Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:27]C)[CH2:18]1)[CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)[CH2:2][CH3:3].Cl.N1C=CC=CC=1.[NH4+].[OH-]>O>[CH2:1]([N:4]([C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[OH:27])[CH2:18]1)[CH2:5][CH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC1OC(=O)c2ccccc21)C1CCc2c(cccc2OC)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCCN(CC[C@@H]1OC(=O)c2ccccc21)[C@@H]1CCc2c(O)cccc2C1

Procedure:
The product of Example 35 and excess pyridine hydrochloride were heated in an oil bath at 200° C. for 1 hr. The reaction was cooled, diluted with H2O, basified with NH4OH and extracted with ether. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography (Silica: 6:4 pet I0 ether/EtOAc) and the product [upper isomer by TLC (Silica: 1:1 pet ether/EtOAc) showed characteristic peaks at: NMR (300 MHz, CDCl3) δ 7.9-6.6(m, 7H), 5.7(dd, 1H), 0.9(t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10]Br)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc(Br)ccc1CBr
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1cc(Br)ccc1CN1CCOCC1
Reaction time: 4 h
Yield: 74.3 %

Procedure:
5-Bromo-2-bromomethylbenzonitrile (2.50 g, 9.1 mmol) is added portionwise to a stirred solution of morpholine (828 μL, 9.5 mmol) and triethylamine (1.27 mL, 9.1 mmol) in methanol (2 mL). After 4 hr, the solvent is removed and the residue is suspended in water that is made basic with sodium hydroxide and then extracted with ethyl acetate. The extract is dried, filtered, and concentrated to give 5-bromo-2-(morpholin-4-yl)methylbenzonitrile (1.90 g, 74%) as a cream solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][CH:15]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2([OH:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:16][CH:15]2[CH3:14])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.5 %

