Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]([O:19][CH3:20])=[O:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>CN(C=O)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>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]([O:19][CH3:20])=[O:18])[CH:30]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 90 °C
Yield: 90 %

Procedure:
To a solution of methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII) (7.0 g, 20.6 mmol) in DMF (80 mL) and water (16 mL) was added K3PO4 (6.56 g, 30.9 mmol), pyridin-3-ylboronic acid (CXXXI) (2.79 g, 22.7 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and. The solution was purged with argon and heated at 90° C. for 3 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% DCM→1.5:98.5 MeOH:DCM) to give methyl 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXXXIX) as an orange oil which solidified at rt (6.28 g, 18.6 mmol, 90% yield). ESIMS found for C19H19N3O3 m/z 338.0 (M+H).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([C:11](=O)[CH2:12][CH:13]([OH:17])[C:14](O)=[O:15])[CH:8]=[CH:9][CH:10]=1>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH:13]([OH:17])[C:14](=[O:15])[NH:2][N:3]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NN
Reactant: O=C(CC(O)C(=O)O)c1cccc(Br)c1
Solvent: CCO
Solvent: O
Product: O=C1NN=C(c2cccc(Br)c2)CC1O
Temperature: 65 °C
Yield: 58.2 %

Procedure:
0.25 g of hydrazine hydrate was added, at room temperature, to a mixture of 10 ml of ethanol and 1.36 g of 4-(3-bromophenyl)-2-hydroxy-4-oxobutyric acid (prepared following the procedure described in Preparation 3), and then the mixture was heated at 65° C. for 1.5 hours. The crystals which precipitated were collected by filtration at the same temperature and then washed with ethanol, giving 0.78 g (yield 58%) of the pure title compound melting at 158°-161° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CCOCC>[CH3:8][C:6]1[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=[C:2]([O:1][C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(OC(=O)Oc2ccccc2)nc(C(Cl)(Cl)Cl)n1
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To 5.6 g (0.02 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 2.0 g (0.02 moles) triethylamine, and 100 ml ether was added 3.2 g (0.07 mole) phenyl chloroformate. The solution refluxed on addition and a precipitate formed. This was stirred 0.5 hour, filtered, and the filtrate rotary evaporated to give 6.6 g (76% yield) thick oily residue. Extraction with ligroin gave, on cooling of the extract, 3.7 g pure product as a viscous oil. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)C(C)C)C.[CH2:35]([NH:39][NH2:40])[CH:36]([CH3:38])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CN(C=O)C>[CH2:35]([N:39]1[C:2]2[C:3](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:4](=[O:6])[NH:40]1)[CH:36]([CH3:38])[CH3:37]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)CNN
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (1.5 g) in DMF (50 mL) was added EDCI.HCl (1.71 g) followed by N-ethyldiisopropylamine (5.51 mL). After 10 minutes isobutylhydrazine.p-toluenesulfonicacid salt (2.32 g) was added. The reaction mixture was stirred at ambient temperature for 22 hours and the reaction was poured onto aqueous 1N HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification via ISCO combiflash chromatography afforded pure desired 1-isobutyl-5-nitro-1,2-dihydro-indazol-3-one (0.9 g) as a yellow solid. MS (ESI−):234.1 ([M−H]−).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10])[CH2:4][OH:5])[CH3:2].[Br:12][CH:13]([CH3:17])[C:14](Br)=[O:15]>>[CH2:1]([CH:3]([NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10])[CH2:4][O:5][C:14](=[O:15])[CH:13]([Br:12])[CH3:17])[CH3:2]
Reactant: CCOC(=O)NC(CC)CO
Reactant: CC(Br)C(=O)Br
Product: CCOC(=O)NC(CC)COC(=O)C(C)Br

Procedure:
by using ethyl 1-ethyl-2-hydroxy-ethylcarbamate and 2-bromopropionyl bromide there is obtained ethyl 1-ethyl-2-(2-bromopropionyloxy)-ethylcarbamate, nD20 1.4736;
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:3][CH:2]=1.O.[OH-].[Na+]>O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.2 %

Procedure:
Methyl 2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (1.2 g, 3.61 mmol) was dissolved in dioxane (15 mL) and water (5 mL) then added a solution of 2N aqueous sodium hydroxide (1.90 mL, 3.80 mmol). The reaction mixture was stirred at room temperature for 2 days then concentrated under vacuum to remove the dioxane. The remaining aqueous solution was diluted with water then added 1N aqueous hydrochloric acid (3.8 mL) to bring the mixture to pH 7. A precipitate formed which was collected on a glass frit, washing with minimal water then dichloromethane. The solid was dried under high vacuum to afford 1.06 g of 2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid as a white solid. MS (ESI, pos. ion) m/z: 319.1 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:8]3[C:7]([Cl:6])=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:13])[N:15]=[CH:16][C:17]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl
Product: Clc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reaction time: 20 h
Yield: 86.8 %

