Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.CCOC(C)=O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(Cl)c3)c2cc1OC
Temperature: 25 °C

Procedure:
THF (5 ml) and NaH (60% disp in oil, approx. 28 mg) is added to a dry flask maintained under inert atmosphere at room temperature. 3-Chlorophenol (0.09 g) is added as a soln. in THF (1 mL) and stirring is continued until the solution became clear. 4-Chloro-6,7-dimethoxyquinazoline is added all at once (as the solid) and stirring was maintained overnight at RT. The solution is partitioned between CH2Cl2 and 5% NaOH. The organic layer is washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (40% EtOAc/Hex) provided the pure compound. An analytical sample is obtained by recrystallization from EtOAc/Hex to provide 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline (0.05 g), white needles, m.p. 152-153° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][N:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]=[C:33]1[CH3:39]>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:37]([C:36]3[N:32]([CH3:31])[C:33]([CH3:39])=[N:34][CH:35]=3)[OH:38])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cc1ncc(C=O)n1C
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2.0 g, 4.64 mmol, Intermediate 5: step d) was added THF (25 mL). The solution was cooled to −70° C. and then n-BuLi (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise. After 2 minutes, 1,2-dimethyl-1H-imidazole-5-carbaldehyde (720 mg, 5.8 mmol in 5 mL THF) was introduced. The reaction mixture was allowed to warm to 0° C. over 60 minutes at which time it was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc:THF (10:1, 5×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with EtOAc:Et2O (1:1), collected by filtration, rinsed with additional Et2O and dried to afford the title compound. The mother liquors were concentrated and chromatographed on silica gel (3% MeOH-DCM increasing to 10% MeOH) to provide additional title compound.
Reaction SMILES: [H-].[Na+:2].CN(C=O)C.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)=[O:11].[H][H]>>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O-:18])=[CH:14][CH:13]=1)([O:9][CH3:8])=[O:11].[Na+:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([O-])cc1
Temperature: 0 °C

Procedure:
The (alkylthio)benzoic acids set forth in Table 2 are prepared according to the following general procedure: To a suspension of sodium hydride (one equivalent, 50% dispersion in mineral oil) in DMF (100 ml per 50 mmole), cooled to 0° C., is added slowly methyl p-hydroxybenzoate (one equivalent). The reaction mixture is stirred under a nitrogen atmosphere until the evolution of hydrogen ceases. To the solution of sodium 4-carbomethoxyphenolate so produced, is added N,N-dimethylthiocarbamoyl chloride [(CH3)2N(CS)Cl] (one equivalent) in one portion. The resulting suspension is heated to 70° C. for 1-3 hours and then is poured into an aqueous solution (1%) of potassium hydroxide (large excess). The suspension is extracted twice with toluene-hexane (4:1 v/v). After drying over MgSO4, the organic extracts are filtered and evaporated to an oil. The oil is purified by chromatography over silica gel using 2% methanol in methylene chloride to give O-(4-carbomethoxyphenyl)dimethylthiocarbamate [p-CH3CO2C6H4O (CS)N(CH3)2 ]. (mp 97°-102° C.). This product is heated under a nitrogen atmosphere at 220° C. for 30-60 min. to give S-(4-carbomethoxyphenyl)dimethylthiocarbamate [p-CH3CO2C6H4S(CO)N(CH3)2 ] which is crystallized from methanol. To S-(4-carbomethoxyphenyl)dimethylthiocarbamate, dissolved in DMSO, is added 2 equiv. of sodium hydroxide (10% aqueous). The mixture is heated at 65°-85° C., and the alkyl bromide (1 equiv.) is added. Heating is continued for 2-4 hours after which the mixture is poured into a large volume of water. Upon acidification, a precipitate forms, which is collected by filtration. The (alkylthio)benzoic acid is crystallized from methanol.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([O:13]C)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][NH2:16]>>[C:1]1([S:7]([CH2:10][C:11]([NH:16][CH3:15])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Product: CNC(=O)CS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The entire isolated, crude and moist phenylsulfonylacetic acid methyl ester (V) was transferred to a 2-L Erlenmeyer flask and dissolved in 1 L (11.7 mol) of 40% aqueous methylamine. The reaction temperature rose to 30° C. The mixture was allowed to cool to ambient temperature, and was maintained at this temperature for an additional hour, followed by cooling overnight in a refrigerator. The precipitate product (IV) was removed by filtration. The filter cake was washed with 3×300 mL of cold water. Drying the recovered white solid at 60° C. at 30 torr over potassium hydroxide flakes for 27 h yielded 402.7 g of the methylacetamide (IV), 97.3% purity by HPLC, mp 106-109° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 85 °C

