Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[S:22][CH:23]=1)=O.[OH-].[Na+]>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Cl:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[S:22][CH:23]=1
Reactant: CC(C)C(=O)Nc1nc(C=O)cs1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)C=Cc3csc(NC(=O)C(C)C)n3)c(N)c2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
7G (2.5 g, 10.4 mmol) was dissolved in THF (25 mL). To the solution was added 11D (2.4 g, 1.2 eq, 12.5 mmol), followed by crushed NaOH powder (0.8 g, 2 eq, 20.8 mmol). The reaction mixture was stirred at room temperature for about 1 hour and the solution was getting darker. After reaction completed, the mixture was poured into ice-water under stirring. The solids were collected by filtration, dried and purified by column chromatography on silica gel to give 2.6 g of pure product 11E.
Reaction SMILES: [C:1]([CH:9]([NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][CH:20]=O)C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[Br:23]Br.[C:25](O)(=O)[CH3:26]>>[CH2:25]([C:20]1[N:11]([CH2:9][C:1]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12](=[O:22])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:19]=1)[CH3:26].[Br:23][CH:25]([C:20]1[N:11]([CH2:9][C:1]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12](=[O:22])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:19]=1)[CH3:26]
Reactant: BrBr
Reactant: CC(NC(=O)c1ccccc1NC=O)C(=O)c1ccccc1
Reactant: CC(=O)O
Product: CC(Br)c1nc2ccccc2c(=O)n1Cc1ccccc1
Product: CCc1nc2ccccc2c(=O)n1Cc1ccccc1

Procedure:
2-Ethyl-3-benzyl-quinazolin-4-one is prepared following the procedure set forth in part (A) above, but substituting N-benzyl-2-(propanoylamino)-benzamide for N-(1-benzoylethyl)-2-(formylamino)-benzamide (“Compound E”). Compound E is brominated by heating in acetic acid with bromine to provide 2-(1-bromoethyl)-3-benzyl-quinazolin-4-one (“Compound F”). Compound F is treated with 4-methoxy-aniline in triethylamine to provide 2-(1-(4-methoxyphenylamino)ethyl)-3-benzyl-quinazolin-4-one (“Compound G”). Compound G is then acylated with benzoyl chloride to provide 2-(1-(N-benzoyl-N-(4-methoxyphenyl)-aminoethyl)-3-benzyl-quinazolin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1C
Yield: 67.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.048 g (68%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl[C:11]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)[C:14]([Cl:31])=[CH:13][N:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[Cl:31][C:14]1[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)=[N:16][C:11]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=2)=[N:12][CH:13]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CC(C)n1cc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of 1-isopropylpyrazol-4-amine (0.083 g, 0.66 mmol), 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.110 g, 0.327 mmol) and TsOH.H2O (0.013 g, 0.066 mmol) in 1,4-dioxane (2.0 mL) was heated in the microwave to 100° C. for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (0-100% EtOAc in petroleum benzine 40-60° C. then 0-10% MeOH in EtOAc) to give the title compound 30 (0.094 g, 68%). LCMS-D: rt 3.355 min; m/z 425.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][N:5]([S:25]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)(=[O:27])=[O:26])[C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH3:22])[C:11]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[N:12][C:8]=2[CH:7]=1.[ClH:39].C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[ClH:39].[ClH:39].[CH3:38][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([S:25]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)(=[O:26])=[O:27])[C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH3:22])[C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH2:44])=[NH:19])=[CH:20][CH:21]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: [NH4+]
Reactant: CN(C)CCN(c1ccc2c(c1)nc(Cc1ccc(C#N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CN(C)CCN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 4-[(5-(N-(2-dimethylamino-ethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([F:17])[CH:11]=1.N1C=CC=CC=1>ClCCl>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[C:12]([F:17])[CH:11]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
3-chloropropane-1-sulfonyl chloride (3.16 ml, 0.026M) was added to a solution of 4-bromo-2-fluoroaniline (5.00 g, 0.026M) and pyridine (2.12 ml, 0.026M) in dichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1 hr, after which time it was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organics were separated and dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a yellow oil (8.3 g). 1H NMR (CDCl3): δ2.54 (m, 2H), 2.90 (m, 2H), 3.64 (d, J=2.56 Hz, 2H), 6.91 (d, J=3.56 Hz, 1H), 7.07 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[C:18]2[C:13](=[C:14]([C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][C:9]1([CH3:34])[C:18]2[C:13](=[C:14]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)[CH2:10]1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cccc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (535.0 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (1.3 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A10. A solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (300.0 mg, 0.82 mmol) and 1,1′-carbonyldiimidazole (442.0 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B10. Solution B10 was added to Solution A10 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (109.0 mg, 30%) as a white solid: MS (ESI) M+1=444.2.
