Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[H][H]>[C].[Pd].C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:15]([F:16])([F:17])[F:18])[CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask, was placed ethyl (2E)-3-[4-hydroxy-2-(trifluoromethyl)phenyl]prop-2-enoate (2.6 g, 9.99 mmol, 1.00 equiv), ethanol (40 mL), Palladium carbon (5 g). To the above hydrogen was introduced in. The resulting solution was stirred for overnight at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.4 g (crude) of ethyl 3-[4-hydroxy-2-(trifluoromethyl)phenyl]propanoate as light yellow oil.
Reaction SMILES: C([N:3]1[CH2:20][CH2:19][C:6]2([O:10][C:9](=[O:11])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]2=[CH2:18])[CH2:5][CH2:4]1)=O.O.NN.C(O)(=O)C>C(O)C>[CH2:18]=[C:7]1[C:6]2([CH2:19][CH2:20][NH:3][CH2:4][CH2:5]2)[O:10][C:9](=[O:11])[N:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C1N(c2ccccc2)C(=O)OC12CCN(C=O)CC2
Agent: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: C=C1N(c2ccccc2)C(=O)OC12CCNCC2
Yield: 41 %

Procedure:
A solution containing 5.4 g of 8-formyl-4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane, 3.0 g of hydrazine monohydrate and 3.6 g of acetic acid in 54 ml of aqueous ethanol of 60% by volume concentration is stirred under argon at a temperature of 62°-65° C. The reaction is followed by TLC. After termination of the reaction the mixture is evaporated under reduced pressure. After taking up the residue in chloroform and saturated aqueous sodium hydrogen carbonate solution, the chloroformic phase is separated, washed to neutral, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate under clarifying by activated carbon to give the title compound in 41.0% yield, m.p.: 185°-186° C.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:13][C:14]1[C:19]2[CH:20]=[CH:21][NH:22][C:18]=2[CH:17]=[CH:16][N:15]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:1]1([S:7]([N:22]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([Cl:13])[C:19]=3[CH:20]=[CH:21]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)nccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
Benzenesulfonyl chloride (3 mL, 23.5 mmol) is added dropwise to a solution of tetrabutylammonium hydrogen sulfate (0.53 g, 1.56 mmol), sodium hydroxide (1.56 g, 38.9 mmol) and 4-chloro-1H-pyrrolo[3,2-c]pyridine (2.38 g, 15.6 mmol) (prepared according to Rasmussen, M. J. Het. Chem, 1992, 29, 359) in CH2Cl2. The mixture is stirred at room temperature for 4 hours the diluted with CH2Cl2 and washed with saturated NH4Cl solution and brine. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with 1% MeOH/CH2Cl2 to 2% MeOH/CH2Cl2 to afford the title product (3.21 g, 11 mmol) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:49])[CH:4]([NH:25][C:26](=[O:48])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>>[Br:33][C:31]1[CH:30]=[CH:29][C:28]([NH:34][S:35]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][CH:43]=2)(=[O:37])=[O:36])=[C:27]([CH:32]=1)[C:26]([NH:25][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1)[C:3]([OH:49])=[O:2])=[O:48]
Reactant: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)NC(Cc2ccc(-c3ccccc3Oc3ccccc3)cc2)C(=O)O)cc1
Yield: 86.5 %