Procedure:
Phosphorus oxychloride (7.96 mL, 85.38 mmol) was added to 1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate BA4) (1.2 g, 4.27 mmol). The resulting solution was stiffed at 100° C. for 20 hours. LCMS showed reaction was complete. The reaction mixture was evaporated. Ice/water and then EtOAc were added. The organic layer to was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with water, dried (MgSO4) and concentrated to give the product (1.110 g, 87%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.46-7.58 (3H, m), 8.45 (1H, s), 8.82 (1H, s); m/z (ES+) (M+H)+=299; HPLC tR=2.77 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C(O)(=O)C>CO.[Rh]>[CH3:10][O:9][C:7]([CH:6]1[CH2:11][CH:12]([OH:14])[CH2:13][CH:4]([C:3]([O:2][CH3:1])=[O:15])[CH2:5]1)=[O:8]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CC(O)CC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of dimethyl-5-hydroxyisophthalate (3.50 g, 16.6 mmol) in methanol (60.0 mL) was added 5% rhodium on alumina (0.80 g) at 0° C., followed by acetic acid (0.60 mL, 10.6 mmol). The reaction mixture was shaken under hydrogen (55 psi) at room temperature overnight and then filtered through Celite® and concentrated under reduced pressure. The residue was purified by CombiFlash® system (12 g silica gel cartridge; gradient: 0 to 50% ethyl acetate in DCM over 30 min) to give 3.00 g (83%) of the title compound, 5-hydroxy-cyclohexane-1,3-dicarboxylic acid dimethyl ester. 1H NMR (400 MHz, CDCl3): δ 3.56-3.78 (m, 7H), 2.15-2.51 (m, 5H), 1.25-1.66 (m, 3 H).
Reaction SMILES: [CH:1]1([C:6]2[N:14]3[C:9]([C:10](=[O:28])[NH:11][C:12]([C:15]4[CH:16]=[C:17]([S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=4[O:21][CH2:22][CH3:23])=[N:13]3)=[C:8]([CH2:29][CH3:30])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:22]([O:21][C:20]1[CH:19]=[CH:18][C:17]([S:24]([N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)(=[O:26])=[O:25])=[CH:16][C:15]=1[C:12]1[NH:11][C:10](=[O:28])[C:9]2=[C:8]([CH2:29][CH3:30])[N:7]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:14]2[N:13]=1)[CH3:23]
Reactant: CN1CCNCC1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
0.42 g (0.92 mmol) of 3-(7-cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonyl chloride are dissolved in 15 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of 4-dimethylaminopyridine, 0.28 g (2.76 mmol) of N-methylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 0.395 g (80%) of a colourless solid.
Reaction SMILES: O1CCCC1.Cl.C(OC([N:14]1[CH2:19][CH2:18][C:17](=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si](C(C)(C)C)(C)C)[CH:39]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:37])[N:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[CH3:29])[CH:22]=2)[CH2:16][CH2:15]1)=O)(C)(C)C>O>[F:36][C:32]1[CH:31]=[C:30]([N:28]([CH3:29])[C:27](=[O:37])[C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=3)=[C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]3)[CH:22]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CN(C(=O)c1cccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)c1)c1cccc(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cccc(C(=C2CCNCC2)c2cccc(O)c2)c1)c1cccc(F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
