Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[CH:19]=1>C(O)(C)C>[N:2]1([N:1]=[CH:17][C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:19][C:13]=3[CH:14]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: NN1CCNCC1
Reactant: O=Cc1cc2cc(Cl)ccc2o1
Solvent: CC(C)O
Product: Clc1ccc2oc(C=NN3CCNCC3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
1-Aminopiperazine (29 g, 287 mmol) was dissolved in isopropyl alcohol (173 ml), to which 5-chlorobenzofuran-2-aldehyde (34.52 g, 191 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford piperazin-1-yl-(5-chlorobenzofuran-2-yl methylene)amine (49.49 g, yield 98%) as a yellow crystalline powder.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH:13]=[CH:14][C:15]([NH:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[O:16])[N:10]=[CH:9]1)=O)(C)(C)C.Cl>CO>[NH:8]1[CH:12]=[C:11]([CH:13]=[CH:14][C:15]([NH:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[O:16])[N:10]=[CH:9]1
Reactant: COC(=O)c1ccccc1NC(=O)C=Cc1cn(C(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: CO
Product: O=C(C=Cc1c[nH]cn1)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Methyl 2-[3-(1-t-butoxycarbonyl-1H-imidazole-4-yl)acrylamido]benzoate (168 mg) was dissolved in methanol (9 ml), 3N.HCl (2 ml) was added. The mixture was stirred at room temperature for 1 hour. Then, methanol was removed and the precipitated solid were filtered. The solid were again dissolved in methanol (9 ml), and 1N-NaOH (0.9 ml) was added. The mixture was reacted with stirring at 70° C. for 1 hour. After removing methanol, the mixture was treated with water and slightly acidified by KHSO4 under ice cooling to give white solids of the title compound (88 mg, yield, 76%). m.p., 263°-265° C.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[ClH:27].OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:25]([Cl:1])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2c(Cl)cccc2Cl)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M−15,1), 279 (11), 279 (9), 277 (64), 275 (100), 163 (11), 163 (5), 161 (6), 121 (33), 114 (12).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH:56](=O)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH2:56]([N:53]1[CH2:54][CH2:55][N:50]([C:41]2([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:40][CH:39]=3)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]2=[O:49])[CH2:51][CH2:52]1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: O=Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(Cc5ccccc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 26.2 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (120 mg, 0.150 mmol) was treated with benzaldehyde (31.8 mg, 2.0 eq) to provide the title barbituric acid (35.0 mg, 26%). MS found: (M+H)+=550.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[C:6]([C:9]2[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])[NH:5][N:4]=1.C([O-])(O)=[O:21].[Na+]>>[Cl:8][C:7]1[C:3]([CH2:2][OH:21])=[N:4][NH:5][C:6]=1[C:9]1[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: Cc1cc(C)c(-c2[nH]nc(CBr)c2Cl)cc1C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C)c(-c2[nH]nc(CO)c2Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3-(bromomethyl)-4-chloro-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid (compound 304.1, 200 mg, 0.58 mmol) and NaHCO3 (0.3 M, 10 mL) was stirred for 30 min at room temperature, then concentrated under reduced pressure. This resulted in 200 ma (crude) of the title compound as a white solid.
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:43]=[CH:42][C:16]([C:17]([NH:19][CH:20]([CH3:41])[C:21](=[O:40])[N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:23]2)=[O:18])=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH:20]([CH3:41])[C:21](=[O:40])[N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:23]2)=[O:18])=[CH:42][CH:43]=1
Reactant: CC(NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(NC(=O)c1ccc(O)cc1)C(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 89 %

