Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(O[C:11](=[O:14])[CH:12]=[CH2:13])C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][C:17]=1[CH3:24].[H-].[Na+]>CCO>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:11](=[O:14])[CH2:12][CH2:13][NH:23]2)=[CH:18][C:17]=1[CH3:24]
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(NN)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2NCCC2=O)ccc1Br
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Triethylamine (625 μL, 13.1 mmol) and acrylic acid ethyl ester (1.82 mL, 5.74 mmol) were added to a solution of (4-bromo-3-methyl-phenyl)-hydrazine (1.05 g, 5.22 mmol) in EtOH (26.1 mL) at room temperature in a nitrogen atmosphere, and the mixture was stirred at 80° C. for 18 hours. The reaction solution was cooled, and 50% NaH (501 mg, 10.4 mmol) was then added to the reaction solution at 0° C. The mixture was stirred at 0° C. for 30 minutes, and 50% NaH (251 mg, 5.20 mmol) was then further added, followed by further stirring for 30 minutes. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate three times. The organic layers were combined and washed with a mixed solution of water:saturated brine (1:1). After separation, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-(4-bromo-3-methyl-phenyl)-pyrazolidin-3-one as a brown form (684 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.I[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:32]([O:30][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:25])([F:26])[F:24])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1)[CH3:33]
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cc(F)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Temperature: 80 °C

Procedure:
A mixture of 1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (0.053 g), iodoethane (0.011 mL) and powdered potassium carbonate (0.090 g) in 1 mL of anhydrous DMF was heated at 80° C. for 18 hours, cooled to room temperature, and diluted with water and filtered. The solid was purified with flash silica gel chromatography using ethyl acetate as the eluent. The product rich fraction were concentrated in vacuo and provided 1-[4-(2-ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one, m.p. 195° C.-196° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]([Sn](C)(C)C)[N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:8]=2[NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=1)#[N:25].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:8]=2[NH:22][C:39]([C:28]2[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[C:26]([C:24]#[N:25])[N:27]=2)=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Sn](C)(C)n1nnnc1-c1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2nnn[nH]2)cc1C1=CCCCC1

Procedure:
The title compound was prepared from 2-cyclohex-1-enyl-4-(1-trimethylstannanyl-1H-tetrazol-5-yl)-phenylamine (as prepared in the previous step), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d)), PyBroP and DIEA according to the procedure in Example 11, step (f). Mass spectrum (ESI, m/z): Calcd. for C24H30N8O2Si, 491.2, found 491.1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([OH:15])([CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:15][C:3]([CH3:14])([C:2]([F:16])([F:17])[F:1])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(O)(C(=O)OCc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OCc1ccccc1)(C(=O)OCc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cooled (0° C.) solution of benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (Int. D1) (100 mg, 0.403 mmol) in DMF (4 ml) was treated with sodium hydride (16.11 mg, 0.403 mmol) followed by benzyl bromide (0.048 ml, 0.403 mmol) and stirred at 0° C. for 2 h. The reaction mixture was allowed to warm to room temperature and stirring continued for a further 3 hrs. The reaction mixture was partitioned between EtOAc and 0.1M HCl solution. The organic phase was washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]=O.[CH:31]([NH2:34])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH:31]([NH:34][CH2:4][CH2:3][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH3:1])([CH3:33])[CH3:32]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CC=O)s1
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CCNC(C)C)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide (88 mg, 0.2 mmol), isopropylamine (0.09 ml) in dichloroethane (1 ml) and methylene chloride (1 ml) was stirred at r.t. for 10 min, sodium triacetoxyborohydride (76 mg) was added and the resulting mixture was stirred at r.t. overnight. The mixture was quenched with water, diluted with sodium hydroxide, and extracted with methylene chloride. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography using 3-5% methanol in methylene chloride, then 5% methanol/0.5% ammonium hydroxide in methylene chloride as eluent to give the title compound as a free base form. The free base was treated with 4 N HCl in doxane (0.1 ml) in methylene chloride (1 ml) and concentrated to dryness. The residue was triturated with hexane, pumped to dryness to give a white solid, LC-MS RT=1.8 min, M+1=481.9.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[C:9]([CH:10]([N:14]([CH3:24])[C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]([CH3:13])[CH3:12])=[CH:8][N:7]=[CH:6][N:5]=1>C(Cl)(Cl)Cl>[C:3]([C:4]1[C:9]([CH:10]([N:14]([CH3:24])[C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]([CH3:12])[CH3:13])=[CH:8][N:7]=[CH:6][N:5]=1)#[N:2]
Reactant: CC(C)C(c1cncnc1C=NO)N(C)C(=O)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)C(c1cncnc1C#N)N(C)C(=O)Cc1ccccc1
Yield: 80 %

