Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1.CCN(C(C)C)C(C)C.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[O:13]=[C:5]1[NH:4][C:3]([CH2:2][NH:1][S:32]([CH2:31][CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])(=[O:33])=[O:34])=[N:8][C:7]2[N:9]=[CH:10][CH:11]=[CH:12][C:6]1=2
Reactant: O=S(=O)(Cl)CCc1ccccc1F
Reactant: NCc1nc2ncccc2c(=O)[nH]1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(CNS(=O)(=O)CCc2ccccc2F)nc2ncccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 12.1 %

Procedure:
To an ice cooled suspension of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (example 84.3; 50 mg, 0.28 mmol) in CH2Cl2 (2 ml) were added DIPEA (0.10 ml, 0.58 mmol) and 2-(2-fluoro-phenyl)-ethanesulfonyl chloride (78 mg, 0.35 mmol). The reaction mixture was stirred for 3 hours at 0° C. Unreacted 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one was filtered off, the filtrate was evaporated to dryness and chromatographed (silica gel, EtOAc) to yield 2-(2-fluoro-phenyl)-ethanesulfonic acid (4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-amide (12 mg, 0.034 mmol; 12%) as a white solid. MS (m/e): 363.1 [M+H+].
Reaction SMILES: C([O:8][C:9]1[C:10]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:11][N:12]2[CH:17]([C:18]3[N:19]=[C:20]([CH3:23])[S:21][CH:22]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:9]1[C:10]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:11][N:12]2[CH:17]([C:18]3[N:19]=[C:20]([CH3:23])[S:21][CH:22]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2c1csc(C)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1nn2c(c1O)C(=O)N(C)CC2c1csc(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(benzyloxy)-5-methyl-7-(2-methyl-1,3-thiazol-4-yl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (64 mg, 0.150 mmol) in anhydrous CH2Cl2 at 0° C. was added 2.0M boron tribromide in CH2Cl2 (112 μL, 0.225 mmol). The reaction was stirred at room temperature overnight, and the solvent was removed in vacuo. The resulting residue was dissolved in 0.025M H2SO4 in EtOH (1.2 mL) and heated to reflux overnight. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product as a viscous oil. ES MS (M+H)=337.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][OH:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)=[CH:3][CH:4]=2)[CH2:9][OH:10])=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: OCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: OCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
2,2-Bis-(4-chloro-phenyl)-ethanol was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.72 [M+]+ 299.00.
Reaction SMILES: CO.C(OC(=O)[N:9]([CH2:34][C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([NH:30][CH3:31])=[O:29])[CH:26]=3)[C:21]([CH3:32])=[CH:20][C:19]2=[O:33])[CH2:12][CH2:11]1)(C)(C)C.[ClH:46].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:46].[O:39]1[C:38]2[CH:43]=[CH:44][C:35]([CH2:34][NH:9][CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:28]([NH:30][CH3:31])=[O:29])[CH:26]=5)[C:21]([CH3:32])=[CH:20][C:19]4=[O:33])[CH2:12][CH2:11]3)=[CH:36][C:37]=2[O:42][CH2:41][CH2:40]1
Reactant: CNC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 5.5 h

Procedure:
To 0.5 mL of methanol solution containing 58 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-7-((methylamino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 5.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 0.032 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-N-methyl-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxamide hydrochloride as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:4][N:3]=1.NCCOCCO>CC(O)C.Cl>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:5]2[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)=[N:7][CH:2]=[N:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(Cc2cnc(Cl)nc2N2CCN(C)CC2)cc1
Agent: Cl
Agent: NCCOCCO
Solvent: CC(C)O
Product: Cc1ccc(Cc2cncnc2N2CCN(C)CC2)cc1

