a solution of O-(1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-yl)hydroxylamine (157 mg, 0.496 mmol) in tetrahydrofuran (5 ml) and the whole was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/hexane: 25/75 to 45/55) to give 1-(4-fluorophenyl)-3-(1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-yloxy)urea (221 mg, 98%) as a white solid: LCMS: 454 [M+1]+. 1H NMR (DMSO-d6) δ: 0.76 (s, 2H), 0.88 (s, 2H), 1.59 (m, 2H), 1.84 (m, 2H), 2.08 (m, 2H), 2.81 (m, 2H), 3.48 (m, 1H), 5.47 (s, 1H), 7.08 (m, 2H), 7.30 (m, 2H), 7.38 (m, 2H), 7.51 (m, 2H), 8.49 (s, 1H), 9.30 (s, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25]OC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C(C)=CC=CN=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][C:3]([CH3:25])=[CH:2][N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1cccnc1Br
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(C)cn1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (200 mg, 0.57 mmol) was reacted with 2-bromo-3-methylpyridine (63 μL, 0.57 mmol) to afford the desired 2-[3-methoxy-4-(5-methylpyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.55–8.53 (d, 1H), 7.98–7.95 (m, 1H), 7.88 (s, 1H), 7.81–7.78 (m, 1H), 7.61–7.56 (m, 2H), 7.46–7.44 (d, 1H), 7.39–7.35 (m, 2H), 7.23–7.19 (m, 1H), 3.91 (s, 3H), 2.19 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([CH:11]=O)=[CH:9][N:10]=1.[NH2:13][C:14]1[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][CH3:24])[N:17]=[C:16]([C:25]([NH:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:26])[CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:13][C:14]1[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][CH3:24])[N:17]=[C:16]([C:25]([NH:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:11][C:8]3[S:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:10][CH:9]=3)[CH2:31][CH2:30]2)=[O:26])[CH:15]=1
Reactant: CCOc1nc(C(=O)NCC2CCNCC2)cc(N)c1C#N
Reactant: O=Cc1cnc(-c2cccs2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4cccs4)s3)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.4 %

Procedure:
The compound prepared in Example 333 (31 mg) and the compound prepared in Example 334 (48 mg) were combined in dichloroethane (1.6 mL) and acetic acid (0.054 mL) was added. Sodium triacetoxyborohydride (0.101 g) was then added. The reaction mixture was stirred at ambient temperature for 17 hours. It was then treated with saturated sodium bicarbonate and extracted with dichloromethane. The combined organics were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=98:2) to obtain the title compound (24 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:40][C:41]([F:46])([F:45])[C:42](O)=[O:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([NH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1)=[O:43]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1CCN(CCN(C(=O)c2ccc(NC(=O)C(F)(F)F)cc2)c2cccnc2)CC1
Reaction time: 3 h
Yield: 81.2 %

Procedure:
4-Amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-pyridyl)benzamide (229.3 mg, 0.51 mmol) was dissolved in methylene chloride (2.0 ml) to which were subsequently added pyridine (0.05 ml, 0.62 mmol) and anhydrous trifluoroacetic acid (0.09 ml, 0.64 mmol) at 0° C. After 3 hours of stirring at 0° C. to room temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution and extracted with chloroform. The resulting organic layer was washed with saturated sodium chloride aqueous solution and water in that order, and dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 224.8 mg (81.2%) of the title compound in a light yellow powder form.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[OH-:12].[Na+]>C(O)CCC>[NH:2]1[C:3]2[CH:7]=[CH:6][S:5][C:4]=2[C:8](=[O:9])[O:10][C:11]1=[O:12]
Reactant: [OH-]
Reactant: COC(=O)c1sccc1N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: O=c1[nH]c2ccsc2c(=O)o1
Reaction time: 2.5 h

