Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([C:25]2[CH:50]=[CH:49][C:28]([O:29][C:30]3[CH:48]=[CH:47][C:33]([C:34]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)=O)=[CH:32][N:31]=3)=[CH:27][CH:26]=2)=O)[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=1>C1COCC1>[CH2:7]([N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:25]2[CH:50]=[CH:49][C:28]([O:29][C:30]3[N:31]=[CH:32][C:33]([CH2:34][NH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:39][CH:38]=4)=[CH:47][CH:48]=3)=[CH:27][CH:26]=2)[CH2:21][CH2:22]1)[C:8]1[CH:16]=[CH:15][C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(NCc2ccc(Oc3ccc(CN4CCN(Cc5ccc6c(c5)OCO6)CC4)cc3)nc2)cc1
Temperature: 0 °C

Procedure:
To a suspension of lithium aluminum hydride (0.106 g, 2.80 mmol) in THF (10 mL) was added dropwise a solution of 6-[4-(4-piperonylpiperazine-1-carbonyl)-phenoxy]-N-(4-trifluoromethylphenyl)nicotinamide (0.423 g, 0.700 mmol) in THF (10 mL) under ice cooled stirring. Once the entire amount was added dropwise, the solution temperature was slowly raised, and stirred under reflux for 2 hours. After cooling, ice water (50 mL) was added to the solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1), to thereby yield 0.125 g of the title compound.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].Br[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].N12CCCNC1C=CCCC2>CN(C)C=O>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[N:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Nc1cc[nH]c(=S)n1
Agent: C1=CC2NCCCN2CCC1
Solvent: CN(C)C=O
Product: Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-thiocytosine (0.51 g.), dimethylformamide (5 ml.), N-(2-bromoethyl)phthalimide (1.12 g.) and 1,8-diazabicyclo[5,4,0]undec-5-ene (0.67 g.) was stirred at room temperature for 6 hours and then evaporated to dryness. The residue was stirred with a mixture of water and ethyl acetate and the unsoluble material collected to give 4-amino-2-(2-phthalimidoethylthio)pyrimidine which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19](C(OCCCC)=O)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH2:30][CH2:31][CH2:32][OH:33])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH2:30][CH2:31][CH2:32][OH:33])[N:7]=1
Reactant: CCCCOC(=O)N1CCN(S(=O)(=O)Nc2cc(OCCCO)nc(SCc3cccc(F)c3F)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc(OCCCO)nc(SCc2cccc(F)c2F)n1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tent-butyl 4-({[2-[(2,3-difluorobenzyl)thio]-6-(3-hydroxypropoxy)pyrimidin-4-yl]amino}sulfonyl)piperazine-1-carboxylate (the product from step ii), 0.83 g) in DCM (5 ml) was added TFA (5 ml) slowly. The reaction was then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield 160 mg
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)[CH3:2].[OH-].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][CH:11]=2)=[N:6][CH:5]=1)[CH3:2]
Reactant: CCCCCCCCBr
Reactant: CCOc1cnc(-c2ccc(O)cc2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ncc(OCC)cn2)cc1
Yield: 77.2 %

