Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].II.[Cl:20]Cl>ClC=C(Cl)Cl>[Cl:20][C:15]1[C:2]([CH3:1])=[C:3]([CH:12]=[C:13]([CH3:17])[C:14]=1[CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1cc(C)c(C(=O)c2ccccc2)cc1C
Reactant: ClCl
Agent: II
Solvent: ClC=C(Cl)Cl
Product: Cc1cc(C(=O)c2ccccc2)c(C)c(Cl)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
33.6 parts of 2,4,5-trimethylbenzophenone and 0.1 part of iodine are dissolved in 150 parts of trichloroethylene. 19.2 parts of chlorine is passed into this solution at 0° to 5°C over a period of 3 hours. The mixture is stirred for another 5 hours at ambient temperature and then distilled at subatmospheric pressure. 26 parts (67.2% of theory) of 3-chloro-2,4,5-trimethylbenzophenone is obtained at 155° to 165°C at 0.1 mmHg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[C@H:27]([CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: C[C@@H]1COC(=O)N1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)c(C)c1
Yield: 58.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (630 mg) described in Preparation Example 100 and (R)-4-methyloxazolidin-2-one (243 mg) described in Preparation Example 25, the title compound (385 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC4(CCN(S(C)(=O)=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (82 mg) and methanesulfonyl chloride (100 μL) in tetrahydrofuran (3 ml) was added triethylamine (100 μL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and water was added. The precipitated crystals were collected by filtration, and washed with water. The obtained crystals were recrystallized from tetrahydrofuran to give the title compound (42 mg, yield 36%) as colorless crystals. melting point 251° C.
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15]N)[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH:17]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]>>[CH2:2]([C:6]1[C:10]2=[C:11]3[C:12](=[CH:13][CH:14]=[C:9]2[S:8][CH:7]=1)[NH:15][C:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][C:22]3=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1csc2ccc(NN)cc12
Reactant: CC(C)N1CCC(=O)CC1
Agent: Cl
Product: CCCCc1csc2ccc3[nH]c4c(c3c12)CN(C(C)C)CC4

Procedure:
The compound is formed analogously to that described in Example 15, from 25.6 g of 3-butyl-5-hydrazinobenzothiophene hydrochloride and 17 g of 1-isopropyl-4-piperidone. Melting point: 157°-158° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][N:49]=1.[CH3:55][O:56][C:57](=[O:78])[CH2:58][CH2:59][CH:60]1[CH2:65][CH2:64][N:63]([C:66]2[S:67][C:68]([C:71]3[CH:76]=[CH:75][CH:74]=[C:73](Br)[N:72]=3)=[CH:69][N:70]=2)[CH2:62][CH2:61]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:55][O:56][C:57](=[O:78])[CH2:58][CH2:59][CH:60]1[CH2:61][CH2:62][N:63]([C:66]2[S:67][C:68]([C:71]3[CH:76]=[CH:75][CH:74]=[C:73]([NH:47][C:48]4[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][N:49]=4)[N:72]=3)=[CH:69][N:70]=2)[CH2:64][CH2:65]1
Reactant: Cc1ccnc(N)c1
Reactant: COC(=O)CCC1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCC1CCN(c2ncc(-c3cccc(Nc4cc(C)ccn4)n3)s2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (91 mg, 0.15 mmol) and palladium acetate (25 mg, 0.11 mmol) were suspended in toluene (7 ml), and after 2-amino-4-picoline (79 mg, 0.73 mmol) and 3-{1-[5-(6-bromopyridin-2-yl)-thiazol-2-yl]piperidin-4-yl}propionic acid methyl ester (300 mg, 0.73 mmol) obtained in Step 2 were sequentially added, cesium carbonate (357 mg, 1.1 mmol) was added, and the mixture was stirred overnight at 100° C. Water was added to the reaction solution and the solution was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over anhydrous sodium sulfate and the residue obtained by vacuum concentration was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:1 to 1:10) and the title compound (250 mg, 55%) was obtained.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([N:43]1C(=O)C2=CC=CC=C2C1=O)[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O.NN>C(O)(C)C>[CH2:1]([O:19][CH2:20][CH:21]([NH2:43])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCOCC(N)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Yield: 84.2 %

