Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][C:31]=2[CH3:38])[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:32][C:31]=2[CH3:38])[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:19]=1[CH3:20])=[O:13]
Reactant: C1COCCN1
Reactant: CCN(c1cc(-c2ccc(C=O)cc2C)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2C)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-formyl-2′,4-dimethyl-[1,1′-biphenyl]-3-carboxamide (410 mg, 0.79 mmol) and morpholine (210 mg, 2.38 mmol) in dichloroethane (10 mL), acetic acid (280 mg, 4.77 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (580 mg, 2.71 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (125 mg, 26.76%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH3:9])[N:7]=1.[BrH:14].BrBr>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[S:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH2:9][Br:14])[N:7]=1
Reactant: CC(=O)c1nc(C(F)(F)F)sc1C
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1sc(C(F)(F)F)nc1C(=O)CBr
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
3 g (0.0144 mol) of 2-Trifluoromethyl-5-methyl-4-acetyl-thiazole are dissolved in 30 ml of glacial acetic acid, and 2.1 ml of a 33% strength solution of hydrogen bromide in glacial acetic acid are added. The mixture is heated to 80° C. and, over the course of 30 minutes, a solution of 2.3 g (0.0144 mol) of bromine in 15 ml of glacial acetic acid is added. After a further 20 minutes, the glacial acetic acid is removed. The residue which remains is a dark oil which is reacted further as the crude product.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][C:17](=[O:31])[NH:18][C@@H:19]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][C:17](=[O:31])[NH:18][C@@H:19]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)NCc1ccc(N)nc1
Reaction time: 1 h

Procedure:
The urea 148 (210 mg) was dissolved in 2 ml of DCM and 2 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture was concentrated and purified by precipitation using AcOEt/Hexane to afford the urea deprotected 149 as yellow solid (204 mg, 89%). HPLC method B tr=17.99 nm (95.8%). ESI-MS m/z: 329.3 [M+H]+.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:19]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCCCCCCCCO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCCCCCCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
To a stirred solution of 51.2 grams (0.320 mole) of 1,9-nonanediol in 500 ml of tetrahydrofuran was added one crystal of p-dimethylaminopyridine, and then 8.9 grams (0.088 mole) of triethylamine was added. To this mixture was added dropwise a solution of 11.2 grams (0.08 mole) of benzoyl chloride in 40 ml of methylene chloride. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in 200 ml of methylene chloride and was washed with five 75 ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. Volatile materials were removed by distillation leaving 11.5 grams of 9-hydroxynonyl benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>C(OCC)C.O>[Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[OH:4]
Reactant: CC(=O)Nc1ccc(C(=O)CBr)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C(O)CBr)cc1
Reaction time: 0.25 h
Yield: 18.9 %

Procedure:
To a solution of N-[4-(2-bromoacetyl)phenyl]acetamide (2.1 g, 0.0082 mol, in 30 mL of methanol) was introduced solid NaBH4 (1.0 g, 0.026 mol) at 0° C. and stirred at that temperature for 15 minutes. The mixture was diluted with diethyl ether (20 mL) and water (20 mL). The ether phase was separated and the aqueous phase was extracted with diethyl ether. The ether phases were combined and washed with brine, dried. Purification on a silica gel column gave the title compound as a white solid (0.40 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[NH:11][C:10](=O)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[Cl:20][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[N:11]=1
Reactant: O=c1nc(-c2ccc(F)cc2)c2c([nH]1)CCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc(Cl)nc3c2CCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 4-(4-fluorophenyl)-1,5,6,7-tetrahydro-2H-cyclopentapyrimidin-2-one (14.3 g) is added phosphorus oxychloride (60 ml), and the mixture is refluxed for 5 hours. After cooling, the reaction mixture is diluted with chloroform (100 ml), and the mixture is added dropwise to ice-water over a period of 20 minutes. After the mixture is stirred for 30 minutes, the organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene and subjected to silica gel column chromatography. The fractions eluted with toluene are collected and the product therefrom is recrystallized from ethanol to give the desired compound (13.6 g), m.p. 106°-107° C.
Reaction SMILES: [SH2:1].C(OC([C@@H](N[C@H](C(N1N=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)[S:23][C@H:22]1[C:34]([OH:36])=[O:35])=O)C)CCC1C=CC=CC=1)=O)C>CO>[CH3:33][S:32][C:29]1[CH:30]=[CH:31][C:26]([C:24](=[S:1])[S:23][CH2:22][C:34]([OH:36])=[O:35])=[CH:27][CH:28]=1
Reactant: S
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccc(SC)cc2)S[C@H]1C(=O)O
Solvent: CO
Product: CSc1ccc(C(=S)SCC(=O)O)cc1

