Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1N>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[F:16])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: Nc1ccccc1F
Reactant: CC(=O)N1c2ccccc2[C@@H](O)C[C@@H]1C
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccccc2F)C[C@@H]1C
Yield: 52.8 %

Procedure:
A compound was produced in the same manner as in Example 12, using 100 mg of trans-1-acetyl-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline and 112 mg of 2-fluoroaniline, and thus 77 mg (53%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.ClCCl.CO.N>>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:1](=[O:5])[C:2]#[CH:3])=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C#CC(=O)O
Agent: N
Solvent: ClCCl
Solvent: CO
Product: C#CC(=O)Nc1ccc(Cl)cc1

Procedure:
Prepared analogously to Example 1.1.b. from propynoic acid and 4-chloroaniline. Yield: 0.56 g (31.2% of theory); C9H6ClNO (M=179.60); calc.: molecular ion peak (M−H)−: 178/180; found: molecular ion peak (M−H)−: 178/180; Rf value: 0.53 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: CCCCOC(=O)c1ncc[nH]1
Product: CCCCOC(=O)c1nccn1Cc1ccccc1
Yield: 88 %

Procedure:
5.4 g (32.1 mmol) of butyl imidazole-2-carboxylate were reacted with 4.1 g (32.1 mmol) of benzyl chloride analogously to procedure 8a. 7.3 g (78%) of the product were obtained.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11]>CO>[CH2:1]([NH:8][CH2:11][CH2:10][C:9]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: NCc1ccccc1
Solvent: CO
Product: COC(=O)CCNCc1ccccc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A solution of 55 mL (0.50 mole) benzylamine in 250 mL methanol was cooled in an ice bath. A solution of 54 mL (0.60 mole) methyl acrylate in 50 mL methanol was added dropwise over 30 minutes. The reaction mixture was then allowed to warm gradually to room temperature. After about 96 hours the reaction mixture was concentrated under reduced pressure and the residue vacuum distilled to provide 74.6 gm (77%) of the desired compound in two fractions.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][CH:8]([SiH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[O:9][CH2:10][CH3:11])[CH3:6].CN(C)C1C=CC=CC=1.Cl.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:10]([O:9][CH:8]([SiH2:12][CH2:13][CH2:14][CH2:15][N:16]=[C:1]=[O:2])[O:7][CH2:5][CH3:6])[CH3:11]
Reactant: CCOC(OCC)[SiH2]CCCN
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(OCC)[SiH2]CCCN=C=O
Reaction time: 3 h
Yield: 71.9 %

Procedure:
In 150 ml of toluene was dissolved 9.9 g of carbonyl chloride, and a solution of 19.1 g of γ-diethoxymethylsilylpropylamine and 24.2 g of N,N-dimethylaniline in 50 ml of toluene was dropped into the above solution at -5° C. to -10° C. over a period of 3 hours to effect reaction. After the reaction, N,N-dimethylaniline hydrochloride was removed by filtration, the filtrate was distilled to recover toluene, and a fraction having a boiling point of 91° C. to 93° C. under 9 mmHg was collected. Then, 1 g of sodium benzoate was added to the fraction. The mixture was then stirred for 3 hours and the pH value became 7. Excessive sodium benzoate and the precipitate were removed by filtration, and the filtrate was distilled to obtain 15.6 g of γ-diethoxymethylsilylpropyl isocyanate as a fraction having a boiling point of 80° C. to 82° C. under 5 mmHg. The product remained stable, even when stored for more than 6 months.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][CH2:11]2)[C:6]1=[O:17].C(S)C.[Na].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([OH:16])[CH2:14][CH2:15]2)[C:6]1=[O:17]
Reactant: COc1cccc(Cl)c1CC1CCN([C@H]2CC[C@@H](O)CC2)C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCS
Product: O=C1C(Cc2c(O)cccc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C