Procedure:
A mixture of trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.50 g, 3.4 mmol) in ethylene glycol dimethyl ether (100 mL) was treated with 4-(benzyloxy)phenylboronic acid (0.853 g, 3.74 mmol), tetrakis(triphenylphosphine)palladium (0.236 g, 0.204 mmol), and a solution of sodium carbonate (0.864 g, 8.16 mmol) in water (35 mL). The reaction mixture was stirred over night at 85° C. under a nitrogen atmosphere. The organic solvent was removed under reduced pressure. Ethyl acetate (100 mL) was added to the aqueous layer. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layers were washed with water and brine (500 mL each), dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane, 10% methanol in dichloromethane, 20% methanol in dichloromethane, then 30% methanol in dichloromethane. The column afforded 0.817 g (49%) of trans-3-[4-(benzyloxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.22 (s, 1H), 7.59-7.57 (m, 2H), 7.53-7.50 (m, 2H), 7.48-7.21 (m, 3H), 7.19-7.17 (d, 2H, J=8 Hz), 5.18 (s, 2H), 4.65-4.60 (m, 1H), 2.5 (s, 3H), 2.45-2.25 (m, 5H), 2.15 (s, 3H), 2.04-1.92 (m, 7H), 1.50-1.44 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.021 min (95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[Br:23]Br>C1COCC1.CC(OC)(C)C>[Br:23][C:15]1[S:14][C:13]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:2]([F:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CCCCCc1ccc(-c2cccs2)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCCCc1ccc(-c2ccc(Br)s2)cc1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
20.0 g (80.5 mmol) of 2-(3-fluoro-4-pentylphenyl)thiophene are initially introduced in 200 ml of THF, and 50.0 ml of n-BuLi (79.6 mmol, 15% solution in hexane) are added dropwise to the solution at a temperature in the range 0-5° C. After 1 h at 0° C., the batch is cooled to −70° C., and 4.1 ml (80.0 mmol) of bromine are metered in. When the addition is complete, the mixture is stirred at 0° C. for 1 h. The batch is diluted with MTBE and washed successively with 2 N HCl, 10% sodium hydrogensulfite solution, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane). 2-Bromo-5-(3-fluoro-4-pentylphenyl)thiophene is obtained as a yellowish liquid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@@H:20]4[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:41])[C@H:29]([NH:33]C(OC(C)(C)C)=O)[CH:30]([CH3:32])[CH3:31])[C@@H:23]([OH:42])[C@H:22]([OH:43])[C@H:21]4[OH:44])[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@@H:20]4[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:41])[C@H:29]([NH2:33])[CH:30]([CH3:32])[CH3:31])[C@@H:23]([OH:42])[C@H:22]([OH:43])[C@H:21]4[OH:44])[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCc1ccc([C@@H]2O[C@H](COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: CO
Product: CCc1ccc([C@@H]2O[C@H](COC(=O)[C@H](N)C(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Yield: 17.3 %

Procedure:
To a stirred solution of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester (2.8 g, 4.6 mmol) in methanol (30 ml) was added 3 N methanolic HCl (30 ml) at room temperature. After refluxing for 2 h, volatiles were evaporated under reduced pressure. The resulting residue was taken in ethyl acetate (50 ml) and washed with aqueous saturated sodium bicarbonate solution (15 ml), brine (15 ml), dried over sodium sulfate, concentrated, and purified by preparative HPLC to give 410 mg of (R)-2-Amino-3-methyl-butyric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C:15]4([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:11][CH:10]=3.[F:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:29][C:24]1[C:23]([C:12]2[CH:13]=[C:14]3[C:15]4([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]4)[C:4]4[CH:3]=[C:2]([C:35]5[CH:34]=[CH:33][N:32]=[C:31]([F:30])[CH:36]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: NC1=NC2(COCC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1ccnc(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=NC2(COCC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 110 °C