Procedure:
Hydrogen sulphide was passed through a solution of the product of step (b) (25.0g) in methanol (250ml) and cooled in an ice bath, for a period of 3 hours.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(I)c[nH]c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.80 g, 5.73 mmol) in CH2Cl2 (20 mL) was added p-toluenesulfonyl chloride (TsCl) (1.09 g, 5.73 mmol) and triethylamine (TEA) (1.60 mL, 11.46 mmol), followed by dimethylaminopyridine (DMAP) (70 mg, 0.573 mmol). After stirring for 1 h at room temperature, the solution was concentrated, and the residue was partitioned between ethyl acetate and H2O. The organic layer was separated, washed sequentially with 1N HCl and 5% NaHCO3. The organic extracts were dried over Na2SO4 and concentrated to give 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)[CH2:30][CH2:29]1
Reactant: OC1CCNCC1
Reactant: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccccc2C)=N/O)ccn1
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCC(O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 39, from (E,R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one oxime (example 142, step 1) and 4-hydroxypiperidine was prepared the title compound as a yellow foam, MS (ESI+): m/z=430.2 ([M+H]+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:29]=[CH:28][C:13]([O:14][CH:15]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:16]([OH:18])=O)=[C:12]([CH2:30][CH2:31][CH3:32])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:45]([C:48]1[CH:53]=[CH:52][C:51]([S:54]([NH2:57])(=[O:56])=[O:55])=[CH:50][CH:49]=1)([CH3:47])[CH3:46].N12CCCN=C1CCCCC2>C1COCC1.CCOC(C)=O>[CH:45]([C:48]1[CH:49]=[CH:50][C:51]([S:54]([NH:57][C:16](=[O:18])[CH:15]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[O:14][C:13]2[CH:28]=[CH:29][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:11][C:12]=2[CH2:30][CH2:31][CH3:32])(=[O:55])=[O:56])=[CH:52][CH:53]=1)([CH3:47])[CH3:46]
Reactant: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of 3.30 g (7.21 mmol) of the crude product from Step C dissolved in 40 mL of anhydrous THF was added 1.75 g (10.8 mmol) of 1,1'-carbonyldiimidazole and the reaction mixture was magnetically stirred and heated at reflux for 10 minutes. The reaction was then cooled to room temperature, 2.15 g (10.8 mmol) of 4-iso-propylbenzenesulfonamide and 1.61 mL (10.8 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added and the reaction was stirred for an additional 30 minutes at room temperature. The mixture was then diluted with EtOAc (80 mL), washed with 10% aqueous citric acid, saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was partially purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH--NH4OH (92:8:0.5). The semi-purified material was combined and repurified on a second silica gel flash chromatography column eluted initially with 35% EtOAc-hexane, later with 50% EtOAc-hexane, and finally with 70% EtOAc-hexane. Combination of the purified fractions and evaporation afforded 3.20 g (69%) of the title compound as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[CH:9][C:8]=1[N:24]1[CH:28]=[N:27][CH:26]=[N:25]1.N1C=CC=CC=1.O>C(#N)C>[Cl:23][C:13]1[CH:14]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:16]=[C:17]([Cl:18])[C:12]=1[N:11]1[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[C:8]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH:9]=[N:10]1
Reactant: CCC(=O)Cl
Reactant: Nc1c(-n2cncn2)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1c(-n2cncn2)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Yield: 81.1 %

