Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[N:12]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1nc(CCO)cs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CCOS(C)(=O)=O)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
To a solution of [4-(2-Hydroxy-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (5 g, 20 mmol) and triethyl amine (5.8 ml, 40 mmol) in DCM (50 ml) was added methanesulfonyl chloride (1.9 ml, 24 mmol) slowly over a period of 10-15 min. The reaction mixture was stirred at r.t. for 4 hr, quenched with brine (10 ml) and extracted in DCM (100 ml), dried over Na2SO4 and passed through a short column of silica gel bed and concentrated to obtain methanesulfonic acid 2-(2-tert-butoxycarbonylamino-thiazol-4-yl)-ethyl ester (6.0 g, 90%) which was used as such for the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>C1COCC1>[CH2:2]([O:1][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:3]([CH2:5][OH:6])[OH:4]
Reactant: BrCc1ccccc1
Reactant: OCC(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCC(O)COCc1ccccc1
Temperature: 25 °C

Procedure:
As an alternative procedure to a stirred solution of the protected glycerol (6.7 g, 0.05 mole) in dry THF (100 mL) was added NaH (1.8 g, 0.075 mole) portionwise at 0° C. The reaction mixture was refluxed for 1.5 h, and benzyl bromide (10.3 g, 0.06 mole) was added. The mixture was stirred at room temperature. Once the reaction was completed, 2 mL of methanol was added at 0° C. to destroy the excess of NaH. The reaction mixture was extracted with 3×50 mL of ethyl ether, and the combined ether layers dried over sodium sulfate. After solvent removal, the residue of (11.9 g, Y=61%). was combined with 60 mL of 10% acetic acid, then heated (oil bath, 100° C.), until the original emulsion disappeared (about 0.5 h), After concentration, the residue was distilled in vacuo, giving 8.1 g (b.p.116-118° C./50μ) (Y=89%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[C:34]3[C:29](=[C:30]([Cl:36])[CH:31]=[C:32]([Cl:35])[CH:33]=3)[CH2:28][N:27]([CH3:37])[CH2:26]2)[CH:20]=1)(=[O:18])=[O:17])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[C:34]3[C:29](=[C:30]([Cl:36])[CH:31]=[C:32]([Cl:35])[CH:33]=3)[CH2:28][N:27]([CH3:37])[CH2:26]2)[CH:20]=1)(=[O:18])=[O:17]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (1.8 g, 3.26 mmol, 1.00 equiv) in THF (30 mL) was added triphenylphosphine (2.6 g, 9.91 mmol, 3.04 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The crude product (5.0 g) was purified by Flash-Prep-HPLC with the following conditions: Column, silica gel; mobile phase, methanol:water=1:9 increasing to methanol:water=9:1 within 30 min; Detector, UV 254 nm. 1.2 g product was obtained. This resulted in 1.2 g (64%) of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C@@H:18]([CH2:21][CH3:22])[CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH3:17][CH:18]([CH2:21][CH3:22])[CH2:19][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: CC[C@H](C)CO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
Five grams of 4-(4'-hydroxyphenyl)benzoic acid, 5 g of (s)-2-methylbutylalcohol and 11 g of p-toluenesulfonic acid were dissolved with 50 ml of benzene. Occurred water in the mixture was removed by azotropic dehydration with refluxing for eight hours. After adding 50 ml of water to the residue, the organic phase was concentrated to obtain 4-(4'-hydroxyphenyl)benzoic acid-2-methylbutyl ester (BJ).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:19][CH:18]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccc(Cl)cc4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccc(Cl)cc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-chlorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 232°-234° C.) and piperazine.
Reaction SMILES: [OH:1][C@H:2]([CH:18]([CH3:20])[CH3:19])[C:3]([NH:5][C@H:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:19][CH:18]([CH3:20])[C@@H:2]([O:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:3]([NH:5][C@H:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH3:7])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](O)C(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OS(C)(=O)=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of methyl 4-[(1S)-1-[[(2R)-2-hydroxy-3-methyl-butanoyl]amino]ethyl]benzoate (40 g; 143 mmol), and triethylamine (22.0 mL, 157 mmol) in CH2Cl2 (400 mL) is cooled to 0° C. A solution of methanesulfonyl chloride (11.1 mL, 143 mmol) in CH2Cl2 (200 mL) is added dropwise over 45 min, and the mixture is stirred to room temperature for 1 h. The mixture is washed sequentially with 1N HCl (100 mL) and aq. NaHCO3 (200 mL). The organic layer is dried over MgSO4, filtered, and concentrated. The crude material is slurried in methyl t-butyl ether (200 mL) and hexane (600 mL) for 30 min, filtered, and dried under vacuum to provide the title compound as a white solid (50 g, 98%). MS (m/z): 358.2 (M+1).
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8](C)C=[CH:6][C:5]=1C)([O-])=O.Br.O=O.C1(C)C=CC=CC=1.[C:22]([OH:25])(=[O:24])[CH3:23]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.[Ti]>[C:22]([OH:25])(=[O:24])[C:23]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1
Agent: [Co+2]
Agent: [Mn+2]
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccccc1