Procedure:
A solution of 1-bromo-4-chlorobenzene (9.24 g, 48.2 mmol) in anhydrous THF (100 mL) was cooled to −78° C. and treated dropwise with 1.6 M n-butyllithium in hexanes (28.7 mL, 46.0 mmol). The mixture was stirred at −78° C. for 45 minutes, during which time a precipitate was observed, then the slurry was treated dropwise with a solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (4.9 g, 22.98 mmol) in anhydrous THF (50 mL). The reaction was stirred at −78° C. for 2 hours, then allowed to slowly warm to −20° C. and quenched with saturated ammonium chloride. The layers were separated, and the organic phase was concentrated in vacuo. The aqueous phase was extracted once with ethyl acetate (300 mL), and the organic phase was combined with the residue from the original organic phase. The mixture was washed 3× with water, and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was digested in boiling hexanes (100 mL) for 1 hour, then the mixture was cooled to room temperature. The solids were collected by filtration, rinsed with a small amount of hot hexanes, and dried under vacuum to yield the title compound (6.25 g, 19.18 mmol, 83% yield) as a white powder. MS (ESI+)=252.2 (M−tert-BuO)+.
Reaction SMILES: [H-].[Na+].[Na].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=1[CH2:24]Br>CCOCC.CO>[CH3:9][O:8][C:6]([C:5]1([C:4]([O:11][CH3:12])=[O:10])[CH2:24][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][C:17]=2[N+:21]([O-:23])=[O:22])[CH2:14]1)=[O:7]
Reactant: O=[N+]([O-])c1cccc(CBr)c1CBr
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
To a solution stirred under nitrogen at room temperature of 5.0 mL methanol in 15.0 mL ether was added 0.84 g 60% sodium hydride (0.021 mol) in small portions (sodium hydride was used because metallic sodium was not available). After the addition was complete, the nearly clear and colorless solution was stirred for 5 minutes. To it was then added 1.3 g dimethyl malonate, giving a slightly cloudy colorless solution. To this was rapidly added a suspension of 3.1 g 1,2-bis(bromomethyl)3-nitrobenzene, which immediate gave a precipitate suspended in a dark green solution. This was removed by filtation and the filtrate was concentrated. The residue was purified on silica (20%-100% CH2Cl2 in hexanes) to give 1.93 g off-white solid (67%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@H:28]3[CH2:32][C@@H:31]([OH:33])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34]I.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:26]=[C:25]([O:27][C@H:28]3[CH2:32][C@@H:31]([O:33][CH3:34])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@@H]3C=C[C@H](O)C3)c3ccccc3n2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@H]1C=C[C@@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)C1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1S,4R)-(4-hydroxycyclopent-2-en-1-yl)oxy]quinazoline [cf. Example 33(3)] (750 mg) and methyl iodide (445 mg) in dimethylformamide (6 ml) is added 60% sodium hydride (oil) (94 mg) with stirring at room temperature, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with ethyl acetate, and washed with water 5 times. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is purified by medium pressure liquid column chromatography [eluent, chloroform, (chloroform:methanol=200:1, v/v)] to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1S,4R)-(4-methoxycyclopent-2-en-1-yl)oxy]quinazoline (710 mg) as oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]2[S:13][C:14]([CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:15][C:11]=2[CH:10]=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:27]=[CH:26][C:12]2[S:13][C:14]([CH2:16][CH2:17][CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:15][C:11]=2[CH:10]=1)[CH2:34][C:30]1[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCc1cc2cc(CNCc3ncc[nH]3)ccc2s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCc1cc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (197.9 mg) obtained in Example 120-6 was dissolved in methanol (10 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (68.0 mg) and sodium cyanoborohydride (64.7 mg). After that, the solution was adjusted to pH 5 with acetic acid, followed by stirring overnight at room temperature. After the solvent had been distilled off, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (228.7 mg) of the subject compound as a white solid.
Reaction SMILES: [OH-].[Na+].Cl.[C:4](=[NH:20])([NH:9][C:10]1[CH:14]=[CH:13][NH:12][C:11]=1[C:15](OCC)=[O:16])[CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(O)C>[CH2:5]([C:4]1[NH:20][C:15](=[O:16])[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[N:9]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(=N)Nc1cc[nH]c1C(=O)OCC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCc1nc2cc[nH]c2c(=O)[nH]1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of sodium hydroxide (1.44 g, 35.9 mmol) in water (7 mL) was added to a solution of ethyl 3-pentanimidamido-1H-pyrrole-2-carboxylate hydrochloride (2.46 g, 8.99 mmol) in ethanol (30 mL). The resultant mixture was heated at reflux for a total of 4 hours. The reaction mixture was cooled to room temperature and the pH adjusted to pH 6.5 with aqueous citric acid. The resultant mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and evaporated to give the title compound as a pale brown solid (1.69 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][CH:4]=1.[CH3:15][O:16]C(Cl)Cl.O>ClCCl>[CH3:14][O:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:15]=[O:16]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(OC)c2ccccc12
Solvent: O
Solvent: ClCCl
Product: COc1cc(C=O)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,4-dimethoxy-naphthalene (5 g, 26.6 mmol) in dichloromethane (100 mL) at 0° C. was added dichloromethyl methyl ether (3.66 g, 31.9 mmol) and stannic chloride (13.8 g, 53.1 mmol). The reaction mixture was stirred for 30 min at this temperature, allowed to warm to room temperature and stirred for an additional 30 min. Water (100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL) and the combined extracts dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, ethyl acetate/hexane: 2/8) to give a white solid: 1H NMR (DMSO-d6) δ 4.06 (s, 3H, CH3), 4.13 (s, 3H, CH3), 7.14 (s, 1H, Ar—H), 7.82 (m, 2H, Ar—H), 8.29 (m, 2H, Ar—H), 10.54 (s, 1H, CHO).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24][CH2:25][CH2:26]Cl>CN(C=O)C>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:26][CH2:25][S:24][CH3:23])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH:13]([CH3:14])[CH3:15])[N:7]=1
Reactant: CC(C)n1nc(Br)c2ccc(O)cc2c1=O
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCCOc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a solution of 7-hydroxy-2-isopropyl-4-bromo-2H-phthalazin-1-one (0.8 g, 0.0028 mol) in DMF (8 ml), was added potassium carbonate (2 g, 0.014 mol). After 5 min, 2-chloroethyl methyl sulfide (0.34 g, 0.0028 mol) was added and the solution was heated to 100° C. for 24 hours. After this time LC-MS indicated the complete consumption of starting material and the mixture was cooled, concentrated under vacuum and purified by flash column chromatography (elution: 70% heptane, 30% EtOAc) to give the title compound (0.3 g, 24% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.[C:16](Cl)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16](=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, 138 g of p-nitroaniline was dissolved in a mixed solvent consisting of 3000 ml of tetrahydrofuran and 140 ml of pyridine while passing nitrogen gas through the flask. Then, 395 g of docosanoylchloride placed in the dropping funnel was gradually dropped into the flask over a time span of 20 minutes, while stirring the reaction mixture. After the completion of the dropping, the reaction mixture was further stirred for 2 hours. A solid reaction product was produced. The solid reaction product was collected by filtering, the filtrate was concentrated under a reduced pressure to produce crystals. The crystals were collected and recrystallized from ethyl alcohol. As a result, 405 g of 4'-nitro-n-docosaneanilide was obtained at a yield of 88%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26].O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=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>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[CH2:3]1
Reactant: CC1CC(=O)C=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CC(=O)C=C(c2ccncc2[N+](=O)[O-])C1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1.0 equiv.) in degassed dioxane and 2M Na2CO3 was added 4-chloro-3-nitropyridine (1.2 equiv.) and Pd(PPh3)4 (0.05 equiv.). The reaction was heated in an oil bath to 120° C. for 2 h. (reaction can also be carried out in the microwave for 10 min at 120° C.). Cooled to room temperature, then diluted with EtOAc, added H2O—dark solution, lots of emulsions. Filtered to get rid of the solids, then extracted the organic phase, dried with Na2SO4, and concentrated. The crude was purified via silica gel chromatography to yield 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone. LC/MS=233.2 (M+H); Rt=0.69 min, LC=2.70 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)[CH:2]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([CH2:12][OH:13])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=Cc1ccc(-c2cccnc2)s1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2cccnc2)s1
Yield: 99.4 %

