Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH2:47]([NH2:56])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([NH:56][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:11]
Reactant: CCCCCCCCCN
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1OC
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a suspension of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzoic acid (150 mg, 0.42 mmol) in CH2Cl2 (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and 1-hydroxybenzotriazole hydrate (77 mg, 0.50 mmol) with stirring at RT. To the resulting yellow solution was added nonylamine (154 μl, 0.84 mmol) at RT. The resulting mixture was stirred 2 h at RT then solvent removed under a dry nitrogen stream. The residue was purified by preparative TLC (5% Et2O, 45% hexanes, 50% CH2Cl2) to give the title compound of Step C (173 mg). MS (APCl+) Calc.: 482.1, Found: 483.2 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Ic1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of 1,4-diiodobenzene (16.5 g, 50 mmol) in THF (350 mL) at −78° C. was added n-BuLi (2.5 M, 24 mL) over 1 hour. After being stirred for an additional 30 minutes, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (7.8 g, 50 mmol) in THF (30 mL) was added in and the resulting mixture was stirred for 3 hours. To the mixture was added TMSC1 (5.4 g, 50 mmol) and the resulting mixture was allowed to warm to rt and stirred at rt for 18 hours. The reaction mixture was neutralized to pH 6.0, and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (95/5 to 100/0). The appropriate fractions were combined to give 8-(4-Iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (12 g, 66.6%) with LCMS: 361.2 (M+H+, 100%) and {[8-(4-iodophenyl)-1,4-dioxaspiro[4.5]dec-8-yl]oxy}(trimethyl)silane (6 g, 27%) with LCMS: 433.1 (M+H+, 100%).
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C(O)(C)(C)C>[C:8]([O:7][C:1](=[O:12])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a solution of tert-butyl alcohol (650 mL) and di-tert-butyl carbonate (24 g) was added 2-aminopyridine (9.4 g) slowly. This mixture was stirred for 24 hours at room temperature. This reaction solution was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (18 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 321.2 %

Procedure:
A mixture of 2-(trimethylsilyl)ethoxymethyl chloride (11.6 g, 0.07 moles), imidazole (9.5 g, 0.014 moles) and dry toluene (100 ml) was stirred at room temperature for 18 hours, and the resulting imidazole hydrochloride was removed by filtration. The filtrate was concentrated to provide 13.4 g (97%) of crude product. Kugelrohr distillation at 94°-100° C. (0.2 mm) gave 8.92 g (65%) of the desired product as a colorless liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11](=[O:15])[NH:12]2)=[CH:8][CH:7]=1.[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.N1CCCCC1>C(O)C>[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)[NH:12][C:11]1=[O:15]
Reactant: O=Cc1ccccc1O
Reactant: O=C1Cc2ccc(-c3cccs3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(-c3cccs3)ccc2C1=Cc1ccccc1O
Yield: 50.1 %

Procedure:
A mixture of 6-thiophen-2-yl-1,3-dihydroindol-2-one (100 mg, 0.5 mmol), 2-hydroxybenzaldehyde (60 mg, 0.5 mmol) and piperidine (0.23 mL) in ethanol (4 mL) was stirred at reflux overnight. The reaction mixture was concentrated and column chromatographed (eluant—isopropanol/dichloromethane) to give 80 mg (50%) of 3-(2-hydroxybenzylidene)-6-thiophen-2-yl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:6]2=[O:23].[CH3:24][C:25]1(OC)[CH2:29][CH2:28][CH:27](OC)O1>CC(O)=O>[CH3:24][C:25]1[N:1]([CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:12]=2[C:13]([F:15])([F:16])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:6]3=[O:23])[CH:27]=[CH:28][CH:29]=1
Reactant: COC1CCC(C)(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Solvent: CC(=O)O