Procedure:
In 50 ml of isopropylalcohol was dissolved 6.4 g of 3-octadecyloxy-2-phthalimido-1-trityloxypropane, and 4 ml of hydrazine hydrate was added to the solution. The mixture was heated at 70° C. for 1 hour, and concentrated under reduced pressure. Ethyl acetate was added to the residue and the insoluble matter was filtered off. The filtrate was concentrated to dryness and purified by silica gel chromatography (eluent: n-hexane-ethyl acetate=3:1) to give 4.41 g (84%) of the desired compound as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[C:21]([F:30])[CH:20]=2)[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[OH:31].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.CCOC(C)=O>C1COCC1>[F:30][C:21]1[CH:20]=[C:19]([C@@H:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:10][C:8]([C:6]2[N:7]=[C:2]3[NH:1][C:33](=[O:35])[O:31][C:3]3=[CH:4][CH:5]=2)=[O:9])[CH:24]=[CH:23][C:22]=1[O:25][C:26]([F:29])([F:27])[F:28]
Reactant: Nc1nc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc2oc(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-6-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide (300 mg, 0.681 mmol) in THF (10 mL) was added TEA (689.4 mg, 0.00068 mmol, S.d fine, India) and triphosgene (242 mg, 0.0008 mmol, Sigma Aldrich, India) at 0° C. The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction, monitored by TLC (TLC eluent: 50% EtOAc in petroleum ether), the reaction mixture was quenched with sat'd NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel (60-120 mesh) column chromatography eluting with 80-100% EtOAc in petroleum ether to afford the title compound as an off white solid. 1H-NMR (400 MHz, DMSO-d6): δ 12.8 (br. s., 1H), 9.46 (d, J=7.2 Hz, 1H), 8.55 (d, J=4.4 Hz, 1H), 7.83-7.77 (m, 3H), 7.57-7.49 (m, 3H), 7.33 (d, J=8.4 Hz, 1H), 6.55 (d, J=6.8 Hz, 1H). MS (ESI, positive ion) m/z: 467.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:23])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:12][C:5]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1CBr
Yield: 86.6 %

Procedure:
A mixture of methyl 5-chloro-2-methyl-3-nitrobenzoate (6 g, 26.2 mmol), NBS (5.1 g, 28.8 mmol), and BPO (0.63 g, 2.6 mmol) in CCl4 (50 mL) was heated to reflux overnight. Water (200 mL) was added and CCl4 was removed under reduced pressure. The residue was extracted with DCM (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude title compound (7 g, yield 87%) as a brown oil which was used in the next step without purification.
Reaction SMILES: [C:1]([O:7][C@@H:8]1[C@@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:10][C@H:9]1[O:36][C:37]1[C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:50][CH:49]=2)[NH:39][N:38]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:68]([CH3:70])[CH3:69]>CC(C)=O>[CH:68]([N:39]1[C:40]2=[N:41][CH:42]=[CH:43][C:44]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:53]=3)=[C:45]2[C:37]([O:36][C@@H:9]2[O:10][C@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:34])[CH3:32])[C@@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[C@H:8]2[O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[N:38]1)([CH3:70])[CH3:69]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c2c(CCc3ccc(OC(=O)C(C)(C)C)cc3)ccnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo-[3,4-b]pyridine (84 mg) in acetone (1.5 mL) were added cesium carbonate (0.11 g) and 2-iodopropane (0.03 mL), and the mixture was stirred at room temperature for 2days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1−2/1) to give 1-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (61 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (26 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[N:6]=[C:7]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=2)[S:8][C:9]=1[C:10]([O:12]CC)=[O:11])=[O:4].[OH-].[Li+]>CO>[CH3:1][N:2]([CH3:27])[C:3]([C:5]1[N:6]=[C:7]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=2)[S:8][C:9]=1[C:10]([OH:12])=[O:11])=[O:4]
Reactant: CCNC(=O)Nc1ccc(-c2nc(C(=O)N(C)C)c(C(=O)OCC)s2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)N(C)C)c(C(=O)O)s2)cn1
Temperature: 50 °C
Yield: 30.9 %