Procedure:
A solution of 2-chloro-5-(4-methylbenzyl)-4-(4-methylpiperazino)pyrimidine (1.46 g, cc mmoles), 2-propanol (25 mL) and 2-(2-aminoethoxy)ethanol (4.79 g, 46 mmoles) was heated in a stainless steel reaction vessel at 155° C. for 16 hours. The vessel contents were spin evaporated in vacuo at 60° C. to give a residue that was partitioned between dichloromethane (35 mL) and water (150 mL). The dichloromethane phase was separated and washed with water (150 mL), and finally with brine (100 mL). The solution was dried over sodium sulfate, filtered, and spin evaporated in vacuo to give a syrup. The syrup was dissolved in 2-propanol (20 mL), 37% hydrochloric acid (15 drops) was added, and the solution was spin evaporated in vacuo. The residue was crystallized from methanol (2 mL) to give 0.34 g of 2-(2-hydroxyethoxy)ethylamino)-5-(4-methylbenzyl)-4-(4-methylpiperazino)pyrimidine as carmel colored crystals, mp 207-209° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[C:4](Br)[CH:5]=[CH:6][CH:7]=1.[Li].B(OC)(OC)[O:15]C.[OH-].[Na+].OO>O1CCCC1.C(OCC)C>[F:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[C:4]([OH:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)c1C(F)(F)F
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1cccc(F)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 3-fluoro-2-(trifluoromethyl)bromobenzene (1 g, 4.1 mmol) in tetrahydrofuran (25 mL) was added dropwise to nbutyl lithium (2.5M in hexanes, 3.2 mL, 8 mmol), at −78° C., and the mixture was stirred at this temperature for 30 minutes. Trimethyl borate (1.84 mL, 16.4 mmol) was added and the reaction mixture was stirred at −78° C. for a further 30 minutes and at room temperature for 18 hours. 2M sodium hydroxide solution (4 mL) and 35% hydrogen peroxide solution (2 mL) were then added and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether (100 mL). The aqueous layer was separated and the organic solution was washed with 2M sodium hydroxide solution. The combined basic washings were acidified with 2M hydrochloric acid, extracted with diethyl ether (2×50 mL) and the organic solution was concentrated in vacuo to afford the title compound as a yellow oil in 40% yield, 300 mg. 1H NMR (400 MHz, CD3OD) δ: 6.64 (m, 1H), 6.75 (d, 1H), 7.36 (q, 1H)
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[CH:11]1[C:12]2[CH:13]([OH:15])[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=c1c2ccccc2sc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A suspension of thioxanthen-9-one [31] (2 g, 9.42 mmol) in anhydrous CH3OH (30 mL) was stirred under N2 and NaBH4 (1.42 g, 37.68 mmol) was added slowly in portions over 15 min. After complete addition the reaction mixture was heated at reflux (3 hr.) and cooled to room temperature. Ice-water was added and the reaction mixture was extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 extracts were washed with water, brine, dried (MgSO4). The solvent was removed under reduced pressure to give a yellow solid, which was recrystallized from pet.ether to give 1.87 g (93%) of the alcohol as pale yellow needles, mp 104-105° C.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH3:23])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Oc1ccc(C)cc1

Procedure:
A solution of 37.70 g of 2-(4-methylphenoxy)-benzoic acid was 12.0 mL of concentrated sulfuric acid in 500 mL of methanol was refluxed for 14 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was added to a mixture of methylene chloride and water. The organic phase was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was kugelrohr distilled (120°-135°/0.025 torr) to furnish 35.08 g of methyl 2-(4-methylphenoxyl)benzoate, m.p. 31°-34°. NMR (200 MHz, CDCl3) δ7.87 (d of d, 1H); 7.39 (t of d, 1H); 7.11 (m, 3H); 6.88 (m, 3H); 3.81 (s, 3H); 2.30 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[C:4](=[O:14])[C:3]=1[C:15](OCC)=[O:16].C(N(C(C)C)C(C)C)C.Cl.[NH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>O1CCOCC1.CCOC(C)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[C:4](=[O:14])[C:3]=1[C:15]([NH:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:16]
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccccc2C(C)(C)C1=O
Temperature: 80 °C
Yield: 49.5 %

Procedure:
Ethyl 4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (425 mg, 1633 μmol) was dissolved in 1,4-dioxane (1633 μL) and N-ethyl-N-isopropylpropan-2-amine (853 μL, 4898 μmol). tert-Butyl 2-aminoacetate hydrochloride (411 mg, 2449 μmol) was added, and the mixture was heated at 80° C. for 4 hours. The reaction mixture was then cooled, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (279 mg) as a white solid after purification via preparatory LC. MS (m/z)=290 (M+H-tBu)+.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:11]([C:13](O)=[O:14])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)=[N:8][C:7]=3[N:6]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:5]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl.O>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:13]([C:11]2[C:12]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[N:5][N:6]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:7]=3[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[CH:10]=2)=[O:14])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)nc2c1c(C1CC1)nn2C1CCCCO1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(C2CC2)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.4 %