Procedure:
2-Nitro-p-xylene (40 g), acetic acid (300 g), cobalt (II) acetate tetrahydrate (1.0 g), manganese (II) acetate tetrahydrate (1.0 g), zirconium (IV) diacetate oxide (0.13 g), and 48% hydrobromic acid (1.4 g) were charged into a stirred, one liter titanium autoclave. Oxidation was initiated at an initial temperature of 325° F. under a 250 psig nitrogen atmosphere by introducing 20.9 volume % oxygen into the reactor at a flow rate of 18 ft3 /hr. After the initial oxygen uptake had ceased, a solution consisting of toluene in acetic acid (0.7 g toluene per ml of solution) was added semi-continuously to the reactor via a single-headed Milton Roy pump at a flow rate of 2-2.5 ml/minute. Oxidation temperature was maintained at an average of 383° F. during the semi-continuous addition of toluene (0.87 moles), followed by a rapid temperature ramp to 415° F. and a pressure of 350 psig. Oxidation was terminated when the vent O2 had reached a steady 19 volume %. Analysis of the reaction products indicated that 2-nitroterephthalic acid was formed in a 74 mole % yield, while benzoic acid was formed in a 91 mole % yield. Toluene and 2-nitro-p-xylene were not detected.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11](Br)([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[N:6]([CH:11]([CH3:13])[CH3:12])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)n1c(Cl)nc2ccccc21
Temperature: 60 °C

Procedure:
A mixture of 2-chlorobenzimidazole (2.0 g), isopropyl bromide (1.36 ml) and potassium carbonate (34 g) in dimethyl sulfoxide (200 ml) was heated at 60° C. for 6 hr and poured into ice. The resulting mixture was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed through silica gel using 5% methanol in dichloromethane. The appropriate fractions were evaporated to give 2-chloro-1-(1-methylethyl)benzimidazole, mp 58°-60° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:12]([CH:18]=1)[C:13]([O:15]CC)=[O:14])[CH2:4][CH2:5][CH3:6].C(O)C>O>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[C:12]([CH:18]=1)[C:13]([OH:15])=[O:14])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ccc(OCC(F)(F)F)c(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(OCC(F)(F)F)c(C(=O)O)c1
Yield: 77.3 %