Product: Cc1cccn1Cc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (150 mg, 0.43 mmol) in conc. CH3CO2H (10 mL) was added 2-methyl-2,5-dimethoxytetrahydrofurane (62.2 mg, 0.43 mmol) and the reaction mixture was stirred for 2 h at reflux temperature. Subsequently, the solvent was evaporated and the crude light-yellow residue was recrystallized from EtOAc/cyclohexane to yield N-[6-(2-methyl-pyrrol-1-ylmethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (130 mg, 0.312 mmol, 73%) as a light-orange solid. 1H-NMR (DMSO-d6, 400 MHz) 3.11 ppm (s, 3H, SO2—CH3; LC-MS rt=3.994 mn; MS: m/z 416.9 [M+H]+ Column: SunFireC18, 4.6*50 mn, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH2:34][OH:35])[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:51]1[CH:58]=[CH:57][C:54]([CH:55]=[O:56])=[CH:53][CH:52]=1>C1COCC1>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[CH2:34][O:35][C:51]1[CH:58]=[CH:57][C:54]([CH:55]=[O:56])=[CH:53][CH:52]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2cccc(OCc3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a stirring solution of triphenylphosphine (1.1 mmols) in THF (2 mLs) was added 34 (1.1 mmols). The solution was immediately cooled to 0° C. and diisopropyl azodicarboxylate (1.1 mmols) was added dropwise and the mixture was stirred at this low temperature for 15 minutes. After this time, 4-hydroxybenzaldehyde (1 mmol) was added to the reaction vessel, still stirring at 0° C. The mixture was warmed slowly to ambient temperature and stirred for 15 hours. At this time, the THF was evaporated, reconstituted in Et2O and filtered through a small portion of silica gel. The eluent was collected and evaporated to dryness. The title product (0.45 mmols) was recovered after flash chromatography. 1H NMR (300 MHz, CDCl3) δ 9.89 (s, 1H), 7.91-7.77 (m, 2H), 7.50-7.30 (m, 6H), 7.03 (ddd, J=5.1, 11.5, 24.0, 5H), 5.13 (s, 2H), 5.08 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 191.04, 163.88, 159.36, 137.82, 136.98, 132.24, 130.09, 128.86, 128.29, 127.74, 120.05, 115.39, 114.79, 114.14, 77.70, 77.27, 76.85, 70.25.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Si:15]([O:22][C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[Si:15]([O:22][C:23]1([CH2:29][CH2:30][CH2:31][NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OC1(CCCN)CCCCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(CCCNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
4-Chloro-3-nitroquinoline (0.700 g, 3.37 mmol) was added in two portions to a solution of 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-amine (0.960 g, 3.54 mmol) and triethylamine (0.610 mL, 4.38 mmol) in dichloromethane (15 mL) at 0° C. After 30 min, the reaction was allowed to warm to rt and stir overnight. The mixture was diluted with dichloromethane (40 mL) and was washed with saturated aqueous sodium bicarbonate (30 mL). The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a yellow solid. The crude product was purified using HPFC (silica gel, gradient elution with 0-2% ethyl acetate/hexanes) to yield N-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-3-nitroquinolin-4-amine as a bright yellow solid (1.40 g, 93%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([N:28]2[CH:36]3[CH:31]([CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:30][CH2:29]2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:28]1([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:36]2[CH:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1cc(Cl)ncn1)N1CCC2CCCCC21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCC2CCCCC21
Temperature: 25 °C

Procedure:
201 mg (0.69 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-on-dihydrochloride were added to 184 mg (0.69 mmol) (6-chloropyrimidin-4-yl)-(octahydroindol-1-yl)-methanone and 488 μL (2.8 mmol) DIPEA in 3 mL DMF. The reaction mixture was stirred at RT over the weekend and then purified by preparative HPLC-MS. The product fractions were combined and the organic solvent was removed using the rotary evaporator. The aqueous solution was neutralised with aqueous 1N NaOH solution and the precipitate obtained was suction filtered. The precipitate was washed with water and dried.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:35].