Procedure:
A vial was charged with (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine (142 mg, 0.346 mmol), 2-fluoropyridin-4-ylboronic acid (122 mg, 0.864 mmol), Pd(AmPhos)2Cl2 (12.24 mg, 0.017 mmol), and potassium phosphate (220 mg, 1.037 mmol). The vial was flushed with Ar (g), then dioxane (1296 μL) and water (432 μL) were added in sequence. The vial was sealed and heated in a microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The crude product was purified by chromatography on silica gel (10-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.71 (d, J=0.4 Hz, 1 H), 8.38 (d, J=5.3 Hz, 1 H), 8.26 (td, J=1.5, 4.8 Hz, 1 H), 8.13 (ddd, J=1.9, 7.5, 10.4 Hz, 1 H), 8.07 (s, 1 H), 7.95 (td, J=1.8, 5.2 Hz, 1 H), 7.72 (s, 1 H), 7.69-7.59 (m, 2 H), 7.50 (ddd, J=1.9, 4.9, 7.4 Hz, 1 H), 7.42 (d, J=8.6 Hz, 1 H), 6.16 (br. s., 2 H), 3.86 (t, J=5.6 Hz, 2 H), 3.72 (q, J=12.8 Hz, 2 H), 3.09-2.90 (m, 2 H). MS m/z=472.0. Calc'd for C26H20F2N5O2: 472.2. The racemic material (104 mg) was subjected to chiral SFC separation, using 35% MeOH with diethylamine to afford 45 mg of the (R)-enantiomer (peak 1) and 44 mg of the (S)-enantiomer (peak 2) as white solids.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](OC)(=[O:12])[CH2:10][CH3:11].ClCCl>CO>[NH:1]1[C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:11]=[CH:10][C:9]1=[O:12]
Reactant: NC1=CC(=O)CCC1
Reactant: CCC(=O)OC
Solvent: CO
Solvent: ClCCl
Product: O=C1CCCc2[nH]c(=O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
With stirring, 113.79 g (1.02 mol) of 3-aminocyclohex-2-en-1-one and 114.37 ml (1.19 mol) of methyl propionate were heated at 105° C. for 1 hour. The dark homogeneous solution formed was then slowly heated further to 170° C. After 20 min (temperature: 135° C.), a viscous material formed, and there was a marked evolution of gas. After a further 15 min (temperature: 160° C.), the reaction material became even more viscous while the evolution of gas subsided. After a total of 42 min, a temperature of 170° C. had been reached. After a further 13 min at this temperature, the reaction material was cooled to room temperature. 200 ml of dichloromethane were then added, the mixture was heated briefly and placed into an ultrasonic bath and the crystalline residue formed was filtered off. This procedure was repeated once more with a further 200 ml of dichloromethane. The crystalline residues obtained in this manner were combined, taken up in 1.6 liters of methanol and then heated with stirring until the solid had dissolved completely. This solution was then slowly cooled to room temperature and then stored in a fridge at about 4° C. for 2 days. The crystalline precipitate was filtered off and dried under reduced pressure. This gave 47.65 g (0.29 mol, 29% of theory) of the target product.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH:25]1[CH2:27][CH2:26]1)([CH3:24])[CH2:20][C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[CH2:20][C:19]([NH:18][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH:25]1[CH2:27][CH2:26]1)[CH3:24]
Reactant: CC(N)(CC(N)=O)C1CC1
Reactant: O=C(O)c1cc(OCC(F)F)c(C2CC2)cn1
Product: CC(CC(N)=O)(NC(=O)c1cc(OCC(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2,2-difluoroethoxy)pyridine-2-carboxylic acid (example 145d) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (55 mg, 52%) as a racemate; MS (ESI, m/z): 368.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH:24]=[O:25])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[BH4-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH2:24][OH:25])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(C=O)n1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CO)n1-c1ccc(F)cc1
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-carbaldehyde (740 mg, 1.96 mmol) in anhyd ethanol (15 mL) was added NaBH4 (91 mg, 2.4 mmol). After stirring 3 h, the mixture was poured into water, and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give (5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methanol as a white solid (670 mg, 88% yield).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O)[CH3:8].Cl>C1C=CC=CC=1>[CH2:7]([O:9][C:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[C:2]1/[C:1](=[O:6])[CH2:5][CH2:4][CH2:3]/1)=[O:21])[CH3:8]
Reactant: CCOC(=O)COc1ccccc1C=O
Reactant: O=C1CCCC1
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)COc1ccccc1/C=C1\CCCC1=O
Reaction time: 2 h