Procedure:
3.5 g (0.037 mole) of propionyl chloride are added dropwise to a solution of 7.3 g (0.02 mole) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(1,2,4-triazol-1-yl)-pyrazole and 2 g (0.025 mole) of pyridine in 60 ml of acetonitrile, with stirring, and, when the addition has ended, the mixture is stirred at room temperature for a further 12 to 15 hours. For working up, the reaction batch is poured into water and extracted with methylene chloride, the organic phase is washed with water and dried over sodium sulphate and the solvent is removed in vacuo. The residue is dissolved in 100 ml of ethanol, 10 ml of aqueous ammonia are added, the mixture is heated to 50° C. for 15 minutes and concentrated in vacuo and the residue is triturated with water and dried on clay. 6.8 g (81% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-propionylamino-4-(1,2,4-triazol-1-yl)-pyrazole of melting point 167° C. to 169° C. are obtained.
Reaction SMILES: [Cl-].[NH2:2][C:3]([NH2:5])=[NH2+:4].CC(C)([O-])C.[K+].[CH2:12]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[C:26]([CH3:32])[C:27](OCC)=[O:28])=[O:18])[CH2:13][CH2:14][CH3:15]>CN(C)C=O>[CH2:12]([N:16]1[C:17](=[O:18])[C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:25]1[CH:26]([CH3:32])[C:27]([NH:4][C:3]([NH2:5])=[NH:2])=[O:28])[CH2:13][CH2:14][CH3:15]
Reactant: NC(N)=[NH2+]
Reactant: CCCCNC(=O)c1ccccc1C=C(C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)c2ccccc2C1C(C)C(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
N-[2-(2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine is prepared as described in Example 30, starting with 3.63 g (38.0 mmol) of guanidinium chloride in 20 cm3 of dimethylformamide and 3.84 g (34.2 mmol) of potassium tert-butoxide. The mixture is stirred for 45 minutes at a temperature in the region of 20° C., followed by dropwise addition of a solution of 1.10 g (3.80 mmol) of ethyl 3-(2-butylcarbamoylphenyl)-2-methylacrylate in 15 cm3 of dimethylformamide, and the mixture is stirred for 3 hours at a temperature in the region of 20° C. After leaving the solution to stand overnight, the solvent is removed and the residue is dissolved in aqueous 2N hydrochloric acid solution. After extracting once with dichloromethane, the organic phase is concentrated and the residue is then taken up in aqueous 2N hydrochloric acid solution, filtered and then freeze dried. 1.07 g of N-[2-(2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine are thus obtained in the form of a mixture of the diastereomers. The pH of the aqueous phase is adjusted to a value of 12 with potassium hydroxide and the precipitate thus obtained is filtered off*. The solid thus obtained is taken up in aqueous 2N hydrochloric acid solution and, after filtration and a freeze drying procedure, about 106 mg of one of the two diastereomers produced (diastereomer A) are obtained in the form of the hydrochloride enriched in a ratio of 5:1 (MS(ES): M+H: 303.1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].N#N.[NH2:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[NH:17][N:16]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1.O>[Cl:31][C:27]1[CH:26]=[C:25]([NH:24][C:22]2[N:21]=[CH:20][N:19]=[C:18]3[NH:17][N:16]=[C:15]([NH:14][CH2:6][C:5]4[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([O:10][CH3:11])[CH:4]=4)[C:23]=23)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: N#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Solvent: CO
Product: COc1cc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)ccc1O
Reaction time: 1 h

