Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[C:10]([O:15][OH:16])([CH2:13][CH3:14])([CH3:12])[CH3:11].C1(O)C=CC=CC=1>O>[C:10]([O:15][O:16][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3])([CH2:13][CH3:14])([CH3:12])[CH3:11]
Reactant: CCC(C)(C)OO
Reactant: C=C(C)c1ccccc1
Solvent: O
Solvent: Oc1ccccc1
Product: CCC(C)(C)OOC(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
Into the 200 ml jacketed reactor described in Example II were added 15.0 grams (0.127 m) alpha-methylstyrene, 15.5 grams (0.1 m) 67.3% t-amyl hydroperoxide and 3.8 grams (0.041 m) phenol. The mixture was stirred to obtain a clear solution and the temperature was adjusted to 20° C. by pumping cool water through the reactor jacket. To this solution was added 1.4 grams (0.009 m) of t-cumyl chloride from the addition funnel over 10 minutes while holding the temperature at 21°-22° C. The reaction was stirred 5 minutes at 22° C., the temperature raised to 25° C. and the reaction stirred 1/2 hour at 30° C., 1/2 hour at 35° C., 11/2 hours at 40° C. and 1/2 hour at 45° C. for a total reaction time of 31/2 hours. At this point essentially all the t-amyl hydroperoxide had been consumed. The reaction was terminated by adding 25 mls of water, stirring 5 minutes, adding 5 mls of 50% NaOH, stirring another 5 minutes and then separating the aqueous caustic layer. The organic layer was washed with saturated NaHCO3 solution, water, 15% NaHSO3, saturated NaHCO3 again and water. The dried material weighed 24.6 grams and contained 54.6% cumyl t-amyl peroxide for a corrected yield of 13.4 grams and a 60.5% yield. The pure cumyl t-amyl peroxide was isolated by fractional distillation under vacuum.
Reaction SMILES: Cl.[NH2:2]O.C(=O)(O)[O-].[Na+].O.[CH2:10]=[C:11]([C:13]1[NH:23][C:16]2[CH:17]=[N:18][C:19]([C:21]#[N:22])=[CH:20][C:15]=2[N:14]=1)[CH3:12]>C(O)C>[CH2:10]=[C:11]([C:13]1[NH:23][C:16]2[CH:17]=[N:18][C:19]([C:21](=[NH:2])[NH2:22])=[CH:20][C:15]=2[N:14]=1)[CH3:12]
Reactant: C=C(C)c1nc2cc(C#N)ncc2[nH]1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=C(C)c1nc2cc(C(=N)N)ncc2[nH]1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (37.7 mg, 0.54 mmol), sodium bicarbonate (68.4 mg, 0.81 mmol), and water (0.54 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (114 mg, 0.27 mmol) dissolved in ethanol (1.3 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-N-hydroxy-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C24H29ClN6O [M+H]+ 453. found 453.
Reaction SMILES: [O-]CC.[Na+].Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[N+:16]([CH:19]([CH3:21])[CH3:20])([O-:18])=[O:17]>C(O)C>[CH3:20][C:19]([N+:16]([O-:18])=[O:17])([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(Cc1ccc([N+](=O)[O-])cc1)[N+](=O)[O-]
Yield: 76 %

Procedure:
To a solution of sodium ethoxide (3.5 g, 50 mmol) in ethanol (100 mL), 1-(chloromethyl)-4-nitrobenzene (8.6 g, 50 mmol) and 2-nitropropane (2.2 g, 250 mmol) were added at room temperature, and the mixture was heated under reflux for 18 hours. The reaction solution was filtered, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 1-(2-methyl-2-nitropropyl)-4-nitrobenzene (8.52 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:14]2[CH2:15][CH2:16][CH:6]1[C:7]1[CH:8]=[C:9]([NH2:17])[CH:10]=[CH:11][C:12]=1[CH2:13]2.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:17][C:9]2[CH:10]=[CH:11][C:12]3[CH2:13][CH:14]4[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:6]([CH2:16][CH2:15]4)[C:7]=3[CH:8]=2)=[N:20][CH:21]=1
Reactant: COCCN1C2CCC1c1cc(N)ccc1C2
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2CCOC)ncc1Cl
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
12-(2-Methoxy-ethyl)-12-aza-tricyclo[7.2.1.0(2,7)]dodeca-2(7),3,5-trien-4-ylamine (101 mg, 0.435 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (0.140 g, 0.443 mmol), and 10-Camphorsulfonic acid (0.141 g, 0.607 mmol) were combined in Isopropyl alcohol (4 mL) and heated with microwave irradiation to 120° C. for a total of 1.5 h. The mixture was treated with Macroporous carbonate resin (3.16 mmol/g loading; 0.45 g, 1.4 mmol) and stirred for 30 min, concentrated in vacuo and chromatographed (ISCO 2×12 g SiO2, 0-10% MeOH:DCM). The amide product elutes with 10% MeOH, while the ester elutes before in ˜8% MeOH. 2-{5-Chloro-2-[12-(2-methoxy-ethyl)-12-aza-tricyclo[7.2.1.0(2,7)]dodeca-2(7),3,5-trien-4-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was isolated as a yellow solid (95 mg, 43%). m.p.