Procedure:
Dissolve 3-(2-chloro-6-methoxy-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Example 57) (150 mg, 0.44 mmol) in DMF (5 mL) and purge with nitrogen. Add sodium ethane thiol (110 mg, 1.3 mmol) and heat to 120° C. for 4 hours. Cool to room temperature and pour into ammonium chloride and extract with methylene chloride, dry over sodium sulfate, filter and concentrate. Purify over silica gel (20% hexanes in ethyl acetate) to yield 90 mg (63%) of the title compound as a pale yellow solid: Mass spectrum (apci) m/z=324.1 (M+H).
Reaction SMILES: [CH:1]([S:4]Cl)([CH3:3])[CH3:2].[C:6]1([NH:12][P:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[CH:1]([S:4][N:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])([CH3:3])[CH3:2]
Reactant: O=P(Nc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)SCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)SN(c1ccccc1)P(=O)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 11.1 parts of isopropyl sulphenyl chloride in 100 parts of carbon tetrachloride is added to a suspension of 30.9 parts of N,P,P-triphenylphosphinic amide and 10.0 parts of triethylamine in 150 parts of carbon tetrachloride at room temperature. The mixture is stirred for a further 1 hour. The triethylamine hydrochloride is filtered off and the filtrates evaporated under reduced pressure to give a white solid. This is recrystallised from methylated spirits to yield 16.5 parts of N-isopropylthio-N,P,P-triphenylphosphinic amide as a colourless solid m.p. 148°-150°C. Found, C, 67.2; H. 6.2; N, 4.0; P, 8.1 percent, C21H22NOPS requires C, 68.7; H, 6.0; N, 3.8; P, 8.45 percent. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[CH3:14][C:15]1[C:23]2[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]3)=[N:21][CH:20]=[N:19][C:18]=2[S:17][CH:16]=1>CC(O)C.CS(C)=O>[OH:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:30][CH:27]1[CH2:26][CH2:25][N:24]([C:22]2[C:23]3[C:15]([CH3:14])=[CH:16][S:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:29][CH2:28]1
Reactant: Cc1csc2ncnc(N3CCC(N)CC3)c12
Reactant: OCc1cccc(OCC2CO2)c1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1csc2ncnc(N3CCC(NCC(O)COc4cccc(CO)c4)CC3)c12
Yield: 26 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 30 h at 80° C. and 20 h at 100° C.), using 220 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 26% yield upon purification by prep. HPLC (reversed phase) and subsequent by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[N+:1]([CH:4]=[C:5]([NH:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: NCCSCCc1ccccn1
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCCc1ccccn1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)-methylthio)ethylamino]ethylene with 2-[2-(2-aminoethyl)thioethyl] pyridine according to the procedure of Example 1 (a) (ii) yields the title compound.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]1[C:11]([NH2:12])=[C:10]([NH2:13])[CH:9]=[N:8]1.[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[NH2:12][C:11]1[N:7]([CH3:6])[N:8]=[CH:9][C:10]=1[NH:13][C:26]([C@@H:25]([NH:24][C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cn1ncc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 1-methyl-1H-pyrazole-4,5-diamine sulfate (2.10 g), (2S)-2-[(benzyloxycarbonyl)amino]-5-[(tert-butoxycarbonyl)amino]pentanoic acid (3.66 g) and triethylamine (3.04 g) in chloroform (50 ml) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.91 g), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product of 1-benzyl 4-tert-butyl {(1S)-1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]tetramethylene}biscarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: C([C:5]1([C:18]([NH2:20])=[O:19])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][NH:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(C)(C)C.[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:33]1[O:35][CH2:34]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:33]([OH:35])[CH2:34][N:6]1[CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:5]1[C:18]([NH:20][C:9]([CH3:17])([CH3:10])[CH3:8])=[O:19])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reactant: CC(C)(C)C1(C(N)=O)NCCc2c1[nH]c1ccccc21
Product: CC(C)(C)NC(=O)C1c2[nH]c3ccccc3c2CCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
A solution of 0.60 g of tert.butyl 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide and 0.66 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 20 ml of methanolwas heated at reflux under argon for 16 hours and then evaporated to give aclear oil. The two diastereomeric products were separated by flash chromatography on silica gel using n-hexane/ethyl acetate (3:1) for the elution. There were obtained 268 mg of isomer A of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide, MS: m/e 569 [M+H]+ and 65 mg of isomer B of the same compound; MS: m/e 569 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:9]1([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH:7]=[CH2:8].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:6]([C:9]1([N:22]([CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=2)(=[O:34])=[O:35])[C:1](=[O:4])[CH:2]=[CH2:3])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)[CH:7]=[CH2:8]
Reactant: C=CCC1(NCc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC1(N(Cc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)C(=O)C=C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Acryloyl chloride (0.360 g, 0.401 mmol) was added at 0° C. to a stirred solution of tert-butyl 4-allyl-4-((1-tosyl-1H-indol-4-yl)methylamino)piperidine-1-carboxylate (0.2 g, 0.382 mmol), diisopropylethylamine (0.32 mL, 1.91 mmol) in DCM (5.0 mL). The reaction mixture was stirred at 0° C. for 30 min and was then allowed to warm to rt and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: 5% ethyl acetate in hexane) to yield the title compound as a white solid (0.16 g, 72%). LCMS RtA=0.774, [M+H-Boc]+=477.9
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25]>>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:27](/[S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)(=[O:26])=[O:25])\[C:28]#[N:29])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)c1ccccn1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccn2)cc(C(C)(C)C)c1O