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[O:35])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 6 (146 mg, 0.313 mmol) in DCM (10 mL) was added TFA (72 μL, 0.939 mmol) followed by a solution of m-CPBA (59 mg, 0.344 mmol) in DCM (2 mL). The resulting mixture was stirred for 1 h at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 15-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH affording 206 as a colorless foam (130 mg, 86%). LCMS: RT 2.47 min [M+H]+ 483.1. 1H NMR (DMSO, 400 MHz): δ 8.59 (1H, d, J=2.27 Hz), 7.93 (1H, s), 7.53 (1H, dd, J=8.53, 2.29 Hz), 7.25 (1H, d, J=8.53 Hz), 5.71-5.58 (1H, m), 4.62-4.50 (4H, m), 2.8-2.75 (2H, m), 2.74-2.58 (2H, m), 2.26 (3H, s), 2.13-2.03 (2H, m), 1.78 (1H, bd, J=12.31 Hz), 1.61 (1H, bd, J=12.24 Hz), 1.50-1.33 (7H, m), 0.90 (6H, d, J=6.54 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:61][OH:62])[C@@H:28]([OH:60])[C@@H:29]([OH:59])[C@H:30]([OH:58])[C:31]([NH:33][C@H:34]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:35][C:36]([O:38][CH:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])=[O:32])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:63](OC(=O)C)(=[O:65])[CH3:64]>N1C=CC=CC=1>[C:63]([O:62][CH2:61][C@H:27]([NH:26][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C@@H:28]([OH:60])[C@@H:29]([OH:59])[C@H:30]([OH:58])[C:31]([NH:33][C@H:34]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:35][C:36]([O:38][CH:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])=[O:32])(=[O:65])[CH3:64]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-((N-benzyloxycarbonyl-L-valyl)-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (200 mg) in pyridine (1 ml) was added acetic anhydride (0.0243 ml) and the mixture was stirred at room temperature for 14 hours. After concentration under reduced pressure, the residue was passed through silica gel column chromatography, followed by elution with ethyl acetate-methanol (20:1). The effective fractions were combined and concentrated under reduced pressure to give a residue, which was recrystallized from mthanol-diethylether to provide the title compound (103 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]cc(Cl)c2ccc(Br)cc12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(Cl)c3ccc(Br)cc3c2=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a screw cap pressure vessel, 7-bromo-4-chloroisoquinolin-1(2H)-one (Ark Chemicals, 2.50 g, 9.67 mmol) was added to a vial followed by cesium carbonate (6.30 g, 19.34 mmol) and DMF (9.67 mL). 1-(chloromethyl)-4-methoxybenzene (1.444 ml, 10.64 mmol) was added, the vial was capped and heated to 50° C. for 1 hours. The reaction was cooled to room temperature and water (20 mL) was added. The reaction was stirred for an additional 1 hour and filtered. The solid was collected and dried under a vacuum to yield 2.25 g of 7-bromo-4-chloro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one as an off white solid. m/z (ESI) 380.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([OH:11])[CH2:5][C:4]1([CH3:13])[CH3:12].[NH:14]([C:20]([O:22]C)=O)[NH:15][C:16]([O:18][CH3:19])=[O:17]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[NH:15]([C:16]([O:18][CH:19]1[CH2:10][C:8]([CH3:9])([CH3:7])[N:3]([O:2][CH3:1])[C:4]([CH3:13])([CH3:12])[CH2:5]1)=[O:17])[NH:14][C:20]([O:11][CH:6]1[CH2:7][C:8]([CH3:9])([CH3:10])[N:3]([O:2][CH3:1])[C:4]([CH3:13])([CH3:12])[CH2:5]1)=[O:22]
Reactant: COC(=O)NNC(=O)OC
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CON1C(C)(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(OC)C(C)(C)C2)CC1(C)C
Yield: 64 %

Procedure:
To a mixture of 15.8 g of 1-methoxy-2,2,6,6-tetramethylpiperidin-4-ol and 5.9 g of dimethyl hydrazine-1,2-dicarboxylate is added 1.4 g of tetrabutyl titanate at room temperature. The mixture is heated at 135°-145° C. for 12 hours and methanol is collected in a Dean-Stark trap. The reaction mixture is partitioned between toluene and water. The organic phase is then washed with water, brine, dried over anhydrous sodium sulfate and evaporated to leave 19.1 g of the crude desired product. Recrystallization of the crude product from acetonitrile affords 11.7 g of the title compound as an off-white solid; mp 147°-149° C.
