Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[CH:17][C:18]2[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][C:19]=2[CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]3[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:20][C:19]=3[CH:32]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A suspension of {4-[(methyloxy)carbonyl]phenyl}boronic acid (0.36 g, 2.0 mmol), 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.66 g, 2.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (70.0 mg, 0.10 mmol), and tripotassium phosphate (1.30 g, 12.0 mmol) in dioxane (20 mL) was refluxed for 3 h, and then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (80 mL), the organic layer was washed with brine (40 mL), dried over sodium sulfate then filtered and concentrated. Column chromatography on silica (ethyl acetate:hexanes 1:4) gave 1,1-dimethylethyl 7-{4-[(methyloxy)carbonyl]phenyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.47 g, 60% yield). 1H NMR (400 MHZ, DMSO-D6): 8.11 (m, 2H), 7.63-7.52 (m, 2H), 7.43 (m, 2H), 7.10 (t, 1H), 4.57-4.43 (br, 2H), 4.08 (m, 2H), 3.82 (m, 2H), 1.40 (s, 9H); MS (EI) for C22H25NO5: 469 (MH+).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].[C:33]([O:36]C(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1].[C:33]([O-:36])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Agent: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: c1ccncc1
Product: CC(=O)[O-]

Procedure:
Then, the secondary hydroxyl group of monoprotected betulin compound 4 was acetylated using acetic anhydride in pyridine (Ac2O/pyridine), to yield monoprotected betulin acetate compound 5 of scheme 2 in 87% yield. Other acetylating agents also can be used. Examples of other acetylating agents include, but are not limited to, acetyl chloride; pentafluorophenyl acetate, triethylamine, and dimethylformamide; acetic anhydride, boron trifluoride etherate, and tetrahydrofuran; ketene, potassium tert-butoxide, and tetrahydrofuran; and acetic acid and trimethylsilyl chloride.
Reaction SMILES: C1(NC(C2(C)CCC3C(C)=C(OC(=O)C)C(C)=C(C)C=3O2)=O)C=CC=CC=1.[C:28]1([NH:34][C:35]([C:37]2([CH3:55])[CH2:42][CH2:41][C:40]3[CH:43]=[C:44]([O:51]C(=O)C)[C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:46][C:39]=3[O:38]2)=[S:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][C:35]([C:37]2([CH3:55])[CH2:42][CH2:41][C:40]3[CH:43]=[C:44]([OH:51])[C:45]([C:47]([CH3:49])([CH3:48])[CH3:50])=[CH:46][C:39]=3[O:38]2)=[S:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(C(=S)Nc1ccccc1)CC2
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Nc1ccccc1)O2
Product: CC1(C(=S)Nc2ccccc2)CCc2cc(O)c(C(C)(C)C)cc2O1

Procedure:
By carrying out the reaction as in Example 2 (2nd process), but replacing the compound of Example 1 with the compound of Example 73, the title product is obtained.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([Li])[CH:4]=1.[C:19]([NH:23][Si:24](Cl)([CH3:26])[CH3:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[CH3:20][C:19]([NH:23][Si:24]([CH3:26])([CH3:25])[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([N:2]([CH3:1])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4]1)([CH3:22])[CH3:21]
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: [Li]C1C=C(N(C)c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN(C1=CC([Si](C)(C)NC(C)(C)C)c2ccccc21)c1ccccc1
Reaction time: 25 h
Yield: 97.5 %

Procedure:
(3-(Methylphenylamino)-1H-indenyl)lithium (3.10 g, 13.64 mmol) was dissolved in 50 mL of THF and added dropwise to a solution of t-butylaminodimethylsilylchloride (2.17 g, 16.35 mmol) in 35 mL. of THF over a 30 minute period, with stirring continued for 25 hours. The solvent was evaporated and the resulting oil was subjected to vacuum for 4 hours. This oil was dissolved in 100 mL of hexane and filtered of from LiCl. Solvent removal in vacuo and overnight vacuum devolatilization provided the product (4.66g, 13.3 mmol) as a dark red oil in 98 percent yield.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=[N:16][OH:17])[CH2:10][C:9]2([CH3:19])[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:16]([CH:11]1[CH2:12][C:13]([CH3:14])([CH3:15])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:9]([CH3:19])([CH3:18])[CH2:10]1)[OH:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1OC1CCCCC1
Reactant: BrCc1ccccc1
Product: CC1(C)CC(N(O)Cc2ccccc2)CC(C)(C)N1OC1CCCCC1
Yield: 50 %