Procedure:
0.25 g (0.77 mmol) of N-[1-(4-hydroxyiminomethylpyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide was dissolved in 30 ml of chloroform, and 0.16 g (0.83 mmol) of 1-(3-(dimethylamino)propyl]-3-ethylcarbodilmide hydrochloride was added and reacted at room temperature for 8 hours. After completion of the reaction, the solvent was distilled off, and water was added, followed by extraction with ethyl acetate. The organic layer was washed with water and an aqueous sodium chloride solution in this order, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.19 g (yield: 88%) of N-[1-(4-cyanopyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide as colorless crystals (melting point: 80-81° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4][N:5]([C:7]2[N:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]([NH:11][CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([OH:17])[C:14](O)=[O:15])=[O:10])[CH:6]=1.Cl.[CH3:36][O:37][NH2:38]>>[Cl:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4][N:5]([C:7]2[N:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]([NH:11][CH:12]([CH:13]([OH:17])[C:14]([NH:38][O:37][CH3:36])=[O:15])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[CH:6]=1
Reactant: CON
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(4-Chloro-3-phenyl-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 506.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]([F:28])([F:27])[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][C:17]([F:16])([F:27])[F:28])=[CH:20][CH:21]=2)=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cnoc1-c1cccc(Cl)c1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cnoc1-c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-(3-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 4-(trifluoromethoxy)benzylamine (11.5 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method B to give a solid (4.5 mg). MS (pos) m/z 397.0 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[CH2:24](N(CC)CC)[CH3:25]>CN(C=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:24][CH3:25])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCN(c2cc3c(cc2Cl)c(=O)c(C(=O)O)cn3CC)CC1
Yield: 22 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1.7 g (0.005 mole), iodoethyl 1.6 g (0.01 mole), triethylamine 1.0 g (0.01 mole) and dimethylformamide (hereinafter DMF) 20 ml was heated at 90°-100° C. for 7 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum. The residue was dissolved in CHCl3, washed with water, dried with anhydrous Na2SO4, and the solvent was distilled off. The residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 0.4 g (22%) of 1-ethyl-6-chloro-7-(4-ethyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless needles.
Reaction SMILES: [CH2:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[C:7]1([CH3:13])[CH:12]=CC=C[CH:8]=1>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Zr+4]>[CH:1]12[CH2:13][CH:7]([CH:12]=[CH:2]1)[CH2:8][CH:3]2[C:4]([OH:6])=[O:5]
Reactant: CCCC(=O)O
Reactant: Cc1ccccc1
Agent: [Zr+4]
Agent: CC(=O)/C=C(/C)[O-]
Product: O=C(O)C1CC2C=CC1C2
Reaction time: 18 h
Yield: 89 %