Tetrahydrofuran (70 mL) and 3 N HCl (50 mL) were added to the above crude 4-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methylcarbamoyl]phenyl}-methylene)piperidine-1-carboxylic acid tert-butyl ester (2.75 g). The resulting mixture was stirred at 60° C. for 4 h. The reaction mixture was cooled to room temperature, followed by the addition of water (100 mL). The resulting solution was extracted with diethyl ether (100 mL×2). The remaining water layer was neutralized to pH≅9. by 10% NaOH. The water layer became cloudy at this stage. The cloudy water mixture was extracted by n-butanol (100 mL×3). The combined n-butanol layers were washed by water (75 mL×2) and brine (75 mL×1), dried by Na2SO4 and concentrated to give crude product (2.27 g; crude), which was purified to give N-(3-fluorophenyl)-3-[(3-hydroxyphenyl)-piperidin-4-ylidene-methyl]-N-methyl-benzamide (579 mg). 1H NMR (600 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.23 (m, 3H), 7.09 (d, 1H, J=10.0 Hz), 7.03 (dd, 1H, J=8.0, 8.0 Hz), 6.96 (ddd, 1H, J=8.5, 8.5, 2.5 Hz), 6.92 (m, 2H), 6.85 (s, 1H), 6.56 (dd, 1H, J=8.0, 2.0 Hz), 6.34 (s, 1H), 6.31 (d, 1H, J=7.5 Hz), 3.35 (s, 3H), 2.65 (m, 2H), 2.55 (m, 2H), 2.13 (bs, 1H), 2.07 (m, 2H), 1.72 (m, 2H); Found: C, 72.87; H, 6.51; N, 5.86. Calc. C, 72.77; H, 6.62; N, 5.98.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([C:17](C)([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])[CH2:14][CH2:15][CH3:16].C(O)C>O>[CH3:23][CH:17]([CH2:13][CH2:14][CH2:15][CH3:16])[C:18]([OH:20])=[O:19]
Reactant: CCCCC(C)(C(=O)OCC)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCCCC(C)C(=O)O
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A mixture of 40 g of p-toluenesulfonic acid monohydrate and 313 g of diethyl butylmethylmalonate was heated to 125°-135° C. in a flask equipped with a distillation column packed with Raschig rings. After 15 minutes, ethanol began to reflux in the distillation head. Ethanol was distilled as it formed and the pot temperature was maintained at 120°-126° C. by periodic addition of water to the pot. After 22 hours, the distillation of ethanol had ceased. The mixture then was cooled and treated with 70 ml of water. The layers were separated to afford 159.2 g (90.6% yield) of 2-methylhexanoic acid (99.8% pure by VPC).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=3)[S:10][C:3]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: COc1cccc(Br)n1
Product: COc1cccc(-c2cc3nccc(Cl)c3s2)n1
Yield: 62.5 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.478 g, 1.44 mmole) with 2-bromo-6-methoxypyridine (0.177 ml, 1.44 mmole) using tereakis(triphenylphosphine)palladium(0) (67 mg) as catalyst in a manner as previously described for example 39b to give a pale yellow solid (0.249 g, 63%). 1H NMR (300 MHz, CDCl3) δ 8.56 (1H, d, J=5.1 Hz), 7.98 (1H, s), 7.66 (3H, m), 6.75 (1H, d, J=8.3 Hz), 4.05 (3H, s); ESIMS (MH+): 276.95.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:5][N:4]1CC)[CH3:2].Cl[O-].[Na+]>>[CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCN1CC(NC(=O)c2ccc(F)cc2)CN1CC
Agent: [Na+]
Agent: [O-]Cl
Product: CCN1CC(NC(=O)c2ccc(F)cc2)C=N1