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][NH:11][C:12]([C@H:14]1[CH2:17][C@@H:16]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[N:15]1CC1C=CC=CC=1)=[O:13])C1C=CC=CC=1.O.[H][H]>CO>[C:18]([C@H:16]1[NH:15][C@@H:14]([C:12]([NH:11][CH2:10][C:9]([OH:35])=[O:8])=[O:13])[CH2:17]1)([OH:20])=[O:19]
Reactant: [H][H]
Reactant: O=C(CNC(=O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)N1Cc1ccccc1)OCc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)[C@H]1C[C@@H](C(=O)O)N1
Yield: 85 %

Procedure:
18.5 mg (39 μmol) of N-[cis-N-benzyl-4-(benzyloxycarbonyl)azetidine-2-carbonyl]glycine benzyl ester in 10 ml of methanol is hydrogenated in a Parr shaker over 34.5 mg of 20% Pd (OH)2 /C (containing 31 % of water) under 4 atm of hydrogen for 4h, 5 ml of water is added, the catalyst is removed by filtration through a double paper filter and washed thoroughly with methanol/water (2:1), and the solution is evaporated. Filtration over SiO2 (isopropanol/water/conc ammonia 14:5:1), evaporation and drying in a vacuum desiccator over P2O5 and KOH affords 6.7 mg (85%) of N-(cis-4-carboxyazetidine-2-carbonyl)glycine as a colorless glass. 1H NMR (D2O):δ4.98 (t, 1H, J =8.5), 4.73 (t, 1H, overlapping), 3.86, 3.74 (AB system, 2H, J =17.5), 3.08 (dt, 1H, J =11.5 (d), 10 (t)), 2.55 (dt, 1H, J =I2 (d), 8.5 (t)).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C=O)C.[CH2:30]1[O:41][C:40]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=2[O:31]1>O>[CH2:30]1[O:41][C:40]2[CH:39]=[CH:38][C:34]([C:35]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:8]=[C:9]5[C:14](=[CH:15][CH:16]=4)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]5)[CH2:2][CH2:3]3)=[O:36])=[CH:33][C:32]=2[O:31]1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(N3CCN(C(=O)c4ccc5c(c4)OCO5)CC3)ccc2N1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2.34 ml of triethylamine were added to 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.7 g of 3,4-methylenedioxybenzoyl chloride. After completion of addition, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 1.6 g of 6-[4-(3,4-methylenedioxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 191°-192.5° C., colorless needles.
Reaction SMILES: O1CCCC1.[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)=[CH:7]1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)=[CH:7]1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccsc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccsc3)cc2)no1
Temperature: 50 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(thiophen-3-ylmethoxy)-phenyl)-acetohydroximoyl chloride (150 mg, 0.532 mmol) described in Manufacturing Example 77-1-4 and 3-ethynyl-pyridin-2-ylamine (40 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (185 μL, 1.33 mmol), which was stirred for 3 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (46 mg, 24%).