Procedure:
To a solution of 13 (116 mg, 0.61 mmol) in CH3OH (5 mL) was added sodium borohydride (23 mg, 0.61 mmol) in one portion. The resultant solution was stirred at room temperature for 10 min, stopped by the addition of aqueous sodium bicarbonate (50:50 satd. soln./water, v:v) and the solvent was removed in vacuo. The residue was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was collected and the aqueous was extracted with EtOAc (2×50 mL). The combined organic extracts were dried (MgSO4) and the solvent was removed in vacuo to afford the title compound 44 (116 mg, 99% yield) as an off white solid: mp=89-90° C.; 1H NMR (CDCl3) δ 8.82 (m, 1H), 8.49 (m, 1H), 7.84 (m, 1H), 7.31 (m, 1H), 7.22 (d, J=4.1 Hz, 1H), 7.01 (d, J=4.1 Hz, 1H), 4.85 (s, 2H); LRMS (ESI) m/z calcd for C11H10NOS [M+H]+ 192. found 192; HRMS (ESI) m/z calcd for C10H10NOS [M+H]+ 192.0483. found 192.0476; HPLC>99% (tR=10.18 min, 55 (A):45 (B) 0.009 (C); tR=3.52 min, 55 (A):45 (B) 0.1 (C)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Cl:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH3:13])[C:2]([N:1]=[C:15]=[O:16])=[CH:11][CH:10]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1c(Cl)ccc(N)c1C
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Cl)ccc(N=C=O)c1C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 14.7 grams (0.074 mole) of methyl 3-amino-6-chloro-2-methylbenzoate in 1000 mL of toluene was stirred and 14.6 grams (0.074 mole) of trichloromethyl chloroformate was added dropwise thereto. Upon completion of the addition, the reaction mixture was warmed to reflux where it stirred for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue, which was assumed to be a theoretical yield (16.7 grams) of the subject compound. The subject compound was taken directly to the next reaction in the sequence.
Reaction SMILES: O[C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C([O-])(O)=O.[Na+]>[CH:16]1([C:13]2[CH:12]=[CH:11][C:10]([C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)CC(C)(O)c1ccc(C2CCCCCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)c1ccc(C2CCCCCC2)cc1
Yield: 42.9 %