Procedure:
Ammonium formate (49 mg, 0.77 mmol) was added to a stirred solution of 4-benzyloxy-N-{1-methyl-2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide (42 mg, 0.07 mmol) in MeOH (10 mL). 10% Pd/c (10 mg) was then added and the resulting mixture stirred at room temperature under an inert atmosphere. The reaction mixture was then stirred at reflux temperature for 2 hrs. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated. The residue was dissolved in EtOAc, washed with water, followed by saturated brine solution. The organic layer was dried over sodium sulphate and concentrated in vacuo to afford 28 mg (82% yield) of 4-hydroxy-N-{1-methyl-2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 95%. 1H NMR (DMSO-d6): δ 7.76 (d, 1H), 7.60 (m, 4H), 7.36 (t, 1H), 7.26 (t, 1H), 6.8 (d, 2H), 5.2 (m, 1H), 4.2 (m, 1H), 3.9-3.4 (m, 8H), 1.4 (dd, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([O:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(O)cc(OCc2ccccc2)c1
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
3-Benzyloxy-5-hydroxybenzoic acid (2.16 g) and acetic anhydride (15 mL) were suspended in acetic acid (15 mL), and the resulting mixture was stirred at 120° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1 to 1/0) to give the title compound (1.74 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:22]
Reactant: c1ccc2scnc2c1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1nc2ccccc2s1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of benzothiazole (1.35 g) in tetrahydrofurane (10 mL) in a dried round bottom baloon is cooled at −70° C. A solution of butyl lithium (4.1 mL) is added and the mixture stirred for 15 minutes. Benzaldehyde (1.03 mL) diluted with tetrahydrofurane (10 mL) is then added. The mixture is stirred at −70° C. for 1 h, allowed to warm to −20° C. and quenched with saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate. Organic extracts are pooled, dried over magnesium sulfate and concentrated under reduced pressure. Trituration of the residue with diisopropyl oxyde affords benzothiazol-2-ylphenylmethanol.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([C:21]4[CH:22]=[CH:23][C:18]([O:17][C:16]([F:15])([F:30])[F:31])=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)Oc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-trifluoromethoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. FDMS m/e=434 (M+ of free base). α[D]589=−13.45 (c=1.04, methanol).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH:24]1([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[S:34][C:35]([C:39](O)=[O:40])=[C:36]([CH3:38])[N:37]=3)[C:29]2=[O:42])[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[S:34][C:35]([C:39]([NH2:7])=[O:40])=[C:36]([CH3:38])[N:37]=3)[C:29]2=[O:42])[CH2:26][CH2:25]1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(N)=O
Yield: 5 %

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 5% yield: mp 198-200° C. (methanol/hexanes); 1H NMR (300 MHz, DMSO-d5) δ 7.29 (s, 2H), 4.02-3.97 (m, 2H), 3.67-3.62 (m, 2H), 3.10 (d, J=7.1 Hz, 2H), 2.45 (s, 3H), 0.99-0.90 (m, 1H), 0.52-0.46 (m, 2H), 0.25-0.20 (m, 2H); 13C NMR (75 MHz, DMSO-d5) δ 163.5, 157.5, 154.7, 155.7, 118.2, 47.7, 41.9, 41.8 17.0, 8.8, 3.1; MS (ES+) m/z 281.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>CCOCC>[Br:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[C:3]([OH:32])=[O:2]
Reactant: COC(=O)c1cc(C)cc(C)c1N(Cc1cccc(Br)c1)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2cccc(Br)c2)c2c(C)cc(C)cc2C(=O)O)cc1
Yield: 70.1 %

Procedure:
In the same manner as described in Example 109, 0.894 g (1.725 mmol) of the product of Example 107 provided 0.61 g (70%) of the desired carboxylic acid after trituration with ether. Electrospray Mass Spec 506.0 (M+H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CN1CCOCC1.[O:13]1[CH2:18][CH2:17][CH:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:19]([CH:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)=[O:20]
Reactant: CNOC
Reactant: O=C(Cl)C1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C1CCOCC1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.23 g, 12.7 mmol) and N-methylmorpholine (3.80 mL, 34.5 mmol) were dissolved in DCM (20 mL) and a solution of oxane-4-carbonyl chloride (1.71 g, 11.5 mmol) in DCM (20 mL) was added drop-wise. The reaction mixture was stirred for 2 h, then diluted to 200 mL with DCM, washed with 1 M aq HCl (2×100 mL), 1M aq Na2CO3 (100 mL) and water (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow oil (1.87 g, 94%). LCMS (ES+): 174.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]([C:23]1[N:27]([CH3:28])[C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:21]([C:23]1[N:27]([CH3:28])[C:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)(=[O:10])=[O:9])=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NC1CCC1)c1ccc(Br)cc1OC(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CCC2)c(OC(F)(F)F)c1
Reaction time: 16 h
Yield: 23.8 %

Procedure:
According to general procedure B, 4-bromo-N-cyclobutyl-2-(trifluoromethoxy)benzenesulfonamide (224 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethoxy)benzenesulfonamide (56 mg, 24%) was provided after purification. MS (ESI) m/z 399. HPLC purity 99.4% at 210-370 nm, 10.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:15])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]>C(Cl)Cl>[Br:1][C:14]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:15])=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COC(=O)c1ccc(OC)cc1O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(OC)cc1O
Reaction time: 5 h
Yield: 97 %