Procedure:
2-[5-Bromo-2-(4-t-butyl-benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl) propionic acid methyl ester (0.04 g, 0.054 mmol ) was treated with LiOH (2 eq, 1 N aqueous solution) according to the general procedure C to give 0.034 g of 2-[5-bromo-2-(4-t-butyl-benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl) propionic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([CH:18]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:21]1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[NH4+].N>O1CCCC1.C(OCC)(=O)C.C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([C:15](=[O:16])[NH2:21])[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(O)c(C(=O)O)c1
Reactant: CN1CCOCC1
Agent: C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(O)c(C(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(tert-Butoxycarbonylamino-methyl)-2-hydroxy-benzoic acid (20.0 g, 74.9 mmol) in 700 mL tetrahydrofuran at 0° C. was added 4-methyl morpholine (12.3 mL, 112.3 mmol), 1-hydroxybenzo-triazole (15.2 g, 112.3 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.5 g, 112.3 mmol). Stir for 1 hour at 0° C., then added concentrated ammonium hydroxide (15.2 mL, 112.3 mmol). The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was then diluted with ethyl acetate and washed with 5% citric acid (3×250 mL), saturated sodium bicarbonate (3×250 mL), and saturated sodium chloride (1×250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a pale yellow powder. The powder was collected and washed with ether, followed by drying under reduced pressure to yield (14.0 g, 71%). 1H NMR (400 MHz, DMSO): δ 12.77 (bs, 1H), 8.33 (bs, 1H), 7.72 (d, 1H), 7.28 (d, 2H), 6.84 (d, 1H), 4.05 (d, 2H), 1.38 (s, 9H); Mass Spectrum (Chemical Ionization, 1% NH3 in CH4) m/z 267 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:4]=2[C:3]=1[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC.Cl.[F-].[K+]>C1(C)C=CC=CC=1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]1([NH:19][C:3]2[C:2]([C:31](=[O:33])[CH3:32])=[CH:7][N:6]=[C:5]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:4]=23)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(Br)cnc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
5-Bromo-N-cyclohexyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine (160 mg, 0.377 mmol) in toluene (3 mL) was stirred with bis(triphenylphosphine)palladium (II) dichloride (35 mg, 0.050 mmol) and tributyl(1-ethoxyvinyl)tin (382 μL, 1.13 mmol) at 75° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and stirred with 1 M hydrochloric acid (2 mL) and potassium fluoride (100 mg, 1.73 mmol) at room temperature for 30 minutes. The reaction mixture was filtered, and the solid was washed with ethyl acetate. The filtrate and the washings were mixed with water and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1→5/1 (v/v)) to give the title compound as a yellow oil (58 mg, yield 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3cc(F)cc(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluorophenyl)methanol and 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)[N:6]=1.[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[C:10]([N:11]([CH3:34])[C:12](=[O:15])[CH2:13][CH3:14])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)[N:6]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCC(=O)Nc1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O=CO
Product: CCC(=O)N(C)c1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 50 mg (0.11 mmol) of N-{4,6-diamino-2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-5-yl}propanamide formate were initially charged in THF (0.47 ml), and 22.3 mg of a 2 N solution of sodium bis(trimethylsilyl)amide in THF (0.12 mmol) were added. After 30 min at 0° C., 14 μl (0.22 mmol) of methyl iodide were added and the mixture was stirred at 20° C. for 20 hours. The mixture was then concentrated and the residue was purified by preparative HPLC (acetonitrile/water (+0.1% formic acid) gradient). This gave 17 mg of the target compound (32% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])([O-:3])=[O:2].[H-].[Na+].I[CH3:18]>CN(C=O)C>[CH3:18][N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Nc1ccccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.6 %