Procedure:
To a stirred solution of ethyl 4-dimethylcarbamoyl-2-[6-(3-ethyl-ureido)-pyridin-3-yl]-thiazole-5-carboxylate (Example 52, 0.7 g, 1.78 mmol) in methanol (15 mL) was added 2 N lithium hydroxide (8 mL). The mixture was heated to 50° C. overnight. After completion of the reaction, the reaction mixture was concentrated to dryness. Water was added and the pH was adjusted with 2 N hydrochloric acid to pH 2. The precipitated solid was filtered and dried under vacuum to afford 0.2 g (35.48%) of the title compound as a pale brown solid. MS (APCI): 364 (M+H+) for C16H18N4O4S; NMR: δ 1.1 (t, 3H), δ 2.8 (s, 3H), δ 3.07 (s, 3H), δ 7.62 (d, 1H), δ 7.75 (br s, 1H), δ 8.25 (d, 1H), δ 8.82 (s, 1H), δ 9.55 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C#N

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J32) (318 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (470 mg, 73%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[CH3:27][O:28][C:29]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([N:36](C2C=CC=CC=2)[C:37](=O)[O-:38])[N:30]=1>O1CCOCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([S:12]([NH:15][C:37]([NH:36][C:31]3[N:30]=[C:29]([O:28][CH3:27])[N:34]=[C:33]([CH3:35])[N:32]=3)=[O:38])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: NS(=O)(=O)c1cccnc1OCC1CC1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2OCC2CC2)n1
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
4.56 g of 2-cyclopropylmethoxypyridin-3-ylsulfonamide and 3.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene are suspended in 50 ml of dioxan and to this suspension are added 5.46 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate. The mixture is stirred for 20 minutes and concentrated by evaporation. The residue is triturated with 10 ml of 2N hydrochloric acid and the precipitated solid is isolated and washed with water and ether, affording 6.90 g of N-(2-cyclopropylmethoxypyridin-3-ylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea with a melting point of 165°-167° C.
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=3)[CH2:29][CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=3)[CH2:29][CH2:28]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(c3nc(C(C)C)no3)CC2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(c3nc(C(C)C)no3)CC2)c1Br
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
The 1.6 mL of benzo[d][1,3,2]dioxaborole (416 mg, 3.47 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (950 mg, 1.93 mmol) and 0.6 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (160 mg, 0.58 mmol) in toluene (20 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3 (5 mL), diluted with EtOAc, and stirred for 20 min. The organic layer was washed with brine and dried (MgSO4). The crude product was filtered, and charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (5-60% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 550 mg (58%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.98/5.87 (s, 1H), 4.95-4.92 (m, 1H), 3.75-3.71 (m, 1H), 3.08-3.01 (m, 3H), 2.88-2.86 (m, 1H), 2.54 (s, 3H), 2.39 (s, 3H), 2.06-2.00 (m, 3H), 1.90-1.83 (m, 2H), 1.27 (d, J=6.6 Hz, 6H), 1.14 (d, J=5.9 Hz, 3H), 1.08 (d, J=5.9 Hz, 3H). UPLC (M+H)=497.2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][Br:1])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(CCBr)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CCBr)cc1
Temperature: 0 °C
Yield: 98 %

Procedure:
4-(2-Bromo-ethyl)-benzoic acid (1.00 g, 4.37 mmol) was dissolved in MeOH (10 mL) and cooled to 0° C. This was followed by dropwise addition of thionyl chloride (0.48 mL, 6.55 mmol). The mixture was refluxed for 2 h, followed by removal of all volatiles by rotary evaporation. The resulting oil was taken up in EtOAc (50 mL) and washed with water (50 mL). The EtOAc portion was separated, dried (Na2SO4) and concentrated to give the product (1.04 g, 98%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 2H, J=6.54 Hz), 7.29 (d, 2H, J=7.1 Hz), 3.92 (s, 3H), 3.59 (t, 2H, J=7.38 Hz), 3.23 (t, 2H, J=7.34 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([O:17]CC)=O)=[C:5]2[OH:20].[C:21]([NH:30][NH2:31])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:31][NH:30][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])=[C:5]2[OH:20]
Reactant: CCOC(=O)c1c(O)c2cc(Br)ccc2n(CC)c1=O
Reactant: CCCCCCCC(=O)NN
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Br)ccc2n(CC)c1=O