Procedure:
A solution of 9.0 g (56.5 mmol) of bromine in 5 ml of CH2Cl2 is added dropwise to a 0° C. solution of 10.0 g (54.9 mmol) of methyl 4-methoxysalicylate in 90 ml of CH2Cl2. The reaction is stirred at 0° C. to 25° C. over five hours and then concentrated in vacuo to give 13.9 g of methyl 5-bromo-4-methoxysalicylate as a white solid: mp 141°-143° C.) (lit mp 143°-144° C.), Cresp, T. M.; Sargent, M. V.; Elix, J. A.; Murphy, D. P. H., J. Chem. Soc., Perkin Trans., 1, 1973, 340). The material is sufficiently pure to be used in the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(N(CC)CC)C>CN(C=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH3:19])=[O:6]
Reactant: Cc1ccccc1N
Reactant: C[Si](C)(C)c1cccc(Br)c1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)c1c(Br)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
The compound of Example c (0.0035 mol, 0.95 g), 15 mL thionyl chloride, and 1 drop of DMF were combined and stirred at RT overnight. Toluene (50 mL) was added and the mixture concentrated to dryness. This process was repeated three times, and the residue dissolved in CH2Cl2 (50 mL). 2-Methylaniline (0.0035 mol, 0.37 g) and triethylamine (0.0035 mol, 0.39 g) were added and the mixture was stirred at RT overnight. The mixture was washed with 10% HCl and twice with water; dried (MgSO4) and concentrated. The title compound was recrystallized from hexanes as a tan solid in 71% yield. m.p. 113°-115° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>O.ClCCl.C(N(CC)CC)C>[OH:51][C:44]1[C:43]([CH2:42][NH:41][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:2]([CH3:1])[CH:3]=2)=[C:48]([CH3:49])[CH:47]=[C:46]([CH3:50])[N:45]=1
Reactant: Cc1cc(C(=O)O)ccc1COc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3ccccc3)c(C)c2)c(O)n1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
A mixture of 3-methyl-4-(phenoxymethyl)benzoic acid (121 mg, 0.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1 mmol), N-hydroxybenzotriazole (135 mg, 1 mmol), triethylamine (0.2 mL) and dichloromethane (5 mL) were stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-4-(phenoxymethyl)benzamide (Compound I-54) as a white solid (51 mg, 26%). LRMS (M+H+) m/z: calcd 376.45. found 376. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.43 (s, 1H), 8.29 (t, J=4.2 Hz, 1H), 7.69-7.63 (m, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.29 (t, J=7.5 Hz, 2H), 7.03-6.91 (m, 3H), 5.85 (s, 1H), 5.11 (s, 2H), 4.29 (d, J=4.8 Hz, 2H), 2.34 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][C:48]1[N:49]=[CH:50][S:51][CH:52]=1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:47][C:48]1[N:49]=[CH:50][S:51][CH:52]=1)[CH2:23][CH2:22]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)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
Reactant: ClCc1cscn1
Product: C=C(C)[C@@H]1CC[C@]2(NCc3cscn3)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 following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-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)benzoic acid using 4-(chloromethyl)thiazole as the alkylating agent in Step 1. MS: m/e 627.5 (M+H)+, 1.56 min (method 12). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (s., 3H) 0.96 (s, 3H) 1.01 (s, 3H) 1.10 (s, 3H) 1.21 (s, 3H) 1.72 (s, 3H) 0.89-1.83 (m, 16H) 1.84-2.05 (m, 3H) 2.07-2.22 (m, 1H) 2.13 (dd, J=17.07, 6.53 Hz, 1H) 2.22-2.32 (m, 1H) 2.33-2.49 (m, 1H) 4.24 (d, J=14.05 Hz, 1H) 4.70 (s, 1H) 4.72 (d, J=13.55 Hz, 1H) 4.81 (s, 1H) 5.31 (dd, J=6.02, 1.51 Hz, 1H) 7.24 (d, J=8.28 Hz, 2H) 7.59 (s, 1H) 8.00 (d, J=8.28 Hz, 2H) 8.83 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:49]([CH3:50])=[CH:48][C:39]([O:40][CH:41]2[CH2:45][CH2:44][C:43]([CH3:47])([OH:46])[CH2:42]2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:37]([CH3:51])=[CH:38][C:39]([O:40][CH:41]3[CH2:45][CH2:44][C:43]([OH:46])([CH3:47])[CH2:42]3)=[CH:48][C:49]=2[CH3:50])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OC2CCC(C)(O)C2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CCC(C)(O)C6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenoxy)-1-methylcyclopentanol (enantiomer 2) following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.81 min.