Procedure:
A mixture of 175 g (0.93 mol) of methyl 3-amino-2-thiophenecarboxylate hydrochloride, 1.8 liters of n-butanol and 77 g of sodium hydroxide is heated to boiling under reflux for 30 minutes. After concentration of the resulting suspension on a rotary evaporator, the mixture of sodium 3-amino-2-thiophenecarboxylate and sodium chloride is used directly in the next step. For this purpose, the mixture is treated with 800 ml of water, 280 ml of concentrated hydrochloric acid and 230 ml of tetrahydrofuran. Phosgene is conducted through this mixture at 15°-25° C. for 2.5 hours and then air is conducted through for 15 minutes. The separated solid material is filtered off under suction, washed with water and dried. There is obtained 2H-thieno[3,2-d][1,3]-oxazine-2,4(1H)-dione of melting point 220°-221° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:15][CH3:16])[C:10]=2[Br:14])[CH:5]=1)(=[O:3])[CH3:2].[C:17](OCCCC)(=[O:19])[CH3:18].C[O-].[Na+].Cl>O>[Br:14][C:10]1[C:9]([O:15][CH3:16])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][C:4]([C:1]([OH:3])=[CH:2][C:17](=[O:19])[CH3:18])=[CH:5]2
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Reactant: CCCCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
50 Grams (0.179 moles) of 2-acetyl-5-bromo-6-methoxynaphthalene and 200 ml of n-butyl acetate are placed in a flask equipped with refrigerator and stirrer and, under stirring and at the temperature of 15° C., 14.5 g (0.268 moles) of sodium methoxide are added. The temperature of the reaction mixture goes up to 25° C. and is kept at this value for 30 minutes, then the mixture is warmed at 65° C. for one hour, is added with 100 ml of water and is brought to pH 4 by adding a concentrated aqueous solution of hydrochloric acid. The reaction mixture is then cooled to 0°÷5° C. and kept at this temperature for one hour. The solid is filtered, abundantly washed with water on the filter, then washed with butyl acetate and dried in oven under vacuum obtaining 53 g of product with a yield equal to 92%.
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][CH2:14][CH:15]([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[N:21][CH:22]=1)[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C1COCC1>[Si:6]([O:13][CH2:14][CH:15]([C:17]1[CH:18]=[C:19]([B:24]([OH:29])[OH:25])[C:20]([F:23])=[N:21][CH:22]=1)[CH3:16])([C:9]([CH3:12])([CH3:10])[CH3:11])([CH3:8])[CH3:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CO[Si](C)(C)C(C)(C)C)c1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
n-Butyllithium (1.55M in hexane) (Aldrich, St. Louis, Mo.; 4.98 mL, 7.72 mmol) was added (dropwise over 5 min) to a solution of 5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridine (1.89 g, 7.01 mmol) in THF (35 mL) at −78° C., and the resulting yellow solution was stirred at −78° C. for 1 h. Triisopropyl borate (Aldrich, St. Louis, Mo.; 1.935 mL, 8.42 mmol) was then added, and the resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was subsequently partitioned between EtOAc (250 mL) and water (90 mL) (1 N aq. HCl (12.0 mL) was added to bring the pH to about 6.5). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridin-3-ylboronic acid (2.25 g, 7.18 mmol, 102% yield) as a colorless oil, which was used directly in the subsequent step. m/z (ESI, +ve) 314.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH3:18][C:19](=O)[CH2:20][C:21](=[O:23])[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:18][C:19]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]2=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:20]=1[C:21](=[O:23])[CH3:22]
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCC2
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
To a stirred solution of 56 mg (0.23 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-phenyl-methanone in 2 ml acetic acid was added 0.016 ml (0.24 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 33 mg (47%) 1-(2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH3:25])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.[BH4-].[Na+]>[Co](Cl)Cl>[NH2:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:18][C:19]=1[CH3:25]
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C#N
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1CN