Procedure:
To a solution of 5-ethoxy-2-(4-hydroxyphenyl)pyrimidine (40 g) dissolved in ethanol (340 ml) were added potassium hydroxide (11.2 g) and octyl bromide (35.8 g), followed by keeping the mixture under reflux for 3 hours, distilling off ethanol (about 300 ml), extracting the residue with toluene (500 ml), washing the resulting organic layer with 2N--NaOH aqueous solution, further washing with water until the washing water became neutral, distilling off low boiling substances in the organic layer and recrystallizing the residue from ethanol to obtain 5-ethoxy-2-(4-octyloxyphenyl)pyrimidine (46.9 g). This product exhibited a phase transition of ##STR11##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:13]1([CH2:12][O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: ClCn1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCn1nnc2ccccc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (8.45 g, 54 mmol) is dissolved in DMF (100 ml) and after addition of 1-(chlormethyl)-1H-benzotriazole (9.96 g, 59.4 mmol) and K2CO3 (9.7 g, 70.2 mmol) the mixture is stirred at 45° C. for 1 h (TLC control). Then the mixture is evaporated under high vacuum. The residue is diluted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation gave 3.9 g of a colorless solid. The product is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:13]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.[CH2:34]([N:36]([CH2:41][CH3:42])[CH2:37][CH2:38]CCl)[CH3:35]>>[CH2:34]([N:36]([CH2:41][CH3:42])[CH2:37][CH2:38][CH2:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:13]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1)[CH3:35]
Reactant: CCN(CC)CCCCl
Reactant: COc1ccc(S(=O)(=O)c2c(-c3ccccc3)sc3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
3-(4-Methoxyphenylsulfonyl)-2-phenylbenzothiophene is demethylated with pyridine hydrochloride as described above and the resulting product is reacted with 3-diethylaminopropyl chloride, also as described above, to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:4]=2[N:5]=[C:6]([N:8]([CH3:10])[CH3:9])[N:7]=1.[CH3:22][NH:23][CH3:24]>C(O)C>[CH3:9][N:8]([C:6]1[N:7]=[C:2]([N:23]([CH3:24])[CH3:22])[C:3]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:4]=2[N:5]=1)[CH3:10]
Reactant: CN(C)c1nc(Cl)c2nnn(Cc3ccccc3F)c2n1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nc(N(C)C)c2nnn(Cc3ccccc3F)c2n1
Reaction time: 0.5 h

Procedure:
In a manner analogous to that described in Example 12, 1.95 g (6.36 mmol) of 7-chloro-5-(N,N-dimethylamino)-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine are dissolved in 200 ml of warm ethanol, 7 ml of aqueous dimethylamine solution (40%) are added and the mixture is left to stand for 30 minutes. After dilution with 200 ml of water, the product is filtered off with suction and recrystallised from ethanol. In this manner 5,7-bis(N,N-dimethylamino)-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine having a melting point of 123°-125° is obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10](=[CH:15][CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:12][CH2:13][NH2:14])[CH3:9].[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[C:19]([NH:14][CH2:13][CH:12]=[CH:11][C:10]([CH2:8][CH3:9])=[CH:15][CH:16]([CH3:17])[CH3:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C=CCN)=CC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C=CCNC(C)=O)=CC(C)C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of triethylamine (2.22 g) and 4-ethyl-6-methyl-2,4-heptadiene-1-ylamine (3.07 g) in dichloromethane (50 ml) at 0° C. was added dropwise acetic anhydride (4.08 g). After one hour, the reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10% methanol-chloroform) to give 1-acetylamino-4-ethyl-6-methyl-2,4-heptadiene (3.86 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[N:39]=[C:38]([CH3:40])[CH:37]=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[N:39]=[C:38]([CH3:40])[CH:37]=[N:36]1)=[O:11]
Reactant: Cc1ccc(-n2ncc(C)n2)c(C(=O)O)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, starting with 5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)benzoic acid. ESI-MS (m/z): 328 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH3:12])[CH2:3][CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C1CCN2C(=NCCC2)CC1.[N+:24]([CH3:27])([O-:26])=[O:25]>C(#N)C>[CH3:1][CH:2]([CH2:11][CH3:12])[CH2:3][CH:4]([CH2:27][N+:24]([O-:26])=[O:25])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=CCC(C)CC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(CC(C)CC)C[N+](=O)[O-]
Yield: 39.2 %

Procedure:
Ethyl 5-methyl-2-heptanoate 12 (6.75 g, 39.70 mmol), DBU (6.0 g, 39.7 mmol), nitromethane (21.97 g, 359.9 mmol) in acetonitrile 80 mL was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated to an oil. A solution of the oil in ether was washed with 1N HCl, brine and dried. It was evaporated to give a light oil which was chromatographed on silica gel, eluting with 5% to 10% ether in Pet. ether to give 13 (3.6 g, 42%). 1H-NMR (CDCl3) δ4.49-4.39 (m), 4.12-4.07 (m), 3.61 (m), 2.36 (m), 1.36-1.18 (m), 0.86-0.79.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[CH:24]=[CH:25][C:26]([Br:28])=[CH:27][C:14]=2[N:13]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([N:16]1[C:15]2[CH:24]=[CH:25][C:26]([Br:28])=[CH:27][C:14]=2[N:13]=[C:12]1[CH:8]([NH2:7])[CH:9]([CH3:10])[CH3:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2n1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)c1nc2cc(Br)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamic acid tert-butyl ester in DCM (2 ml), was added trifluoroacetic acid (0.5 ml). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo to give the free amine product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=1>CC(C)=O>[C:5]1([C:3]2[N:11]=[C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccnc(N)n1
Solvent: CC(C)=O
Product: Nc1ccn2cc(-c3ccccc3)nc2n1
Reaction time: 0.25 h