Procedure:
Reagents: Comp 36 (0.36 mmols, 0.12 g); octanoyl hydrazine (0.4 mmols, 0.06 g). Yield: 0.13 g (80%), white solid, m.p.=171° C.-172° C.
Reaction SMILES: C([O:8][P:9]([O:36][CH2:37][CH2:38][NH:39][C:40](=[O:66])[CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][NH:55]C(OCC1C=CC=CC=1)=O)([O:11][CH2:12][CH:13]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:14][O:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:10])C1C=CC=CC=1.CC(O)(C)C>[Pd].O>[NH2:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][C:40]([NH:39][CH2:38][CH2:37][O:36][P:9]([OH:10])([O:11][CH2:12][CH:13]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:14][O:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[O:8])=[O:66]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)OCC(COP(=O)(OCCNC(=O)CCOCCOCCOCCOCCNC(=O)OCc1ccccc1)OCc1ccccc1)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)OCC(COP(=O)(O)OCCNC(=O)CCOCCOCCOCCOCCN)OC(C)(C)C

Procedure:
A suspension of 9 (30.2 mg, 0.0313 mmol) and 10% Pd/C (11.3 mg) in 6:1 t-BuOH:H2O was shaken under an atmosphere of H2 (50 psi) for 5.5 hours. The reaction was filtered through a pad of Celite 545 and the pad was washed with 6:1 t-BuOH:H2O (10 mL) and EtOH (2×10 mL). The solvents were evaporated and the product was used in subsequent steps without further purification. RF=0.59 (10:5:1 CHCl3:MeOH:H2O); δH (CD3OD): 4.16 (dt, 1H), 4.05 (dd, 1H), 3.80-4.02 (m, 5H), 3.71-3.79 (m, 4H), 3.59-3.71 (m, 13H), 3.45 (m, 2H), 3.14 (t, 2H), 3.02 (t, 2H), 2.50 (t, 2H), 2.30-2.39 (m, 2H), 1.63 (quin, 2H), 1.47 (quin, 2H), 1.43 (s, 9H), 1.28-1.28 (m, 2H), 1.22 (s, 9H); δP (CD3OD): 0.28; MALDI-MS: 732.4 ((M+H)+, 100.0).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](#N)C.C(N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Reactant: CC#N
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g) in methanol (1.32 ml)/acetonitrile (40 ml) was treated with N,N-diisopropylethylamine (1.78 ml). Trimethylsilyldiazomethane (2M, 8.73 ml) was added dropwise and the resulting mixture was stirred at room temperature, under argon for 24 h. The mixture was diluted with ethyl acetate, washed with 2M HCl, saturated aqueous sodium hydrogen carbonate, brine then dried (magnesium sulfate). The solvent was removed under reduced pressure to afford the title compound (2.10 g)
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[CH:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>>[CH:35]([C:38]1[CH:43]=[CH:42][C:41]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:13]=2)=[CH:40][CH:39]=1)([CH3:37])[CH3:36]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(C)C)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-isopropyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.88 (dd, J=6.60, 3.42 Hz, 6H), 1.20 (d, J=6.85 Hz, 6H), 1.44-1.49 (m, 1H), 1.64-1.67 (m, 1H), 1.91-1.96 (m, 1H), 2.83-2.88 (m, 1H), 3.73 (t, J=7.70 Hz, 1H), 7.25 (d, J=8.07 Hz, 2H), 7.51 (dd, J=8.44, 1.83 Hz, 4H), 7.67 (m, 3H), 7.77 (d, J=8.07 Hz, 2H); Calcd for C28H29ClF3O2 (M+H) 455.5, Found 455.