Procedure:
Following a similar procedure as described for Example F2, 4-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methylbenzonitrile from Example G1 (1.5 g, 4.6 mmol) was treated with cobalt (II) chloride (2.2 g, 9.2 mmol) and sodium borohydride (1.75 g, 46 mmol) to afford a pale yellow solid, yield 680 mg, 44%.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>C(#N)C>[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:32]2[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]2)=[CH:20][CH:19]=1
Reactant: OC1CCNCC1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: OC1CCN(Cc2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Sodium triacetoxyborohydride (1.67 g, 7.89 mmol) was added to a solution of 4-(trifluoromethoxy)-benzaldehyde (1 g, 5.26 mmol) and 4-hydroxy piperidine (798 mg, 7.89 mmol) in acetonitrile (2 ml) while cooling in an ice-bath, and the mixture was stirred for 30 minutes, and then at room temperature overnight. The reaction mixture was poured into 7.5% sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol 10/1) to afford 1-(4-trifluoromethoxybenzyl)piperidin-4-ol (1.21 g, yield 84%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=O)[N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:14])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Product: Nc1nc(Cl)c2ccnc-2[nH]1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
2-Aminopyrrolo[2,3-d]pyrimidin-4-one (45 g) was suspended in phosphorus oxychloride (150 ml) and the suspension was stirred at 110° C. for 3 hours. The excess amount of phosphorus oxychloride was distilled off under reduced pressure and ice water (600 ml) was added to the residue, whereby the residue was thoroughly dissolved. The solution was cooled with stirring and adjusted to pH 9 with concentrated aqueous ammonia. The resulting precipitate was collected by filtration, washed with water and recrystallized from hot methanol (4 l) to give the above-identified compound (34.6 g).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:22])[C:9]([O:20]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1>>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:22])[C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(OC)c(Cl)c1C2
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC12CCC(=O)C(C)=C1c1ccc(O)c(Cl)c1C2
Temperature: 195 °C

Procedure:
A mixture of 9a-butyl-8-chloro-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (36.6 mg) and pyridine hydrochloride (2.66) was stirred and heated in an oil bath at 190-200° C. for 80 minutes. After cooling to room temperature, the mixture was partitioned between EtOAc (20 mL) and water (30 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 10% EtOAc in CH2Cl2. The UV visible product band was eluted with EtOAc, the eluant evaporated under vacuum, and the residue lyophilized from benzene to afford 9a-butyl-8-chloro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[O:59](C1C=C(C=CC=1)C(Cl)=O)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[C:6]([O:59][C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(Oc5ccccc5)c4)cc3)cc2C1=O
Yield: 70 %

Procedure:
The compound of example 147 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-phenoxy benzoyl chloride.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O[C:15]1[C:23]2[CH:22]=[CH:21][S:20][C:19]=2[C:18]([CH:24]=[O:25])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([CH2:10][CH2:11][O:12][C:15]2[C:23]3[CH:22]=[CH:21][S:20][C:19]=3[C:18]([CH:24]=[O:25])=[CH:17][CH:16]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(C(C)(C)C)nc1CCO
Reactant: O=Cc1ccc(O)c2ccsc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1oc(C(C)(C)C)nc1CCOc1ccc(C=O)c2sccc12
Reaction time: 4 h
Yield: 47.5 %

Procedure:
0.800 g of the above prepared (example 1, step f]) 2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethanol (4.37 mmol) was dissolved in 25 ml of toluene and treated successively at 0° C. with 0.778 g of 4-hydroxy-benzo[b]thiophene-7-carbaldehyde (4.37 mmol), 1.145 g of triphenylphosphine (4.37 mmol), and 0.883 g (4.37 mmol) of DIAD. The cooling bath was then removed and stirring continued for 4 h. Pouring onto crashed ice, twofold extraction with EtOEt, washing with dil. NaOH and water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=6/4) and crystallization from EtOEt, produced finally 0.713 g of the title compound as off-white crystals of mp. 140–42° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH:13]=[CH2:14]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:16]([NH:15][CH2:12][CH:13]=[CH2:14])=[O:17])=[O:7])=[CH:4][CH:3]=1
Reactant: C=CCN=C=O
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: C=CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 19.00 g (111.4 mmol) of 4-chlorobenzoic acid hydrazide are placed in 150 ml THF. 9.44 g (111.6 mmol) of allyl isocyanate, dissolved in 110 ml THF, are added dropwise at 50° C. and the mixture further stirred overnight at 50° C. The solvent is then evaporated in vacuo, diethyl ether is added to the residue and the solid formed is isolated and purified by filtration and further washing with diethyl ether. 26.80 g (95% of theory) of the target compound are thus obtained.