Procedure:
and 25 ml of toluene were continuously added to the 250 ml flask. Zirconium acetyl acetonate [Zr(acac)4] (0.658 g, 0.135 mmol, 1 mol %) was added thereto, and azeotropic reflux was performed. The temperature of the heated bath was controlled to 150° C. and the reaction was performed for 18 hours. After that, the reaction was finished after the GC check, and it was cooled to normal temperature. Thereafter, 30 mlm of ethyl acetic acid was added thereto. After the undissolved solid compound is precipitated, 30 ml of 1 M (mol/L) dilute hydrochloric acid solution was added thereto, and the washing was performed. This process was performed twice, and 30 ml of the saturated aq.NaHCO3 solution was added thereto and washed. This process was performed twice, and MgSO4 was added to the separated organic solution to remove a small amount of water. After water was removed, this was filtered by using MgSO4, and the solvent was removed under reduced pressure. The purification process was carried out to obtain 4.15 g of the compound (molecular weight=342.15, yield 89%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([NH:32][C:33]([NH2:35])=[O:34])[C:30]#[CH:31]>CO>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][NH:32][C:33]([NH2:35])=[O:34])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#CCNC(N)=O
Solvent: CO
Product: Cc1ccc(-n2cc(CNC(N)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.15 mmol) and prop-2-ynyl-urea (0.30 mmol). The crude product was purified by flash chromatography using EtOAc as the eluent to afford a solid. Trituration in MeOH gave the title compound as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:13][C:14]([C@@H:16]([NH2:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].C(O)(=O)C.[CH3:26][C:27]([CH3:32])([CH3:31])[CH2:28][CH:29]=O>CO>[CH3:26][C:27]([CH2:28][CH2:29][NH:21][C@H:16]([C:14]([NH:13][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([OH:20])=[O:19])([CH3:32])[CH3:31]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: CC(C)(C)CC=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.6 %

Procedure:
Aspartame (5.88 g), acetic acid (1.20 g) and methanol (100 ml) were charged to a hydrogenation vessel, followed by 3,3-dimethylbutyraldehyde (2.00 g). The vessel was pressure purged with nitrogen (4×), and 0.24 g of 4% palladium on carbon (containing 50% water) was added. After pressure purging the reactor with nitrogen (4×), followed by hydrogen (4×), the mixture was hydrogenated at 50 psig for 12 hours at room temperature. After completion of the reaction, the vessel was purged with nitrogen (4×). The catalyst was removed from the reaction mixture by filtration through powdered cellulose. Methanol (20 ml) was used to rinse the reaction vessel and the filter cake. The combined filtrate and wash was evaporated to dryness. The residue was stirred with 50 ml of deionized water and 50 ml of heptane for 4 hours at room temperature. The crystallized solid was isolated by filtration and washed with 20 ml heptane. The wet product was dried under vacuum at 40° C. to give 7.15 g of neotame (>97% by HPLC).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>CN(C)C=O>[CH2:2]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH2:3][CH2:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC(=O)CCCBr
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCC(=O)CCCn1ccnc1

Procedure:
1-Bromo-4-dodecanone 6.45 and imidazole (8.34 g) in dimethylformamide (10 ml) at 0° C. were stirred overnight at ambient temperature, then one day at 80° C. The resulting mixture was poured into water (200 ml), extracted with ether (3×75 ml) and the extracts were dried (magnesium sulfate) and evaporated. Chromatography of the product on silica gel eluting with 7% methanol in methylene chloride gave 1-(dodecan-4-on-1-yl)imidazole.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:20]1[S:21][C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)=[CH:18][CH:19]=1)(=[O:23])=[O:24]
Reactant: Cc1noc(N)c1Br
Reactant: COc1cccc(-c2ccc(S(=O)(=O)Cl)s2)c1
Product: COc1cccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)c1
Yield: 48 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(3-methoxyphenyl)thiophene-2-sulfonyl chloride in 48% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) give a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15].F[C:19]1[C:20]([CH3:39])=[N:21][C:22]2[C:27]([N:28]=1)=[C:26]([C:29]1[NH:37][C:36]3[CH2:35][CH2:34][NH:33][C:32](=[O:38])[C:31]=3[CH:30]=1)[CH:25]=[CH:24][CH:23]=2>CS(C)=O>[CH3:11][O:12][CH2:13][C:14]([NH:17][C:19]1[C:20]([CH3:39])=[N:21][C:22]2[C:27]([N:28]=1)=[C:26]([C:29]1[NH:37][C:36]3[CH2:35][CH2:34][NH:33][C:32](=[O:38])[C:31]=3[CH:30]=1)[CH:25]=[CH:24][CH:23]=2)([CH3:16])[CH3:15]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: COCC(C)(C)N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 28.1 %