=233-236° C.; LCMS (m/e) 511 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 9.22 (s, 1H), 8.53 (m, 1H), 8.17 (s, 1H), 7.51 (m, 2H), 7.42 (m, 1H), 7.15 (m, 1H), 6.77 (s, 1H), 3.59 (m, 1H), 3.41 (m, 3H), 3.28 (m, 1H), 3.23 (s, 3H), 2.95 (m, 1H), 2.75 (m, 3H), 2.55 (m, 1H), 2.25 (m, 1H), 2.04 (m, 2H), 1.45 (m, 2H). 2-{5-Chloro-2-[12-(2-methoxy-ethyl)-12-aza-tricyclo[7.210(2,7)]dodeca-2(7),3,5-trien-4-ylamino]-pyrimidin-4-ylamino}-3-fluoro-benzoic acid isopropyl ester was isolated as a yellow foam (15 mg, 6%). LCMS (m/e) 540 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 8.08 (s, 1H), 7.81 (d, 1H, J=7.8 Hz), 7.38 (dd, 1H, J=9.5, 10.1 Hz), 7.0-7.2 (m, 3H) 6.84 (m, 2H), 5.24 (sept, 1H, J=6.3 Hz), 3.75 (m, 1H), 3.53 (m, 3H), 3.34 (s, 4H), 3.09 (m, 1H), 2.2-2.3 (m, 3H), 1.72 (m, 1H), 1.33 (d, 6H, J=6.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+]([O-])=O)=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([O:24][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[CH2:23][CH2:22][CH:21]=[O:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ccc2CCC=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-chloro-2-fluoro-1-nitrobenzene (2 g, 11.40 mmol) and 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester in 40 mL of anhydrous DMF, add NaH (0.55 g, 22.79 mmol) at 0° C. in portions. Stir the mixture at room temperature for 1 h, then, pour into ice-water, extract with EtOAc (3×50 mL), dry over MgSO4 and evaporate to afford the compound pure enough to use in the following step without further purification (yellow solid, 4.15 g). Follow a procedure similar to preparation 49 substituting 3-(5-chloro-2-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert butyl ester for 1-(5-chloro-2-nitro-phenyl)-pyrrolidine to prepare the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH3:25])[C:19]3[CH2:20][NH:21][CH2:22][CH2:23][C:18]=3[C:17](=[O:24])[O:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:26]([NH:33][C:34]([N:21]1[CH2:22][CH2:23][C:18]2[C:17](=[O:24])[O:16][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)([CH3:25])[C:19]=2[CH2:20]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC1(c2cccc(OCc3ccccc3)c2)OC(=O)C2=C1CNCC2
Solvent: ClCCl
Product: CC1(c2cccc(OCc3ccccc3)c2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A mixture of 3-(3-benzyloxyphenyl)-3-methyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.15 mmol) and benzyl isocyanate (27 μL, 0.22 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (43 mg, 61.6%). 1H NMR (300 Hz, CDCl3) δ 1.84 (s, 3H), 2.38 (br s, 2H), 3.26-3.32 (m, 1H), 3.51-3.58 (m, 1H), 3.79 (d, J=18.0, 1H), 4.37-4.30 (m, 3H), 4.94 (t, J=6.0, 1H), 5.04 (s, 2H), 6.87-6.94 (m, 3H), 7.24-7.39 (m, 11H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:38]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1)([O-:40])=[O:39].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:17]=[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[N:8]1[C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:45](=[O:46])[C:44]2[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:49][CH:48]=2)[CH2:7][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of trans-2-(4-hydroxy-cyclohexyl)-isoindole-1,3-dione (38 g, 155 mmol), triphenylphosphine (65 g, 248 mmol), and 4-nitrobenzoic acid (41 g, 248 mmol) in 1500 mL of THF was added dropwise diisopropyl azodicarboxylate (50 g, 248 mmol) at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated, and the resulting solid was recrystallized from methanol to afford 53 g (87%) of the title compound as a white solid. 1H NMR (CDCl3): δ 8.40-8.36 (m, 4H), 7.79 (ddd, J=0.12, 0.02, and 0.02 Hz, 4H), 5.39 (s, 1H), 4.37-4.22 (m, 1H), 2.82-2.65 (m, 2H), 2.27-2.16 (m, 2H), 1.84-1.65 (m, 4H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[O:23][CH:24]=1.O>CN(C)C=O>[N:13]1([CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:19][C:20]3[N:21]=[C:22]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[O:23][CH:24]=3)=[CH:5][CH:6]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1csc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)c1
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