Procedure:
M34 was prepared with 3,5-di-t-butyl-4-hydroxybenzaldehyde and (pyrid-2-yl)sulfonly acetonitrile under similar conditions as described for M26.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(CN)c1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3[N+](=O)[O-])ncn2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine 3.1b (500 mg, 1.57 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), m-methylbenzylamine (285 mg, 2.36 mmol, 1.50 equiv), and potassium carbonate (650 mg, 4.71 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 2×50 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This resulted in 0.5 g (79%) of N-(3-methylbenzyl)-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidin-4-amine as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[N:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29](=[O:38])[NH:30][CH:31]([C:35](F)=[O:36])[CH:32]([CH3:34])[CH3:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([NH:10][C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:38])[CH:32]([CH3:34])[CH3:33])=[CH:8][CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cnccc1N
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnccc1NC(=O)C(NC(=O)OCc1ccccc1)C(C)C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
Formula 506 where R1, R3 and R4 are H; R6 is Isopropyl; R6′ is H: W, Y and Z are —C═; and X is —N═: To a solution of dichloromethane (100 mL), 4-amino-nicotinic acid methyl ester (4.60 g, 30.2 mmol) and diisopropylethyl amine (8.25 mL, 46.7 mmol), was added (1-fluorocarbonyl-2-methyl-propyl)-carbamic acid benzyl ester (11.8 g, 46.7 mmol) at room temperature and the mixture stirred overnight. The solvent was removed under reduced pressure and the residue purified by flash silica gel chromatography using hexane-EtOAc (stepwise gradient from 3:1 to 1:1) as eluents to obtain the desired amide of Formula 506, 4-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-nicotinic acid methyl ester (10.5 g, 90.1%). MS (Cl) M/E: 386.2.
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH3:17])[CH:8]=2)[C:3]=1[CH:18]=[O:19].[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([OH:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([CH:26]=1)[O:27][C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH3:17])[CH:8]=2)[C:3]=1[CH:18]=[O:19]
Reactant: Cc1cnc2c(C=O)c(Cl)n(-c3ccccc3)c2c1
Reactant: Cc1ccc(F)cc1O
Product: Cc1cnc2c(C=O)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c2c1

Procedure:
The title compound was prepared analogously as described in example 1, step 6, from the compound of example 51, step 6, (150 mg, 554 μmol) and 5-fluoro-2-methylphenol.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:14]CCC(C1C=CC=CC=1)=O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH:7]=[CH:8][CH:9]=[C:10]3[NH:12][CH2:14]1
Reactant: Nc1cccc2cccc(N)c12
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2c3c(cccc3c1)NCN2
Yield: 47.4 %