Procedure:
Prepared according to Example 127, using DIPEA (264 μl, 1.519 mmol), (2-methoxy-1,1-dimethylethyl)amine hydrochloride (78 mg, 0.759 mmol, ChemBridge Corp., San Diego, Calif.), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.253 mmol), and DMSO (2.2 mL) and stirring at 100° C. for 3 h. Purification by reverse phase HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 80%) provided 2-(3-((2-methoxy-1,1-dimethylethyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (27 mg, 28.1%). 1H NMR (DMSO-d6) δ: 11.83-11.94 (m, 1H), 7.77-7.83 (m, 1H), 7.56-7.62 (m, 1H), 7.31-7.39 (m, 1H), 6.90-6.98 (m, 1H), 5.87-5.92 (m, 1H), 3.62-3.68 (m, 2H), 3.40-3.46 (m, 1H), 3.16-3.20 (m, 2H), 2.81-2.88 (m, 2H), 2.66-2.69 (m, 2H), 2.31-2.36 (m, 3H), 1.50-1.56 (m, 6H). m/z (ESI, +ve) 380.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:19]1>>[CH3:26][O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:1][C:2]2[C:3]([C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=2)=[O:24]
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Nc1cc(Cl)c(Cl)cc1C(=O)c1ccccc1
Product: COC(=O)c1c(C2CC2)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 6 step A from a mixture of (2-amino-4,5-dichloro-phenyl)-phenyl-methanone and methyl 3-cyclopropyl-3-oxopropanoate. Yellow solid. MS (ESI): 372.1 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl-:11]>N1C=CC=CC=1>[C:1]([Cl:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: [Cl-]
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1O

Procedure:
In the first step, salicylic acid is mixed with thionyl (or oxalyl) halide, most preferably chloride, (molar ratio in the general range of from 1:1 to 2:1) in an anhydrous, typically non-polar, solvent, in the presence of pyridine catalyst, at a temperature of from 20 to 45° C. for 0.5-2 hours. At the end of this reaction, salicylic acid chloride is obtained. Optionally, the solvent is distilled at least partially.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][CH2:49][C:50]([OH:52])=O)=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:43]=[CH:44][C:45]([NH:48][CH2:49][C:50]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:52])=[CH:46][CH:47]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)CNc1ccc(F)cc1
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CNc3ccc(F)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using (4-fluorophenylamino)acetic acid as the reacting carboxylic acid. LCMS: m/e 681.7 (M+H)+, 6.62 min (method 3).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[N:30]1[N:31]([CH2:35][C:36](O)=[O:37])[N:32]=[CH:33][CH:34]=1>>[N:30]1[N:31]([CH2:35][C:36]([NH:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[O:37])[N:32]=[CH:33][CH:34]=1
Reactant: O=C(O)Cn1nccn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cn1nccn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Proceeding as in Example 1, but substituting (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide and 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride, gave Compound 138, (S)-2-(2-(2H-1,2,3-triazol-2-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide. 1H-NMR (400 MHz, CDCl3): σ 8.33 (s, 1H), 7.75 (s, 1H), 7.52 (s, 1H), 7.38-7.21 (m, 7H), 7.04-7.00 (m, 2H), 6.96-6.89 (m, 4H), 5.29-5.20 (m, 2H), 4.71-4.61 (m, 3H), 4.53 (d, 1H), 4.03 (dd, 1H), 3.53 (t, 1H). MS (EI) for C26H24FN5O4. found 489.9 (MH+).