Sodium hydride (90 mg) was added to a solution of 1-[3-(4-hydroxyphenyl)propyl]imidazole (405 mg) in N,N-dimethyl formamide at room temperature and stirred for 1.5 hours. 4-Chloromethyl-2-(2-thienyl)oxazole (480 mg) was added, and the resultant was stirred at 90° C. for further 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel chromatography. From the fraction eluted with ethyl acetate-methanol (50:1, v/v), 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)oxazole (650 mg, 89%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 84-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27]CC)=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(OCC(=O)O)cc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (500 mg), ethyl bromoacetate (0.2 ml), and potassium carbonate (245 mg) in N,N-dimethyl formamide (1 ml) was stirred at 80° C. for 3 hours. The mixture was cooled and poured into ice-water. The separated solid was filtered and dissolved in a mixture of ethanol (15 ml) and tetrahydrofuran (15 ml). To the solution containing 2-(4-chlorophenyl)-6-ethoxycarbonylmethoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide was added aqueous 1N-sodium hydroxide solution (2.2 ml) in one portion at ambient temperature. The solution was stirred for one hour at ambient temperature and concentrated in vacuo. The residue was extracted with methylene chloride. The organic layer washed with brine, dried, and evaporated to give the crude product, which was crystallized from methanol to yield 2-(4-chlorophenyl)-6-carboxymethoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (213 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9](B(O)O)[CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1COCC1.[Ag]=O>[Cl:1][C:2]1[C:3]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccnc1I
Reactant: CC(C)CB(O)O
Agent: O=[Ag]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ncccc1Cl
Temperature: 75 °C
Yield: 52.9 %

Procedure:
3-Chloro-2-iodopyridine (1.552 g, 6.482 mmol), isobutylboronic acid (0.725 g, 7.112 mmol), potassium carbonate (2.7 g, 0.0195 mol) and silver oxide (3.8 g, 0.0164 mol) were suspended in THF (25 mL). The mixture was degassed three times and 1,1-Bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane (1:1) (0.520 g, 0.637 mmol) was added. The reaction mixture was heated at 75° C. under nitrogen for seven hours. The mixture was diluted EtOAc (15 mL) and washed with an aqueous solution of hydrochloric acid (2.0 M, 2×15 mL). The organic layer was discarded and the aqueous layer basified with careful addition of a saturated aqueous solution of sodium hydrogen carbonate (50 mL). The product was extracted with EtOAc (2×15 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 5% EtOAc in heptane to yield the title compound as a colourless oil (0.582 g, 53% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:11]4[CH2:20][CH2:19][CH2:18][CH:12]4[C:13](=O)[NH:14][C:15]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:11]4[CH2:20][CH2:19][CH2:18][CH:12]4[C:13](=[S:30])[NH:14][C:15]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(N3CCOCC3)ccc2C2CCCC12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: S=C1Nc2cc(N3CCOCC3)ccc2C2CCCC12
Yield: 84.3 %

Procedure:
Analogously to Example 4, 7-(4-morpholinyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (100 mg, 0.37 mmol) is reacted with Lawesson's reagent (164 mg, 0.41 mmol) to form 90 mg (84%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[N:10][NH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[C:17]([NH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:19])[CH3:18].N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[N:10][N:9]([C:25]3[CH:26]=[C:21]([NH:20][C:17](=[O:19])[CH3:18])[CH:22]=[CH:23][CH:24]=3)[C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1cn[nH]c(=O)n1Cc1ccc(Cl)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-n2ncc(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
According to Scheme 4 Step 2: To a stirred solution of 4-(4-chlorobenzyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.250 g, 1.1 mmol) in DMF (5 mL) were added 3-acetamidophenylboronic acid (0.28 g, 1.6 mmol), copper(II) acetate (0.19 g, 1 mmol) and pyridine (0.17 g, 2.1 mmol) and the mixture was stirred overnight at 60° C. The reaction was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water then with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by C18 reverse phase column, 15 g column: starting from 20% CH3CN and gradually increasing the percentage of CH3CN (10% each 300 ml) the product came out at 60% of CH3CN. 0.160 g (39%) of N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 7(B) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:11].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH2:10][Br:20])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: COC(=O)c1c(C)cccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Br)cccc1CBr