Procedure:
Bromoacetophenone (2.71 g, 14 mmol) was added to a solution of 2,4-diaminopyrimidine (1.00 g, 9 mmol) in acetone (40 ml), and the mixture was heated to reflux for 5 h. The cooled suspension was filtered, the precipitate was washed (acetone), and then stirred for 15 min in a mixture of 10 ml water and 15 ml NH4OH (25%). The suspension was filtered, washed (water), and dried under vacuum. The crude product (1.9 g, quant.) was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccccc1C(=O)OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1C(C)Br
Reaction time: 2 h

Procedure:
A mixture of 10.7 g. (0.065 mole) of methyl 2-ethylbenzoate, 12.5 g. (0.07 mole) of N-bromosuccinimide, 50 mg. of benzoyl peroxide, and 125 ml. of carbon tetrachloride is stirred at reflux until the reaction is complete in 2 hours. The precipitated succinimide is filtered from the cooled mixture and the filtrate is evaporated to dryness under reduced pressure leaving methyl 2-(1-bromoethyl)benzoate as the residual yellow oil in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:15][C:7]=2[C:6]([C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1)[CH2:14][CH2:13][S:12][CH2:11]3.[C:19]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:15][C:7]=2[C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1)[CH2:14][CH2:13][S:12][CH2:11]3
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)O)c2c1OC1(CCSC1)O2
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC)c2c1OC1(CCSC1)O2
Reaction time: 8 h
Yield: 14.2 %

Procedure:
A suspension of 7-methoxy-4′,5′-dihydro-spiro[1,3-benzodioxole-2,3′-(2H)-thiophen]-4-carboxylic acid (161 mg, 0.600 mmol), K2CO3 (166 g, 1.20 mmol) and dimethyl sulphate (74 μL, 0.78 mmol) in acetone (1 mL) was kept at 50° C. overnight. At room temperature water (15 mL) was added and the aqueous phase was extracted with ethyl acetate (2×20 mL). The organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard HPLC purification afforded compound 505 (24 mg, 14%). 1H NMR (CDCl3) δ 7.44 (d, 1H), 6.56 (d, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.32 (d, 1H), 3.24 (d, 1H), 3.05 (t, 2H), 2.49 (td, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:5][N:6]=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>O1CCCC1>[C:40]([NH:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:25])=[CH:5][N:6]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4ccccc4)s3)CSC12

Procedure:
On treating 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.5 g) with benzoyl chloride (1.11 cc) in dry tetrahydrofuran (55 cc) in the presence of triethylamine (1.23 cc), using the working method of Example 1 (B), 3-(2-benzamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (1.8 g) is obtained in the form of cream-coloured crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.Br[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.COCCOC.O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Brc1cccc2ccccc12
Reactant: OB(O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Brc1ccccc1-c1cccc2ccccc12
Temperature: 85 °C
Yield: 52.5 %