Procedure:
A solution of 2.5 g (0.062 mole) of sodium hydroxide in 60 ml of water was combined with 9.9 g (0.031 mole) of ethyl 5-butoxy-2-(2,2,2-trifluoroethoxy)benzoate and 50 ml of ethanol. The reaction mixture was heated at reflux for about sixteen hours then concentrated to remove most of the ethanol, diluted with water and acidified with 10% hydrochloric acid. The resulting solid was collected then recrystallized from a mixture of ethanol and water to provide 7.0 g of white crystalline 5-butoxy-2-(2,2,2-trifluoroethoxy)benzoic acid, m.p. 88.5°-90° C. Analysis: Calculated for C13H15F3O4 : %C, 53.4; %H. 5.2; Found: %C, 53.3; %H, 5.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([OH:34])(=[O:33])[CH2:28][CH2:29][CH2:30][C:31]#[CH:32].C(N(CC)CC)C>COCCOC.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:32]#[C:31][CH2:30][CH2:29][CH2:28][C:27]([OH:34])=[O:33])=[CH:20][CH:19]=1)=[O:26])[CH3:9]
Reactant: C#CCCCC(=O)O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(C#CCCCC(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.200 g, 0.46 mmol) and 5-hexynoic acid (0.06 mL, 0.55 mmol) in DME (5 mL) was added copper iodide (0.017 g, 0.09 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.05 mmol), and the mixture was purged with N2 for 5 minutes. Triethylamine (0.26 mL, 1.83 mmol) was added, and the reaction was purged with N2 for another 10 minutes and then stirred at 80° C. for 2 hours. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[O:5][C:4]1=[O:23])[CH3:2].O.O.Cl[Sn]Cl>CO>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:6]3[O:5][C:4](=[O:23])[N:3]([CH2:1][CH3:2])[N:7]=3)[CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: CCn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)oc1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: CCn1nc(C2CCN(c3ccc(N)cc3)CC2)oc1=O
Yield: 88.4 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.16 g, 4 mmol) on reacting with C2H5Br (0.53 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-ethyl-5-[1-(4-nitro phenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6b, 1.17 g, 92%). Nitro compound (6b, 1.27 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7c, 1.02 g, 89%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7c, 0.29g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperi dino]phenyl-5-nitro-2-furamide (8c, 367 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C.CN(C)C=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:24][CH:21]2[CH2:20][CH2:19][N:18]([CH:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH2:23][CH2:22]2)[CH:3]=1
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 200 °C
Reaction time: 0.02 h

Procedure:
400 mg (0.0018 mol, 1 eq) of 4-bromo-2-fluoro-1-nitro-benzene, 330 mg (0.0018 mol, 1 eq) of D9, 350 mg (0.0027 mol, 1.5 eq) of diisopropylethylamine, and 5 mL of dimethylformamide were combined, heated to 200° C. and held for 1 min in a microwave reactor. 80 mL of water was then added and the reaction extracted with 2×75 mL of dichloromethane. The dichloromethane layers were combined, dried with sodium sulfate, and evaporated to yield N-(5-bromo-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine which was used without further purification in the next step. MS (ESI): 385 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[CH3:14][C:15]1([CH3:33])[C:19]([CH3:21])([CH3:20])[O:18][B:17](C2C=CC(N3N=NC=N3)=CC=2)[O:16]1>>[CH3:14][C:15]1([CH3:33])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[O:5][C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[O:16]1
Reactant: Ic1cccc(Oc2nccs2)c1
Reactant: CC1(C)OB(c2ccc(-n3ncnn3)cc2)OC1(C)C
Product: CC1(C)OB(c2cccc(Oc3nccs3)c2)OC1(C)C

Procedure:
The title compound (1.33 g) was prepared as a crude brown solid from 2-(3-iodophenoxy)-1,3-thiazole (500 mg, 1.65 mmol) using a procedure analogous to that described for 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole, Example 1, Step A. MS (LCMS) m/z 304.0 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:27]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:15]3[CH:7]=[C:8]([CH3:27])[S:9][C:10]=3[N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2ncnc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl
Reactant: c1nc[nH]n1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 5-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4](Br)[N:3]=1.[C:10]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])#[CH:11].C(N(CC)CC)C.C1COCC1>C(#N)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.[Cu]I>[Br:8][C:6]1[CH:5]=[C:4]([C:11]#[C:10][Si:12]([CH:13]([CH3:15])[CH3:14])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Nc1cc(Br)cc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1cc(Br)cc(N)n1)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 17 h