Procedure:
228 mg (1.50 mmol) of 4-hydroxy-3-methoxy-benzaldehyde are added (N2 atmosphere) to a solution of 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 26 ml of DMEU and 120 mg (2.0 mmol) of acetic acid. After 1 hour, 440 mg (7.0 mmol) of NaCNBH3 are added to the clear solution and stirring is then carried out at RT for 7 days. The reaction solution is poured into 0.8 liter of water and stirred overnight to complete the reaction, during which time the product precipitates. Filtering with suction, washing with water, stirring in hot ethyl acetate, cooling and filtering yield 4-(3-chloro-phenylamino)-3-[(3-methoxy-4-hydroxy-benzyl)-amino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 223-225° C.; HPLC: TRet (Grad5-40)=19.8; FAB-MS: (M+H)+ =397.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[F:24])=[CH:11][N:10]([CH3:25])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.[CH2:26]([OH:30])[CH2:27][C:28]#[CH:29]>O1CCCC1.C(N(CC)CC)C.[Cu]I>[CH2:22]([S:19]([C:17]1[CH:16]=[CH:15][C:14]([F:24])=[C:13]([C:12]2[C:4]3[C:5](=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]#[C:28][CH2:27][CH2:26][OH:30])[CH:3]=3)[N:10]([CH3:25])[CH:11]=2)[CH:18]=1)(=[O:21])=[O:20])[CH3:23]
Reactant: C#CCCO
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c3c(OC)nc(Br)cc23)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c3c(OC)nc(C#CCCO)cc23)c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
A mixture of Example 126A (300 mg, 0.702 mmol), but-3-yn-1-ol (63.8 μl, 0.843 mmol), Pd(dppf)CH2Cl2 (57.3 mg, 0.070 mmol), and copper(I) iodide (13.4 mg, 0.070 mmol) in tetrahydrofuran (9 mL) and triethylamine (3 mL) was purged with nitrogen and then stirred at 70° C. in a sealed tube for 2.5 hours. The mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel column (0-8% MeOH in dichloromethane) to give the title compound (200 mg, 68.4% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH:4]=1.C1C(=O)N([I:32])C(=O)C1>CC#N>[I:32][C:4]1[C:5]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[N:6][C:7]([S:9][CH3:10])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(SC)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1nc(SC)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I

Procedure:
Compound 18 (1.00 g, 2.82 mmol) was dissolved in MeCN (50 mL) and NIS (952 mg, 4.23 mmol) was added and the reaction was heated to reflux for 1 h. The solution was concentrated and the residue was dissolved in EtOAc, wash with a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of NaS2O3, dried (MgSO4), filtered and concentrated to give the title compound as a light yellow solid. LCMS 2.06 min, 481 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)[CH:5]=[CH:6][C:7]=1[Br:8].[OH:26]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)=[O:26])[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: Cc1cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)ccc1Br
Reactant: OO
Product: Cc1cc(S(=O)CCCCOc2ccc3[nH]c(=O)ccc3c2)ccc1Br

Procedure:
Prepared analogous to Example 123 from 6-[4-(3-methyl-4-bromo-phenylmercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([O:20][Si](C(C)(C)C)(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(O[Si](C)(C)C(C)(C)C)CC1NC(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(O)CC1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 2-(benzyloxycarbonylamino)-1-(tert-butyldimethylsilyloxy)cyclopropanecarboxylate (1.45 g, 3.69 mmol) in THF (35 mL) under N2 was added HF.pyridine (1.0 mL, 38 mmol). The reaction mixture was stirred for 5 h. After this time, additional HF.pyridine (1.0 mL, 38 mmol) was added and stirring was continued for 19 h. The reaction mixture was then cooled to 0° C. and diluted with Et2O (150 mL). The mixture was then carefully quenched with saturated aqueous NaHCO3 until gas evolution ceased. At this time, the organic layer was separated and the remaining aqueous layer was extracted with Et2O (300 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography eluting with 20%-50% EtOAc/hexanes afforded the title compound (0.960 g, 93%): 1H NMR (300 MHz. CDCl3) δ 7.34-7.30 (m, 5H), 5.11-4.83 (m, 3H), 4.21 (q, J=7.2 Hz, 2H), 3.37-3.25 (m, 2H), 1.73-1.68 (m, 1H), 1.27 (t, J=7.2 Hz, 3H), 1.14-1.06 (m, 1H); ESI MS m/z 280 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([CH:37]=O)=[N:29]1.N1CCCCC1>CO>[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: O=Cc1n[nH]c2ncccc12
Reactant: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A solution of tert-butyl 4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperidine-1-carboxylate (0.120 g, 0.319 mmol) synthesized in the same manner as that of Example B57, Step 1 in methanol (5 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (0.0469 g, 0.319 mmol) and piperidine (0.100 mL, 1.01 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration. The resulting solid was suspended in 50% ethyl acetate in hexane and thereby washed to obtain tert-butyl (Z)-4-(2-{2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0652 g, 41%).