Procedure:
To a 250-mL round bottom flask equipped with a magnetic stir bar was added water (25 mL) and 1,2-dimethoxyethane (25 mL). The solution was sparged with nitrogen for 20 minutes, then potassium carbonate (6.67 g, 48.3 mmol, 3 equiv), 2-bromophenylboronic acid (3.80 g, 18.9 mmol, 0.98 equiv) and 1-bromonaphthalene (2.70 mL, 19.3 mmol, 1 equiv) were added. The flask was then purged with N2 for 10 minutes before finally adding palladium(II) acetate (87 mg, 0.39 mmol, 0.02 equiv) and triphenylphosphine (405 mg, 1.55 mmol, 0.08 equiv). The reaction mixture was heated to 85° C. under a positive pressure of nitrogen for 16 hours. After cooling to room temperature, the phases were partitioned and the organic layer was collected, and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude material was purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: ramp up from heptane to 99:1 heptane:ethyl acetate over 1.5 column volumes, hold at 99:1 for 1.5 column volumes, ramp up to 92:8 heptane:ethyl acetate over 6 column volumes, hold at 92:8 for 6 column volumes) and then recrystallization from 99:1 heptane:ethanol to afford the title compound as a white solid (2.81 g, 93 area % by HPLC, 51% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.91 (dd, J=8.3, 0.8 Hz, 2H), 7.74 (dd, J=8.0, 1.2 Hz, 1H), 7.57-7.29 (m, 8H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N+:13]([O-])=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C.CCN(CC)CC>C(#N)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([C:22]#[N:23])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1nccc2c1cnn2-c1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide (0.300 g, 1.31 mmol) in acetonitrile (10 mL) was added trimethylsilyl cyanide (TMSCN) (931 μL, 6.99 mmol) followed by Et3N (0.930 mL, 6.69 mmol) and the mixture was warmed at reflux. After 3 hours, the mixture was diluted with water and the solid collected by filtration washing with water. The flakey solid was then dissolved in methanol and concentrated to afford 1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine-4-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:16])[N:9]([CH2:17][C:18]([OH:20])=O)[N:8]=2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH:23]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:16])[N:9]([CH2:17][C:18]([NH:21][CH2:22][CH:23]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:20])[N:8]=2)=[CH:4][CH:3]=1
Reactant: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)O)c1=O
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1C(F)(F)F
Product: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)NCC(NC(=O)OC(C)(C)C)c2ccccc2C(F)(F)F)c1=O

Procedure:
Analogously to the procedure of Example 63, 47 mg (146 μmol) of the compound of Example 52A were reacted with 49 mg (161 μmol) of tert-butyl {2-amino-1-[2-(trifluoromethyl)phenyl]-ethyl}carbamate. This gave 60 mg (68% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22]([Cl:41])(C1C=CC=CC=1)(C1C=CC=CC=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.OCC1C=CC(CCl)=CC=1.C1(C)C=CC=CC=1>Cl.CCCCCCC>[C:16]1([C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:2][CH2:1][C:26]2[CH:27]=[CH:28][C:23]([CH2:22][Cl:41])=[CH:24][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: OCc1ccc(CCl)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: ClCc1ccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask was charged with triphenylmethyl methyl ether (2.74 g, 10 mmol), trityl chloride (2.79 g, 10 mmol), p-hydroxymethylbenzyl chloride (3.13 g, 20 mmol), toluene (12 mL), heptane (12 mL) and 32% HCl (2 drops). The solution was heated to reflux and 12 mL solvent was distilled over 2 hours. The solution was cooled to room temperature and the resulting slurry diluted with 12 mL heptane. After cooling in an ice bath, the product was isolated by vacuum filtration and dried in vacuo at 40° C. to give 6.27 g (79% yield) of crude product. Recrystallization from 20 mL acetonitrile gave 5.46 g (88% recovery) of the desired product. The product had a melting point of 126°-128° C. 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ7.6-7.2 (complex, 19H), 4.6 (s, 2H), 4.2 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]#[N:9])=[C:5]([NH2:7])[N:6]=1.CN(C)C=O.[SH2:15]>C(N(CC)CC)C>[CH3:1][C:2]1[S:3][C:4]([C:8](=[S:15])[NH2:9])=[C:5]([NH2:7])[N:6]=1
Reactant: S
Reactant: Cc1nc(N)c(C#N)s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)c(C(N)=S)s1
Yield: 58 %

Procedure:
5.5 parts of 2-methyl-4-amino-5-cyano-thiazole in 50 parts of dimethylformamide and 10 parts of triethylamine are reacted with 3 parts of hydrogen sulfide as described in Example 1(a). 4.0 parts of 2-methyl-4-amino-5-thiocarbamoylthiazole (58% of theory) of melting point 209°-213° C. are obtained.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].Cl.[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]2[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]2)[S:7][C:8]=1[C:16]([CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: COC1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1CCN(CC(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
Compound 531 (120 mg, 0.300 mmol) and 4-methoxypiperidine hydrochloride (139 mg, 0.900 mmol) were suspended in THF (4 mL), and triethylamine (0.140 mL, 0.990 mmol) was added dropwise thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=49:1), followed by reslurrying with a mixed solvent of diisopropyl ether and diethyl ether to afford the entitled Compound 545 (96.0 mg, 74%) as a white solid.