Procedure:
Under argon atmosphere dichlorobis(triphenylphosphine)palladium(II) (1.6 g, 2.2 mmol) is added to a mixture of 2-amino-4,6-dibromopyridine (5.44 g, 21.6 mmol), ethynyl-tri(propan-2-yl)silane (5.1 g, 28.1 mmol), copper(I) iodide (0.44 g, 2.3 mmol) and triethylamine (9 ml, 64 mmol) in ACN (32 ml) with THF (16 ml). After stirring at 50° C. for 17 h the mixture is diluted with water and extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 4.7 g (62%). HPLC-MS: M+H=353/355; tR=1.80 min (METHOD—1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[O:33])[CH:27]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([CH:32]([OH:33])[C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[CH:7]=1
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide (3.0, 14.2 mmol) was dissolved in 15 mL THF in a dry 100 mL flask fitted with a rubber septa and nitrogen inlet and cooled to 0° C. in ice water bath for 25 minutes. A solution of 2.5M BuLi in hexane (17.0 mL, 42.6 mmol) was added and the mixture stirred for 45 minutes. To the thick yellow precipitate that formed was added a solution of pyridine-3-carboxaldehyde (3.03 g, 28.4 mmol) in 15 mL THF. The ice bath was removed and the mixture was allowed to stir at room temperature for 45 minutes and the reaction was quenched with 25 mL H2O. The mixture was transferred to a separating funnel, and the aqueous phase was discarded. The organics were dried in vacuo to yield product as an orange oil. 1H NMR (CDCl3) δ 8.85 (m, 1H) 8.54 (m, 1H) 8.42 (m, 1H) 8.10 (dd, J=8.8 Hz, 2.8 Hz, 1H) 7.50 (d, J=8.0 Hz, 1H) 7.31 (m, 1H) 7.23 (m, 1H) 7.10 (m, 1H) 5.85 (m, 1H) 1.70 (d, 1H) 1.08 (s, 9H); MS (ES) m/z=319.1 (MH)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:29]([NH:36][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CNc2nccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)n2)cc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To the solution of [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) (220 mg, 0.54 mmol) and benzyl-amine (70 mg, 0.65 mmol) in DMSO (15 mL) was added DIPEA (84 mg, 0.65 mmol). The mixture was heated at 130° C. with stirring under N2 for 4 hours. The solvent was removed under reduced pressure. The residue was first purified by column chromatography (silica gel, dichloromethane:MeOH, 50:1 to 30:1), then by prep-HPLC. Concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give [3-(2-benzylamino-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine; hydrochloride. (Yield 40 mg, 17.1%).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[CH:8]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[S:20]([CH3:23])(=[O:22])=[O:21])[NH:7][C:6](=[O:24])[N:5]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[C:4]=2[CH2:3]1.C(C1[C@@H](C2C=CC(C#N)=CC=2S(C)(=O)=O)N([C:55]([NH:57][CH2:58][CH2:59][OH:60])=[O:56])C(=O)N(C2C=CC=C(C(F)(F)F)C=2)C=1C)#N.C(C1C=CC([C@@H]2C(C#N)=C(C)N(C3C=CC=C(C(F)(F)F)C=3)C(=O)N2)=C(S(C)(=O)=O)C=1)#N>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH:8]2[N:7]([C:55]([NH:57][CH2:58][CH2:59][OH:60])=[O:56])[C:6](=[O:24])[N:5]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[C:4]3[CH2:3][N:2]([CH3:1])[C:10](=[O:11])[C:9]2=3)=[C:13]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:14]=1)#[N:17]
Reactant: CN1CC2=C(C1=O)C(c1ccc(C#N)cc1S(C)(=O)=O)NC(=O)N2c1cccc(C(F)(F)F)c1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NCCO)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Product: CN1CC2=C(C1=O)C(c1ccc(C#N)cc1S(C)(=O)=O)N(C(=O)NCCO)C(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from (rac)-4-{6-methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile (Example 34) analogously to the multi-step preparation of (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-(2-hydroxyethyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide (Example 10) from (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (Example 6).