Reaction SMILES: [Cl:1][CH2:2][SiH2:3][CH:4](Cl)Cl.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].CCCCCC.C([Li])CCC.Br[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1.C([Li])CCC>O1CCCC1.C(OCC)(=O)C>[Cl:1][CH2:2][SiH:3]([C:31]1[CH:32]=[CH:27][CH:28]=[CH:29][C:30]=1[Cl:33])[CH2:4][C:12]1[CH:11]=[CH:10][C:9]([Cl:14])=[CH:8][CH:13]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Clc1ccccc1Br
Reactant: ClC[SiH2]C(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: ClC[SiH](Cc1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 6.3 ml (8.2 g, 0.05 mol) of chloromethyl(dichloro)methylsilane and 8.1 g (0.05 mol) of 2-bromochlorobenzene in 75 ml of dry tetrahydrofuran was chilled to -60° under N2 and stirred while 31 ml (0.05 mol) of 1.6 molar n-butyllithiumhexane solution was added at a rate that held the mixture below -55°. With continued cooling and stirring, 8.1 g (0.05 mol) of 4-bromochlorobenzene was added as a solid, followed by another 31 ml portion of the 1.6 molar n-butyllithium solution at a rate that held the mixture below -55° C. The resulting thin slurry was allowed to warm to room temperature, treated cautiously with 10 ml of ethyl acetate, and worked up as in Example 8 to give 15.0 g of a clear yellow oil. Distillation provided 5.9 g (37%) of the title compound: bp 150°-165° (0.7 mm); nD20 1.5916; ir (neat) 3060, 3020, 2960, 2920, 2870, 1580, 1560, 1490, 1420, 1380, 1255, 1125, 1115, 1085, 1035, 1015, 805, 750 cm-1 ; nmr (CDCl3) 0.8 (3H, s), 3.3 (2H, s), 7.2-7.7 (8H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH2:12].C(N(C(C)C)C(C)C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH:12][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NNc1ccc([N+](=O)[O-])cc1Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NNc1ccc([N+](=O)[O-])cc1Br
Yield: 60.7 %

Procedure:
To a stirred and chilled (0°) solution containing 200 g (0.86 mol) of 2-bromo-4-nitrophenylhydrazine (m.p. 143°-145°) and 116.8 g (0.9 mol) of ethyldiisopropylamine in 1000 ml of tetrahydrofuran was added dropwise 108.5 g (0.9 mol) of pivaloyl chloride. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated to dryness under reduced pressure. The residue was treated with water, filtered and recrystallized from ethanol to give 165 g (52%) of product as a light yellow solid; m.p. 145° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[N:8]=[CH:9][N:10]([CH3:12])[CH:11]=1)[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[Cl:18][C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([NH:1][C@@H:2]([CH2:6][C:7]1[N:8]=[CH:9][N:10]([CH3:12])[CH:11]=1)[C:3]([OH:5])=[O:4])=[O:20].[ClH:18]
Reactant: Cn1cnc(C[C@H](N)C(=O)O)c1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)N[C@@H](Cc1cn(C)cn1)C(=O)O
Product: Cl
Yield: 748.4 %

Procedure:
Cap-127 was prepared according to the method for Cap-126 above starting from (S)-2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoic acid (1.11 g, 6.56 mmol), NaHCO3 (1.21 g, 14.4 mmol) and ClCO2Me (0.56 mL, 7.28 mmol). The title compound was obtained as its HCl salt (1.79 g, >100%) contaminated with inorganic salts. LCMS and 1H NMR showed the presence of ca. 5% of the methyl ester. The crude mixture was used as is without further purification.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[C:30]1([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>ClCCl.C(OCC)C>[C:30]1([C:36]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=2)([OH:40])[CH2:37][CH2:38][CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC(=O)c1ccccc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC(O)(c1ccccc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 200 mg (0.46 mmol) 4-iodo-1-trityl-imidazole in 3 ml anhydrous dichloromethane was added at ambient temperature 0.16 ml (0.48 mmol) 3M ethyl magnesium bromide in diethyl ether. The mixture was stirred for 1 hour then a solution of 55 mg (0.37 mmol) 1-phenyl-butan-1-one in 0.1 ml anhydrous dichloromethane was added in one portion and the reaction mixture was stirred for 16 hours. Saturated aqueous ammonium chloride (5 ml) was then added to the reaction mixture and the whole was extracted with dichloromethane (3×5 ml). The organic phase was washed with water (3×5 ml) then brine (3×5 ml), dried over MgSO4, concentrated and purified by preparative HPLC to give 90 mg rac-1-phenyl-1-(1-trityl-1H-imidazol-4-yl)-butan-1-ol as colourless oil: MS (ISP): 459.0 ((M+H)+.); 1H-NMR (CDCl3): 0.80 (3H, t, CH3), 1.30 (2H, m), 2.05 (2H, m, CH2), 3.45 (1H, s, br, OH), 6.70 (1H, s), 7.05-7.45 (21H, m).