Procedure:
To a cooled (0° C.) solution of N-(2-nitrophenyl)methanesulfonamide (50 mg, 0.231 mmol) in DMF (2 mL) was added sodium hydride (11 mg, 0.46 mmol) and the reaction was warmed to room temperature and stirred for 20 minutes. The reaction was then re-cooled to 0° C. and iodomethane (0.029 mL 0.46 mmol) was added. The reaction was warmed to room temperature and stirred for 3 hours. The crude reaction was concentrated and purified by silica gel chromatography to provide N-methyl-N-(2-nitrophenyl)methanesulfonamide (20 mg, 38% yield). 1H NMR (300 MHz, CDCl3) δ 7.91 (m, 1H), 7.70-7.50 (m, 3H), 3.34 (s, 3H), 3.01 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][CH:3]=1.C(O)(=[O:24])C>O.[O-2].[O-2].[O-2].[Cr+6]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:24])=[CH:6][CH:7]=1
Reactant: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1cc(CS(=O)c2ccc(O)cc2)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
3,4,5-Trimethoxybenzyl 4-hydroxyphenyl thioether (500 mg, 1.63 mmol), prepared as described in Example 1, was dissolved in 10 mlof acetic acid, and heated to 80° C. A solution of chromium trioxide in 30 ml of distilled water was added dropwise to the above solution. The mixture was stirred for 30 min, cooled to room temperature, diluted with 20 ml of water, and then extracted with 30 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and purified on silica gel column chromatography (ethyl acetate/n-hexane=1/4) to give 348 mg (66% yield) of 3,4,5-trimethoxybenzyl 4-hydroxyphenyl sulfoxide as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.C(#N)C>[CH3:30][S:31]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])(=[O:33])=[O:32]
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (37 mg, 0.12 mmol) in 3 mL of dichloromethane/acetonitrile (1:1) was added triethylamine (0.048 mL, 0.34 mmol) and methanesulfonyl chloride (0.0098 mL, 0.13 mmol). After one hour, another portion of methanesulfonyl chloride (0.005 mL) was added. After another 10 minutes, the mixture was partitioned between ethyl acetate and saturated NH4Cl solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting solid was triturated with acetonitrile/methanol (1:1) to give the titled compound as a white solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C14H18N3O7S2 (M+H+): 404.0581. Found 404.0620.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.CCN=C=NCCCN(C)C.[Cl:28][C:29]1[C:30]([C:35](O)=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=1>C1C=CC2N(O)N=NC=2C=1.O>[I:1][C:2]1[CH:3]=[C:4]([NH:10][C:35]([C:30]2[C:29]([Cl:28])=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:36])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: CNc1ncc(I)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CNc1ncc(I)cc1NC(=O)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 9 h
Yield: 121.4 %

Procedure:
To a mixture of 5-iodo-N2-methyl-pyridin-2,3-diamine (1.9 g) and pyridine (6 ml) were added WSC (1.28 g), HOBt (86 mg) and 3-chloro-pyridin-2-carboxylic acid (1.3 g), and the mixture was stirred at room temperature for 9 hours. To this reaction mixture was added water, and the mixture was filtered to collect the precipitated powder. The collected powder was washed with chloroform to give 3-chloro-pyridin-2-carboxylic acid (5-iodo-2-methylamino-pyridin-3-yl)-amide (3.6 g), which is hereinafter referred to as “intermediate compound (M20-7)”.
Reaction SMILES: C[O:2][C:3](=[O:32])/[C:4](/[NH:28][C:29](=[O:31])[CH3:30])=[CH:5]\[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][C:15](=[O:17])[NH:14][S:13]2(=[O:19])=[O:18])=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1.[OH-].[Na+]>>[C:29]([NH:28]/[C:4](=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][C:15](=[O:17])[NH:14][S:13]2(=[O:19])=[O:18])=[C:8]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:7]=1)/[C:3]([OH:32])=[O:2])(=[O:31])[CH3:30]
Reactant: COC(=O)/C(=C\c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N/C(=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of (E)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid methyl ester is added 3 equivalents of NaOH (3N solution). After 4 h, three additional equivalents of NaOH is added and stirring is continued for 18 h. The solvent is removed under reduced pressure and the residue acidified with 1N HCl and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound. This is used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:18]=[C:17]3I)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:18]=[C:17]3[C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)c(I)nn3C(=O)OC(C)(C)C)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)c(C#C[Si](C)(C)C)nn3C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 105.7 %

Procedure:
A suspension of tert-butyl 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-iodo-1H-indazole-1-carboxylate (200 mg; 0.38 mmol; 1.0 eq.), (Trimethylsilyl)acetylene (53 μl; 0.38 mmol; 1.0 eq.), TEA (158 μl) and bis(triphenylphosphine)palladium(II) chloride (10.7 mg; 0.02 mmol; 0.04 eq.) was heated at 70° C. overnight in a sealed tube. The reaction mixture was diluted with EtOAc and washed with a saturated solution of NH4Cl and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give the tittle compound as a brown gum (200 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J=8.7 Hz, 1H), 7.63-7.54 (m, 2H), 4.15-4.04 (m, 2H), 2.99-2.74 (m, 3H), 1.86-1.74 (m, 2H), 1.64 (s, 9H), 1.61-1.52 (m, 2H), 1.42 (s, 9H), 0.32 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N:12]=[N:13][CH:14]([C:24]([CH3:26])=[O:25])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N:12]=[N:13][CH:14]([C:24]([CH3:26])=[O:25])[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:16])(=[O:29])[CH3:28]
Reactant: CC(=O)C(N=Nc1cc(S(=O)(=O)O)ccc1O)C(=O)Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(S(=O)(=O)O)cc1N=NC(C(C)=O)C(=O)Nc1ccccc1