Procedure:
A solution of 21.2 g of morpholine enamine of cyclopentanone, 24.0 g of 2-formylphenoxyacetic acid ethyl ester, and 200 ml of benzene was refluxed through a condenser equipped with a Dean-Stark trap for about 4.5 hours. The resulting solution was cooled to about room temperature, and treated with 35 ml of 6 normal (N) hydrochloric acid. After stirring for about 2 hours at about room temperature, the benzene layer was separated and the aqueous layer was extracted with two 15 ml portions of benzene. The combined benzene layer and extracts were washed with 5% sodium bicarbonate and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent in vacuo, 27.6 g of nearly pure product was obtained. The product was crystallized in 50% ethanol to give 26.0 g of 2-(E)-(2-ethoxycarbonylmethoxyl-benzylidene) cyclopentanone as colorless crystals. The melting point of this intermediate compound was determined to be 77°-79° C.
Reaction SMILES: [CH3:1][C:2]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.Cl[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:28][O:27][C:25]([N:8]1[CH2:7][C:6]2[S:5][C:4]3[N:3]=[C:2]([CH3:1])[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=[O:26]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCNC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N1CCc2c(sc3nc(C)c(C(C)=O)c(-c4ccccc4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 394.3 %

Procedure:
To a stirred solution of 50 mg (0.15 mmol) 1-(2-methyl-4-phenyl-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl)-ethanone (the preparation of which is described in example 23) in 5 ml dichloromethane was added 0.02 ml (0.022 mmol) methyl chloroformate and 32 mg (0.022 mmol) potassium carbonate. The mixture was stirred at RT for 1 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 1:1) afforded 33 mg (56%) 3-Acetyl-2-methyl-4-phenyl-5,8-dihydro-6H-9-thia-1,7-diaza-fluorene-7-carboxylic acid-methyl ester as a light yellow solid. ES-MS m/e (%): 381 (M+H+, 100);
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:21]=3[CH:20]=2)=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:21]=3[C:20]=2[C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:7])=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C)cc2)cc1
Yield: 66.1 %

Procedure:
In a manner similar to that used in Preparation 3, 2.32 g (15 mmol) of 4-methylbenzoyl chloride, 2 g (7.4 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene, and 5.3 g (40 mmol) of AlCl3 were converted to 1.9 g of the title compound, crystallized from Et2O and isolated as a light yellow powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:9]2=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=[C:8]2[NH:7][CH:6]=1)[CH3:4].[NH4+:18].[Cl-]>CN(C=O)C>[CH2:3]([C:5]1[C:9]2=[N:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=[C:8]2[N:7]([NH2:18])[CH:6]=1)[CH3:4]
Reactant: [NH4+]
Reactant: CCc1c[nH]c2ccc(C(F)(F)F)nc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn(N)c2ccc(C(F)(F)F)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A suspension of NaH (4.65 g, 116 mmol, 60% in mineral oil) in DMF (40 mL) at 0° C. is treated with 3-ethyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine (2 g, 7.75 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (4.4 g, 38.8 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, treated with solid NH4Cl (3 g), and filtered through a pad of Celite. The filtrate is extracted with Et2O (3×150 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30%-50% EtOAc in heptane to afford 3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.5 g, 84%). MS: 230 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 7.97 (d, 1H), 7.59 (d, 1H), 7.54 (s, 1H), 6.12 (s, NH2, 2H), 2.78 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:14][C:12]1[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1)[CH:20]=[CH2:19]
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1nc(-c2ccc(N)cn2)nc(C)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound of example 16 (0.275 g, 1.1620 mmol) in DMF (3 mL) at 0° C., was added NaH (0.046 g, 1.1620 mmol) and allyl bromide (0.14 g, 1016 mmol) slowly and the reaction mixture was stirred at 25° C. for 4 hours. DMF was removed under vacuum, and the reaction mass quenched by water, extracted with ethyl acetate (3×20 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 8% methanol in chloroform as an eluent to obtain the title compound.