Procedure:
In accordance with the procedure of Example 12, N-(1,2-diethyl-4-pyrazolidinyl)-4-fluorobenzamide is reacted with sodium hypochlorite and the product is isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]3[NH:27][C:26](=[O:28])[O:25][C:24]([CH3:30])([CH3:29])[C:23]=3[CH:31]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:32]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]3[NH:27][C:26](=[O:28])[O:25][C:24]([CH3:29])([CH3:30])[C:23]=3[CH:31]=2)=[O:32])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OO
Reactant: COc1ccc(SCCCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC
Product: COc1ccc(S(=O)CCCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 2 from 6-[6-(3,4-dimethoxy-phenylmercapto)-hexyloxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11]OS(C(F)(F)F)(=O)=O)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:20]#[N:21].Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: N#Cc1ccc2c(c1Cl)CC(COS(=O)(=O)C(F)(F)F)O2
Reactant: BrCCc1ccccc1
Product: N#Cc1ccc2c(c1Cl)CC(CCCc1ccccc1)O2
Yield: 68 %

Procedure:
Following the process described in example 3 (point B), starting from 4-chloro-2-trifluoromethanesulfonyloxymethyl-2,3-dihydrobenzofuran-5-carbonitrile and 2-bromoethylbenzene, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl ether, 95:5 (68% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([O:17]C)=O)[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[NH3:19]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([NH2:19])=[O:17])[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1
Reactant: N
Reactant: COC(=O)Cc1ccnc(N2CCN(C)CC2)c1
Product: CN1CCN(c2cc(CC(N)=O)ccn2)CC1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of methyl 2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetate (750 mg, 2.81 mmol) in methanolic ammonia (10 ml) was heated in a steel bomb at 90° C. for 72 h. The reaction mixture was cooled to room temperature, concentrated and dried in vacuum to afford the crude product. Purification by triturating with diethyl ether afforded 370 mg (31%) of 2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetamide as a light brown color solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1>>[OH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH2:19][CH2:18][CH2:17][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:22][CH:23]=1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Reactant: OCc1ccc(OCCCBr)cc1
Product: OCc1ccc(OCCCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 88.6 %

Procedure:
1-(4-Piperidyl)indoline (263 mg) and 4-(3-bromopropoxy)benzyl alcohol (389 mg) were treated as in Example 2 to give the title compound (422 mg) as a pale orange amorphous solid (yield: 92%).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([NH2:27])=O)[CH3:22]>C1COCC1.CC(=O)OCC>[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([NH2:27])=[S:2])[CH3:22]
Reactant: CCOC(OCC)C(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(OCC)C(N)=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a suspension of phosphorus pentasulfide (27 g) in dry THF (100 ml) at 0° C. under vigorous stirring, Na2CO3 (13 g) was added. The reaction mixture was stirred for 30 min at 0° C. and for 30 min at r.t., then diethoxyacetamide (6 g) was added and stirring was continued at r.t. for 70 h. The reaction was then diluted with EA, washed with 10% Na3PO4, brine, dried over Na2SO4 and the solvent removed in vacuo. The crude residue was purified by flash-chromatography (EE/PE 1/1) to give the title compound as a white solid (4.4 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]#[CH:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]#[CH:12])[C:6]3[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=3[O:4][C@@H:3]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: C#CCN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C#CCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a stirred solution of (2R,3S)-3-amino-2-phenyl-5-prop-2-yn-1-yl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (67c) (65 mg, 0.222 mmol) in dichloromethane (3 mL) was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (65 mg, 0.267 mmol), HOBt (40 mg, 0.296 mmol), NMM (31 mg, 0.306 mmol) and EDAC-HCl (55 mg, 0.286 mmol). After stirring at ambient temperature under nitrogen overnight the solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic solution was separated, washed with 1N aqueous HCl then dried, filtered and evaporated. The residue was purified by recrystallization from 1:1 (v/v) ethyl acetate:hexanes to afford the title compound (86 mg, 74%) as a white solid. TLC Rf=0.25 (diethyl ether). 1H NMR (300 MHz, CDCl3) δ1.22 (d, 3H, J=7.0 Hz), 2.31 (m, 1H), 3.48 (s, 2H), 4.23 (m, 1H), 4.69 (d, 2H, J=2.2 Hz), 5.11 (t, 1H, J=7.0 Hz), 5.69 (d, 1H, J=7.4 Hz), 5.87 (d, 1H), 6.18 (d, 1H), 6.69-6.86 (m, 3H), 7.26-7.53 (m, 9H). MS APCI, m/z=518 (M+1). LC/MS: 2.63 min.
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[CH:34]([C:37]1[NH:38][CH:39]=[CH:40][N:41]=1)([CH3:36])[CH3:35]>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:38]3[CH:39]=[CH:40][N:41]=[C:37]3[CH:34]([CH3:36])[CH3:35])=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Reactant: CC(C)c1ncc[nH]1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2ccnc2C(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 23b using (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy)quinolin-3-yl]methyl}phenyl)boronic acid and 2-isopropyl-1H-imidazole.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH3:15][CH:16]([NH2:22])[CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:22][CH:16]([CH3:15])[CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Reactant: CCC(C)CC(C)N
Product: CCC(C)CC(C)NC1=NS(=O)(=O)c2cc(Cl)ccc2N1

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (500 mg; 1.99 mmol) and 1,3-dimethylpentylamine (1 g; 8.68 mmol) and with the use of same procedure as in example 21 230 mg (35.1%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.41 (s, 1H, NH), 7.68 (d, 1H, H-8), 7.60 (dd, 1H, H-5), 7.2 (d, 1H, H-7), 7.0 (br, 1H, NH), 3.95 (m, 1H, CH), 1.5 (m, 8H), 0.9 (m, 6H, 2×CH3); MS:EI/70eV: 329 (M+), 301, 258, 231, 190, 126, 69, 44. Analysis: C14H20ClN3O2S requires C, 50.98; H, 6.11; N, 12.74; (found C, 51.23; H, 6.42; N, 12.53).