Procedure:
α-(2-Hydroxy-5-sulfophenylazo)acetoacetanilide (40 g) was dissolved in boiling pyridine (750 ml) and acetic anhydride (100 ml) added. Some material precipitated while the reaction mixture was hot. After being cooled, the product was filtered off and dried. Yield: 38 g.
Reaction SMILES: [Mg].II.[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7]Br)[CH3:5].Br[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH3:5]
Reactant: Brc1ccsc1
Reactant: CCCCC(CC)CBr
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Dry magnesium turnings (10.2 g, 0.42 mol) and 40 mL of anhydrous THF were placed in a three-necked round-bottomed flask. A crystal of iodine was added to initiate the Grignard reaction. 2-Ethylhexyl bromide (79.0 g, 0.41 mol) in 100 mL of anhydrous THF was then added dropwise to magnesium turnings. After the addition, the reaction was heated to reflux for 1 h, then cooled down to room temperature, and diluted with 100 mL of THF. In another flask were added 3-bromothiophene (50.0 g, 0.31 mol), [1,3-bis(diphenylphosphino)propane]dichloronickel (1.7 g, 0.003 mol), and 100 mL of THF and the flask was cooled in an ice-bath. The Grignard reagent was added to the above solution via a cannula. After stirring at room temperature overnight, the reaction was quenched with 2N HCl, extracted with ethyl ether. The combined organic phase was washed with brine and dried over MgSO4. The crude product was purified by column chromatography on silica gel using hexane as an eluent to give 27.5 g pure product as light yellow liquid (46% yield). 1H NMR (CDCl3) δ (ppm): 0.84-0.89 (m, 6H), 1.19-1.33 (m, 8H), 1.53-1.57 (m, 1H), 2.56 (d, J=6.8 Hz, 2H), 6.87-6.90 (m, 2H), 7.19-7.23 (m, 2H); 13C NMR (CDCl3): 10.86, 14.12, 23.05, 25.70, 28.95, 32.58, 0.34, 40.46, 120.64, 124.79, 128.80, 141.93; FD-MS: m/z 196 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][C:8]2([CH3:18])[CH3:17])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][C:8]2([CH3:18])[CH3:17]
Reactant: CC1(C)Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Nc2ccccc2-c2c(N)cnn21
Yield: 75.3 %

Procedure:
3.8 g (0.015 mole) of 1-nitro-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline is reduced with hydrogen in ethanol in the presence of palladium/carbon. When the hydrogen consumption ceases, the catalyst is removed and the solvent is evaporated. Thus, 2.42 g (76%) of 1-amino-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 181°-183° C. The hydrochloride can be precipitated by treating the free amine in ethanol with anhydrous hydrogen chloride dissolved in ethyl acetate. M.p.: 244°-245° C.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=1)([CH3:3])[CH3:2].O[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([CH2:16][O:14][C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])[CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: COC(=O)c1ccc(C(C)C)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)C)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.6 %

Procedure:
The methyl 4-isopropyl-2-hydroxybenzoate (4.4 g, 22.7 mmol) was dissolved in THF (100 mL). Then 3-(hydroxy-methyl)-1-tert-butoxycarbonylpiperidine (4.88 g, 22.7 mmol) and triphenylphosphine (7.14 g, 27.24 mmol) were added. The mixture was placed in an ice bath, and then diisopropyl azodicarboxylate (4.59 g, 22.7 mmol) in methylene chloride (15 mL) was added dropwise. The reaction mixture was allowed to warm gradually to room temperature. After 16 h, the solvent was removed under vacuum. The solid residue was subjected directly to flash chromatography on silica (0 to 30% EtOAc in hexane gradient), giving the title compound (3.34 g, 43% yield) as an oil.