Procedure:
To a solution of ethyl 3-hydroxy-3-(4′-cycloheptylphenyl)-butanoate (2c, 28.75 g) in benzene (175 ml) was added p-toluenesulfonic acid and was refluxed for 1 h. The reaction mixture was diluted with NaHCO3 and benzene layer was separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to give 11.6 g (42.9% yield) of ethyl 3-(4′-cycloheptylphenyl)-but-2-enoate (3c, formula 3, R=cycloheptyl) as viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:37][CH2:38][CH:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:40][CH2:41]2)(=[O:34])=[O:35])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)CC1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and tert-butyl (1-((2-bromophenyl)sulfonyl)piperidin-4-yl)carbamate. MS (ESI): mass calcd. for C28H30FN5O4S, 551.20; m/z found, 552.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.81 (d, J=2.4, 1H), 8.18-8.04 (m, 2H), 7.69-7.59 (m, 2H), 7.60-7.48 (m, 1H), 7.48-7.30 (m, 4H), 6.85 (dd, J=3.7, 1.9, 1H), 4.44 (d, J=8.2, 1H), 3.79 (d, J=13.2, 1H), 3.49-3.27 (m, 3H), 2.91 (t, J=11.7, 1H), 2.47 (t, J=12.2, 2H), 1.98 (d, J=13.4, 1H), 1.79 (d, J=11.8, 2H), 1.42 (d, J=9.5, 12H), 1.31-1.10 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cccc(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1cccc(Br)c1)S(C)(=O)=O
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of N-(3-bromophenyl)methanesulfonamide (5.15 g, 20.6 mmol, Combi-Blocks) in dry dimethylformamide (100 ml) was treated with potassium carbonate (4.3 g, 31.2 mmol) at room temperature with stirring under argon. After stirring for 10 minutes methyl iodide (2.9 g, 20.6 mmol) was added dropwise over 5 minutes and stirring continued at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate (250 ml), and water (3×150 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a brown oil (4.90 g, 90%); 1H-NMR (400 MHz, CDCl3): 2.86 (3H, s), 3.32 (3H, s), 7.26 (1H, m), 7.35 (1H, m), 7.43 (1H, m), 7.53 (1H, m).
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.[H][H]>C(OC)(=O)C.O1CCCC1.[Ni]>[NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: COC(C)=O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1N

Procedure:
0.5 gm (0.00168 mol) of (E)-2-[(amino)-(2-nitrophenyl)methylene]-benzo[b]thiophen-3(2H)-one was dissolved in a mixture of 10 cc of methyl acetate and 10 cc of tetrahydrofuran, and after adding 0.5 gm of Raney nickel the mixture was hydrogenated at room temperature and a hydrogen pressure of 5 bar until hydrogen uptake was at an end. The catalyst was then filtered off, the solvent was evaporated at reduced pressure, and the residue was recrystallized twice in the presence of activated charcoal from tetrahydrofuran/petroleum ether (1:1). 330 mgm (73% of theory) of yellow crystals were obtained, m.p. 186°-187° C. (petroleum ether/tetrahydrofuran 1:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]2[CH3:14].[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]2[CH3:14]
Reactant: COc1cccc(B(O)O)c1OC
Reactant: CC1=CC(C)(C)Nc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: COc1cccc(-c2ccc3c(c2)C(C)=CC(C)(C)N3)c1OC
Temperature: 25 °C
Yield: 60.2 %

Procedure:
6-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline (256 mg, 1.02 mmol) (Example 8) and 2,3-dimethoxyphenyl boronic acid (370 mg, 2.03 mmol) were combined in DMSO (2 mL). 2 M K3PO4 (1 mL) was added, followed by PdCl2(dppf) (50 mg). The contents were placed in a microwave reaction vessel assembly and irradiated at 120° C. for 15 minutes. The reaction was cooled to room temperature. Purification of the crude product by chromatography afforded 6-(2,3-dimethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (190 mg, 61%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:28])[N:8]([CH:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5]=2[NH:4][N:3]=1.CCCCCC.C(O)C.C(NCC)C>>[NH2:1][C:2]1[C:6]2[C:7](=[O:28])[N:8]([C@@H:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:13][N:12]=3)[C:5]=2[NH:4][N:3]=1
Reactant: CC(C)C(C)n1cc(-c2ccc(N3CCOCC3)cn2)c2[nH]nc(N)c2c1=O
Solvent: CCCCCC
Solvent: CCNCC
Solvent: CCO
Product: CC(C)[C@@H](C)n1cc(-c2ccc(N3CCOCC3)cn2)c2[nH]nc(N)c2c1=O
Yield: 47.8 %

Procedure:
Racemic 3-amino-5-(3-methylbutan-2-yl)-7-(5-(morpholin-4-yl)pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Example 116 (90 mg) was resolved by HPLC (column: CHIRALCEL OJ, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol/diethylamine=700/300/1(v/v/v)) to give the title compound (43 mg) having a shorter retention time.