Temperature: 25 °C

Procedure:
2-Bromo-6-methyl-benzoic acid methyl ester (2.18 g), NBS (4.89 g), and AIBN (0.486 g) were taken into CCl4 (15 mL) and heated at reflux for 8 h. After cooling to RT, the solid was removed by filtration, and the filtrate was concentrated to give an orange oil as crude material. Purification by chromatography (silica gel, 100 g, 5-15% EtOAc/hexanes) afforded 2-bromo-6-bromomethyl-benzoic acid methyl ester as colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH3:13].[Li]CCCC.[C:19](=[O:21])=[O:20].Cl>C1COCC1>[CH:10]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:19]([OH:21])=[O:20])=[C:3]([CH3:13])[CH:4]=1)([CH3:12])[CH3:11]
Reactant: Cc1cc(OC(C)C)c(C)cc1I
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c(C)cc1OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A solution of 1-iodo-4-isopropoxy-2,5-dimethylbenzene (450 mg, 1.6 mmol) in THF (7.8 mL) was cooled to −78° C. before nBuLi (620 mL, 2.5 M, 1.6 mmol) was added dropwise. The mixture was allowed to warm to 0° C., then it was cooled to −78° C. before it was added dropwise to a flask containing crushed, dry CO2. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and was acidified with 1N HCl. The mixture was extracted with ethyl acetate (3×) and the combined organics were washed with brine, dried over sodium sulfate, and concentrated to give 4-isopropoxy-2,5-dimethylbenzoic acid (67 mg, 10%). ESI-MS m/z calc. 208.1. found 209.1 (M+1)+; Retention time: 1.55 minutes (3 min run).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl.[OH:41][NH2:42]>CCO>[NH2:32][C:31](=[N:42][OH:41])[C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH2:10][CH:9]2[O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C#N)ccc1O2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C(N)=NO)ccc1O2

Procedure:
To a suspension of 18.2 g of tert-butyl 4-{[tert-butyl(dimethyl)silyl]oxy}-6-cyano-spiro[chroman-2,4′-piperidine]-1′-carboxylate in EtOH was added 16.3 mL of Et3N and 8.12 g of hydroxyamine hydrochloride at rt, and the reaction mixture was stirred at 85° C. for 1d. The resultant solution was cooled to rt, and concentrated in reduced pressure. To the residue was added H2O, the resultant white solid was filtered, washed with H2O, and dried in vacuo to give a crude product, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:36])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([Cl:36])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)cc2)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(F)cc2)c1OC(C)=O
Temperature: 90 °C
Yield: 59.7 %

Procedure:
A mixture of 4-acetoxy-7-cyano-1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (103 mg), NCS (38 mg) in MeCN (2 mL) in a closed vial was heated at 90° C. for 1 h. Then the solvent was removed, the residue was purified with column to give the desired product (67 mg). The title compound, ESI MS (m/z): 416 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]4)=[O:21])[CH:14]=3)/[O:7][C:8]2=O)=[CH:4][CH:3]=1.CN(C)C=O.O.[NH2:36][NH2:37]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]4)=[O:21])[CH:14]=3)=[N:36][NH:37][C:8]2=[O:7])=[CH:4][CH:3]=1
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cc(Cl)ccc43)ccc2F)CC1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cc(Cl)ccc34)ccc2F)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
(Z)-6-chloro-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (67) (25 mg, 0.06 mmol) was taken up in water (1 mL) and N,N-dimethylformamide (0.5 mL) and treated with Hydrazine monohydrate (20 μL, 0.41 mmol). The resulting mixture was stirred at 105° C. for 1 hour. The reaction mixture was cooled and diluted with water (˜5 mL) and mixture extracted with DCM (2×5 mL). Combined organics were evaporated to dryness to afford the crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white foam (10 mg, 39% yield); 1H NMR (400.132 MHz, DMSO) δ 1.26-1.35 (1H, m), 1.40-1.49 (1H, m), 1.67-1.74 (1H, m), 1.83-1.90 (1H, m), 2.99-3.06 (1H, m), 3.26 (3H, s), 3.26-3.36 (2H, m), 3.39-3.45 (1H, m), 3.88-3.95 (1H, m), 4.33 (2H, s), 7.22 (1H, t), 7.31 (1H, dd), 7.38-7.42 (1H, m), 7.94 (1H, dd), 8.00 (1H, d), 8.21 (1H, d), 12.72 (1H, s); m/z (LC-MS, ESI+), RT=2.23 (M+H 430.7).