Reaction SMILES: [CH3:1]O[ClH][NH2:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24](=O)[C:25]([O:27][CH3:28])=[O:26])=[N:13]2)=[CH:8][CH:7]=1.[CH3:30][OH:31]>>[CH:18]([O:17][CH:14]([CH3:15])[CH3:1])([CH3:19])[CH3:23].[CH3:30][O:31]/[N:4]=[C:24](\[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[CH:16][N:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)[N:13]=1)/[C:25]([O:27][CH3:28])=[O:26]
Reactant: CO
Reactant: COC(=O)C(=O)c1ccccc1Oc1ccn(-c2ccc(Cl)cc2)n1
Product: CC(C)OC(C)C
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccn(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Approximately 30 ml of methanol and 2.88 g of O-methylhydroxyl-amino hydrochloride were added to the second half of the dimethyl sulfoxide solution of Example 1. The mixture was stirred for a further 12 hours at room temperature, and the batch was worked up as described for Example 1. The dried methyl tert-butyl ether phase was filtered through silica gel. After evaporation of the residue on a rotary evaporator, there remained 3.2 g of crude product. To concentrate the desired E isomer, the crude product was taken up in 50 ml of saturated methanolic hydrochloric acid, and the mixture was stirred for 3 hours at room temperature. For working-up, the mixture was treated with methyl tert-butyl ether. The organic phase was washed with sodium chloride solution until neutral, dried over sodium sulfate and concentrated. Some of the remaining oil crystallized. After trituration with diisopropyl ether, 1.05 g of the title compound were obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH2:13].CC(C)([O-])C.[K+].[Cl:20][CH2:21][C:22](OCC)=[O:23].O>C1COCC1>[Cl:20][CH2:21][C:22]([NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=2)[N:9]=[CH:8][CH:7]=1)=[O:23]
Reactant: CCOC(=O)CCl
Reactant: COc1ccc2nccc(N)c2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nccc(NC(=O)CCl)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
To a solution of 6-methoxy-[1,5]naphthyridin-4-ylamine (553 mg, 3.16 mmol) in THF (45 mL) was added potassium tert-butoxide (390 mg, 1.1 eq.) at 0° C. The resulting brown suspension was stirred at rt for 1.5 h and then added dropwise to a solution of ethyl chloroacetate (387 mg, 1 eq.) in THF (30 mL) at −5° C. The mixture was allowed to warm to rt and was further stirred for 3 h. Water was added and the mixture was concentrated under reduced pressure. The resulting precipitate was filtered and further dried at HV to afford the title intermediate as a beige solid (357 mg, 45% yield).
Reaction SMILES: OO.[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[O:12]B(O)O>S([O-])(O)=O.[Na+]>[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[OH:12]
Reactant: Cc1cc(F)c(F)c(OB(O)O)c1
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Product: Cc1cc(O)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under cooling with an ice bath, 53.1 g of aqueous hydrogen peroxide was slowly added dropwise to the compound (3) having been dissolved in 300 mL, followed by stirring at room temperature for 3 hours. Under cooling with an ice bath, 100 mL of a saturated sodium hydrogen sulfite aqueous solution was added dropwise thereto to terminate the reaction. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated sodium hydrogen sulfite aqueous solution and a saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to obtain 22.7 g of 2,3-difluoro-5-methylphenol (4).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10](=[O:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:5][C:4]=1[CH3:17].[BH4-].[Na+]>>[CH3:1][N:2]([CH3:18])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH:10]([OH:16])[CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])=[CH:5][C:4]=1[CH3:17]
Reactant: Cc1cc(C(=O)CS(C)(=O)=O)cc(C)c1N(C)C
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(C(O)CS(C)(=O)=O)cc(C)c1N(C)C

Procedure:
A suspension of 12 g. of 4'-(dimethylamino)-3',5'-dimethyl-2-(methylsulfonyl)acetophenone and 6.6 g. of sodium borohydride in 300 ml. of alcohol was stirred at room temperature for 20 hours, resulting in a solution. After the addition of 300 ml. of water, the alcohol was removed under vacuum. The crystals formed were removed by filtration with suction, washed with water and dried, whereby there was obtained 4-(dimethylamino)-3,5-dimethyl-α-[(methylsulfonyl)-methyl]benzyl alcohol having a melting point of 133°-134° C.