Reaction SMILES: OC1C=C(N2C3C(=NC(OC)=CC=3)N=C2)SC=1C(OC)=O.[OH:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32]3=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=[C:31]3[N:30]=[CH:29]2)[S:25][C:24]=1[C:39]([O:41][CH3:42])=[O:40].C([O-])([O-])=O.[K+].[K+].Br[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:60])([F:59])[F:58]>CN(C)C=O>[CH3:38][O:37][C:34]1[N:33]=[C:32]2[N:28]([C:26]3[S:25][C:24]([C:39]([O:41][CH3:42])=[O:40])=[C:23]([O:22][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:57]([F:58])([F:59])[F:60])[CH:27]=3)[CH:29]=[N:30][C:31]2=[CH:36][CH:35]=1
Reactant: COC(=O)c1sc(-n2cnc3ccc(OC)nc32)cc1O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: COC(=O)c1sc(-n2cnc3nc(OC)ccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccc(OC)nc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B3, 1.4 g of an isomeric mixture of methyl 3-hydroxy-5-(5-methoxy-1H-imidazo[4,5-b]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)thiophene-2-carboxylate (example C9) and 0.76 g K2CO3 and 1.31 g 1-(bromomethyl)-2-(trifluoromethyl)benzene in 20 ml N,N-dimethylformamide yield compound B7a and compound B7b as crude material. These compounds were used for the next step (examples 22 and 23) without further purification.
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1O.S(=O)(=O)(O)O>O>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:18]3[C:19]([CH3:23])=[CH:20][C:21]([CH3:22])=[C:16]([CH3:15])[C:17]=3[O:5][C:3]2=[O:4])=[CH:7][CH:8]=1)([CH3:14])[CH3:13]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(C(C)C)cc1
Temperature: 115 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a mixture of hydroxy(4-isopropylphenyl)acetic acid synthesized in Reference Example 1 (11.8 g, 60.8 mmol) and 2,3,5-trimethylphenol (12.4 g, 91.2 mmol) was added 70% sulfuric acid (10 mL) at room temperature, and the mixture was stirred at 115° C. for 12 hours. The mixture was added to water and was extracted with diisopropyl ether. The extract was washed with water and a saturated sodium hydrogen carbonate solution, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane ethyl acetate=8:1) to obtain 10.9 g (yield 65%) of the title compound. Melting point: 107-108° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.Br[CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].CCN(CC)CC>CCO>[OH:21][C@@H:13]([CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[C:26]2=[O:35])[CH2:19][CH2:20]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCN4C(=O)c5ccccc5C4=O)CC3)ccc2s1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (500 mg, 1.63 mmol) in EtOH (25 mL) was added N-(2-bromoethyl) phthalimide (435 mg, 1.71 mmol) and Et3N (0.79 mL, 5.7 mmol). The reacting solution was shaken at 90° C. for 16 hours. Upon cooling, the solution was concentrated to an oil and purified via flash column chromatography (4:1 EtOAc/MeOH) to afford 2-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzo[c]azolidine-1,3-dione.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][C:16](OC)=[O:17])[CH:11]=[CH:12][CH:13]=1>O1CCOCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][C:16](=[O:17])[CH2:2][C:1]#[N:3])[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1cccc(OC)c1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cccc(CCC(=O)CC#N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
Acetonitrile (3.36 ml, 64.25 mmol, 1 eq) was added to a slurry of sodium hydride (2.57 g dispersion in mineral oil, 64.25 mmol, 1 eq) in anhydrous 1,4-dioxane (50 ml) and the mixture was stirred at room temperature for 20 mins. Methyl 3-(3-methoxyphenyl)propanoate (10.4 g, 53.54 mmol, 1 eq) in 1,4-dioxane (25 ml) was added and the reaction was refluxed for 2 h. The reaction mixture was cooled and quenched with water. The residue was dissolved in 2M HCl and extracted into ethyl acetate. The organic layer was separated, washed with 2M HCl, water and brine and dried over magnesium sulphate. Evaporation under reduced pressure gave yield to a yellow oil, which was purified by silica column chromatography, eluting with a mixture of 0-50% ethyl acetate in hexanes. Fractions containing the product were combined and evaporated to leave 5-(3-methoxyphenyl)-3-oxo-pentanenitrile (5.37 g, 49% yield).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.F[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37]>>[CH:35]1([CH:36]([OH:37])[C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:34]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Reactant: O=Cc1ccccc1F
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (10 g) and 2-fluorobenzaldehyde (2.6 cc), 4-dimethylamino-1-(2-fluorophenyl)-2-phenyl-2-buten-1-ol (Z) hydrochloride (3.5 g) is obtained in the form of a white powder melting at 175° C. after recrystallisation from a mixture (90 cc) of isopropanol and isopropyl ether (60/40 by volume).