Procedure:
To a suspension of 0.80 g of 3-cyclopropyl-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 13 ml of DCM were added 1.4 ml of Hünig's base, 0.98 g of BEP and 0.47 g of tert-butyl-1-piperazine carboxylate. The reaction was stirred at r.t. for 4 h. For workup it was diluted with water and DCM and the layers were separated. The organic layer was washed with water twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 0.79 g (68%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)=[CH:5][N:4]=1.Cl>CO>[NH:11]([C:6]1[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)[NH2:12]
Reactant: COc1ncc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)n1
Agent: Cl
Solvent: CO
Product: COc1ncc(NN)c(OC)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
Di-tert-butyl 1-(2,4-dimethoxypyrimidin-5-yl)hydrazine-1,2-dicarboxylate (Step 46.7) (453 g, 1.223 mol) was dissolved in MeOH (2.5 L) and cooled down to 0° C. HCl 4N in gioxane (2.5 L, mol) was added and the resulting mixture was stirred at RT overnight. The reaction was concentrated under reduced pressure, NH3 4 N (2 L) was added, the resulting mixture was stirred for 1 hr and concentrated under reduced pressure. CH2Cl2 (2 L) was added, the suspension was filtrated off and the filtrate was concentrated under reduced pressure. The crude product was stirred with Et2O (2 L) at 0° C. for 30 min. The resulting suspension was filtrated off and dried to afford the title product (150 g, 864 mmol, 70% yield) as light beige solid. tR: 0.32 min (LC-MS 1); ESI-MS: 171 [M+H]+ (LC-MS 1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.Cl>CO.C(OCC)C.O1CCCC1>[Si:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
50 ml of a dry tetrahydrofuran solution containing 1 g of 16-hydroxyhexadecanoic acid, 1.1 g of tert-butyldimethylsilyl chloride and 0.75 g of imidazole, was stirred at room temperature for 12 hours under an inert atmosphere of nitrogen gas. The solvent was distilled off under reduced pressure, and then 200 ml of ethyl acetate was added. The mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup product. Then, 40 ml of diethyl ether, 30 ml of methanol and 30 ml of 1N hydrochloric acid were added thereto, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and then 200 ml of ethyl acetate was added. The mixture was washed once with 200 ml of a saturated sodium hydrogencarbonate aqueous solution and then washed twice with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup product. This product was purified by silica gel column chromatography (ethyl acetate: hexane =1:1) to obtain 1.4 g of 16-tert-butyldimethylsilyloxyhexadecanoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:24])OC3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:35][C:36]1[S:37][C:38]([S:42]([NH2:45])(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1>>[CH3:35][C:36]1[S:37][C:38]([S:42]([NH:45][C:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([N:6]3[C:2]([CH3:1])=[C:3]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:4]([C:25]([F:26])([F:27])[F:28])=[N:5]3)=[CH:12][CH:11]=2)=[O:24])(=[O:43])=[O:44])=[C:39]([CH3:41])[N:40]=1
Reactant: Cc1nc(C)c(S(N)(=O)=O)s1
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: Cc1nc(C)c(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C(F)(F)F)c(-c4ccccc4)c3C)cc2)s1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 2,4-dimethyl-1,3-thiazole-5-sulfonamide: MS (ESI) m/z 564 [M+H]+, 562 [M−H]−, 1H-NMR (CDCl3) δ 7.45-7.32 (9H, m), 6.19 (1H, br.s), 3.49 (2H, t, J=6.6 Hz), 2.89 (2H, t, J=6.6 Hz), 2.67 (3H, s), 2.60 (3H, s), 2.21 (3H, s).
Reaction SMILES: Br[C:2]1(Br)[CH2:10][C:9]([CH3:12])([CH3:11])[C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]1=O.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[NH:21][C:22]([NH2:24])=[S:23]>C(O)C>[CH3:11][C:9]1([CH3:12])[C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]2[N:24]=[C:22]([NH:21][C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[S:23][C:2]=2[CH2:10]1
Reactant: CC1(C)CC(Br)(Br)C(=O)c2cn[nH]c21
Reactant: NC(=S)Nc1ncccn1
Solvent: CCO
Product: CC1(C)Cc2sc(Nc3ncccn3)nc2-c2cn[nH]c21
Reaction time: 0.67 h
Yield: 1477832.5 %