Procedure:
A stirred mixture of 1.411 g of 1,8-diaminonaphthalene, 1.629 g of 4-chlorobutyro-phenone, 3 mg of p-toluenesulfonic acid monohydrate, and 10 mL of toluene was heated to reflux under a nitrogen atmosphere using a Dean-Stark trap to remove the water evolved from the reaction for 10 hr. The mixture was filtered to remove unreacted starting material, partioned between ethyl acetate and 5% sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2.04 g of crude product. This was further purified by chromatography on silica gel, eluting with 1:1 diethyl ether/petroleum ether, and collecting the initial band to yield 0.719 g of dihydroperimidine intermediate.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:13][C:12]3[CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Reactant: Oc1cccc(O)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Oc1cccc(Oc2ncnc3[nH]c(Br)cc23)c1
Temperature: 150 °C
Yield: 32.7 %

Procedure:
6-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.41 mmol), prepared as in reference 1, is mixed with resorcinol (451 mg, 4.1 mmol) and diisopropylethylamine (714 μL, 4.1 mmol) in dioxane (1.3 mL). The mixture is heated to 150° C. for 3 days, with stirring. The reaction is then cooled to ambient temperature and the solvent is removed. The resultant crude product is purified by flash column chromatography using a gradient of 3-5% MeOH in DCM to yield 5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yloxyl)-phenol (41 mg; 32%).
Reaction SMILES: [CH:1](Br)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([CH3:22])[NH:17]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]([N:20]1[CH2:19][C@H:18]([CH3:22])[NH:17][C@H:16]([CH3:15])[CH2:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1
Reaction time: 8 h

Procedure:
Benzhydryl bromide (4.33 g, 17.5 mmol) is added to s stirred solution of 2,6-cis-dimethylpiperazine (2.00 g, 17.5 mmol) and diisopropylethylamine (2.94 g, 22.8 mmol) in anhydrous dichloromethane (50 mL) at 0° C. The resultant mixture is allowed to stir overnight. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 1-3%, benzhydryl-3,5-cis-dimethyl-piperazine is obtained as a white solid (3.0 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](Cl)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](Cl)=[O:15]>N1C=CC=CC=1>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[N:1]1[C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: Nc1nc2ccccc2[nH]1
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Aminobenzimidazole (13.3 g.) is dissolved in 50 ml. of pyridine, and 10.2 g. of phthaloyl chloride is added, causing immediate precipitation. On mixing and heating on the steam-bath, all dissolves. The solution is heated 2 hours on the steam-bath with occasional swirling. It is cooled to room temperature and quenched in 200 ml. of water. After 1 hour agitation, the mixture is filtered free of solids and the solids washed with water. The yield of N-(benzimidazol-2-yl)phthalimide is 11.6 g. Recrystallization from glacial acetic acid results in bright yellow crystals of N-(benzimidazol-2-yl)phthalimide which, after drying, melts at 266°-268° C., λmax. 295.0, E11%cm. 529.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([C:15]1[CH:14]=[C:13]([CH3:12])[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=1)=[O:6]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(F)cc(F)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
1.45 g (8.21 mmol) 3,5-difluorobenzoic acid chloride, 1.22 g (8.21 mmol) 4-methyl-3H-benzoxazol-2-one and 4.40 g (33.0 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. The mixture was mixed with ice water and the product precipitated as a solid was suction filtered and washed with water. After trituration of the precipitate with MeOH it was suction filtered, washed with MeOH and dried i. vac.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.C([O:16][C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH:21]=[O:22])=O)(C)(C)C>C1COCC1>[CH3:23][C:20]1([CH3:24])[CH:21]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[O:22][C:17](=[O:16])[NH:19]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)NC(=O)OC1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A cold (−78 ° C.), stirred solution of (trimethylsilyl)acetylene (4.42 g, 45.0 mmol) In anhydrous THF (20 mL) was treated with nBuLi (18 mL, 45.0 mmol) under nitrogen. The colorless solution was stirred for 30 minutes and followed by the addition of 2(tert-butoxycarbonylamino)-2-methyl propionaldehyde (2.80 g, 15 mmol) in anhydrous THF (20 mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched with water. After removal of THF, tne residue was partitioned between ether (150 mL) and water (100 mL). The separated organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated to give the crude 4,4-Dimethyl-5-trimethylsilylethynyl-2-oxazolidinone (100%) as yellow oil which was carried to the next step.