Procedure:
According to Scheme 2 Step 4: A solution of 5,5-dibromo-7,7-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (6.09 mmol, 1.96 g) and of 1-(pyrimidin-2-yl)thiourea (6.09 mmol, 939 mg) in ethanol (18 mL) was microwaved at 150° C. for 90 minutes and then at 140° C. for 40 minutes. After filtration, the reaction mixture was concentrated to dryness. The crude residue was partitioned between DCM and a saturated solution of Na2CO3. The aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4 and concentrated. The crude residue was purified by flash chromatography over silica gel using DCM/MeOH (98:2 to 90:10) as eluent to yield 5,5-dimethyl-N-(pyrimidin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (90 mol, 27 mg) as a brown solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:27](OC)=[O:28])=[CH:9][N:10]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:8]([CH2:27][OH:28])=[CH:9][N:10]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1cc(CO)c(-c2ccccc2)c1-c1ccccc1
Yield: 88.1 %

Procedure:
Using methyl 4,5-diphenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (439 mg) and a 1.5 mol/L solution (3.2 mL) of diisobutylaluminum hydride in toluene, a procedure as in Reference Example 5 was performed to give the title compound as a brown oil (yield 361 mg, 88%).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:31])[C:11]2[C:16]([C:17]=1[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:31])[C:11]2[C:16]([C:17]=1[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
1M PBr3 (0.36 ml, 0.363 mmol) in DCM was added drop-wise to a solution of tert-butyl 4-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate B12, 135 mg, 0.363 mmol) in DCM (5 ml). Reaction mixture was then dried under reduced pressure and dissolved in DCM (5 ml). Di-tert-butyl dicarbonate (0.34 ml, 1.454 mmol) and DMAP (89 mg, 0.727 mmol) were added simultaneously, and the mixture stirred overnight at RT. Reaction mixture was straightforward purified on Biotage SNAP 50 g silica cartridge with a gradient of hexane and EtOAc give the title compound (100 mg, 63.3%) as a yellowish oil.
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[C:29]([OH:35])(=[O:34])[CH2:30][CH2:31][C:32]#[CH:33].C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C>>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([C:33]#[C:32][CH2:31][CH2:30][C:29]([OH:35])=[O:34])[N:3]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:4]=[C:5]2[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:7]1=[O:13]
Reactant: C#CCCC(=O)O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCC(=O)O)n(Cc3cccc4ccccc34)cc21

Procedure:
The sub-title compound was prepared from 5-iodo-3-methyl-1-(2-methylpropyl)-6-(1naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione, and 4-pentynoic acid in the presence of bistrimethylsilyltrifluoroacetamide in a manner analogous to the method of Example 13 above.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].Cl.[CH3:21]O>>[ClH:1].[NH2:2][CH:3]([CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH3:21])=[O:5]
Reactant: NC(C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Through a solution of 2-amino-3,3-diphenylpropanoic acid hydrochloride (35.0 g, 126 mmol) in methanol (500 ml) was bubbled hydrogen chloride for 3 h. The solution was stirred at room temperature for 120 h and the solvent removed in vacuo. Addition of diethyl ether gave methyl 2-amino-3,3-diphenylpropanoate hydrochloride, m.p.=213°-215° C.(dec.). 1H NMR (360 MHz, DMSO-d6) δ8.70 (3H, vbs), 7.20-7.57 (10H, m), 4.94 (1H, d, J=11 Hz), 4.36 (1H, d, J=11 Hz), 3.39 (3H, s). m/z (CI+) 256(MH).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[OH-:12].[K+:13].Cl>O>[NH2:1][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:4](=[O:5])[C:2]([O-:12])=[O:3].[K+:13]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Nc1ccccc1C(=O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
A 250 mL one-necked flask was charged with 18.3 grams of isatin (0.124 mol), 37.1 mL. of 30% potassium hydroxide (0.196 mol) and 50 mL of water. The mixture was stirred at room temperature for 6 hours. At the end of this time, the pH of the mixture was adjusted to 7.36 by the addition of 10% hydrochloric acid. Water was removed from the mixture by means of a rotary evaporator, and the crude potassium 2-aminophenylglyoxylate obtained in this manner was dried in a desicator. The crude, dried material weighed 22.1 grams, indicating a yield of 87 percent.