Procedure:
Following the procedure of Example 1, the title compound is prepared from 1-cyclohexyloxy-2,2,6,6-tetra-methylpiperidin-4-one oxime (3.7 g, 13 mmol) and benzyl bromide (2.4 g, 14 mmol) in a 50% yield to give 2.3 g of product as white crystals melting at 133° C. after recrystalization from ethanol.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:16]=O)=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.COC1C2C(=CC=CC=2)C(OC)=CC=1/[CH:32]=[C:33](\C)/[C:34]([O:36][CH2:37][CH3:38])=[O:35].O(C(C)C)C(C)C>>[Br:1][C:2]1[C:3](/[CH:16]=[C:33](\[CH3:32])/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1c(Br)c(C=O)c(OC)c2ccccc12
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Solvent: CC(C)OC(C)C
Product: CCOC(=O)/C(C)=C/c1c(Br)c(OC)c2ccccc2c1OC

Procedure:
Compound 98e was prepared from 38 (0.515 g, 1.75 mmol) as described above for 28a to give 0.373 g (0.984 mmol, 56%) of the product as a white solid following flash chromatography (1:19 i-Pr2O:hexanes) and recrystallization from Et2O/hexanes. (0.314 g E; 0.059 g Z)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[CH3:12].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Cl)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1cc(CO)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
4-Chloro-3-methylbenzoic acid, methyl ester (Lancaster) (29 mmol, 5.40 g) was dissolved in methylene chloride (30 ml) and cooled to 0° C. Diisobutylaluminum hydride (1 M in toluene, 64 ml) was added slowly (over ca. 10 minutes). One hour after complete addition, the reaction was quenched with methanol (64 ml), then poured into ether (500 ml). This mixture was stirred at room temperature 1 hour, filtered through silica gel and Celite®, eluting with addition ether. Concentration afforded 4-chloro-3-methylbenzyl alcohol (23 mmol, 3.53 g) as a solid, which was diluted with methylene chloride (46 ml), combined with Celite® (3.5 g) and MgSO4 (1.5. g), and cooled to 0° C. Pyridinium chlorochromate (45 mmol, 9.67 g) was added over 2-3 minutes. In 1 hour's time, the reaction mixture was filtered through silica and concentrated to afford 4-chloro-3-methylbenzaldehyde as a waxy solid (2.10 g, 47% overall), which was used in the next step.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][N:27]2[CH2:32][CH2:31][NH:30][C@H:29]([C:33]([F:36])([F:35])[F:34])[CH2:28]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CN2CCN[C@@H](C(F)(F)F)C2)=CC=1)(O)C.FC(F)(F)[C@@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CN2CCN[C@@H](C(F)(F)F)C2)=CC=1)(O)C>>[F:38][C:2]([F:1])([F:37])[C@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:20])[CH2:14][C@@H:13]2[CH2:26][N:27]2[CH2:32][CH2:31][NH:30][C@H:29]([C:33]([F:34])([F:35])[F:36])[CH2:28]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCN[C@H](C(F)(F)F)C2)cc1)C(F)(F)F
Agent: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCN[C@@H](C(F)(F)F)C2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCN[C@@H](C(F)(F)F)C2)cc1)C(F)(F)F
Product: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCN[C@H](C(F)(F)F)C2)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-4-(2-thiophenylsulfonyl)-2-(((3S)-3-(trifluoromethyl)-1-piperazinyl)methyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-4-(2-thiophenylsulfonyl)-2-(((3R)-3-(trifluoromethyl)-1-piperazinyl)methyl)-1-piperazinyl)phenyl)-2-propanol; and (2R)-1,1,1-trifluoro-2-(4-((2S)-4-(2-thiophenylsulfonyl)-2-(((3R)-3-(trifluoromethyl)-1-piperazinyl)methyl)-1-piperazinyl)phenyl)-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([CH:8]=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1.Br[C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:33]([F:44])[CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([C:8]([C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])=[C:33]([F:44])[CH:32]=3)=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Reactant: Clc1cc(N2CCOCC2)c2nc([C@@H]3C[C@@H]3c3ccc4ccccc4n3)cn2n1
Product: CC(C)(C)OC(=O)c1ccc(-c2c([C@@H]3C[C@@H]3c3ccc4ccccc4n3)nc3c(N4CCOCC4)cc(Cl)nn23)cc1F

Procedure:
Compound 79d (100 mg, 0.246 mmol) was coupled with tert-butyl 4-bromo-2-fluorobenzoate (102 mg, 0.370 mmol) using the procedures described in Example 20, Step A to afford compound 81a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H31ClFN5O3: 600.2 (M+H). found: 600.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To a solution of 3-bromo-5-fluorophenol (2.54 g, 0.013 mol) in DMF (12 mL) under a N2 atmosphere was added potassium carbonate (3.59 g, 0.026 mol) and the reaction was stirred for 20 min at RT. 2-Chloro-5-trifluoromethylpyridine (2.4 g, 0.013 mol) was added and the reaction mixture was refluxed at 110° C. overnight. Water was added and the mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give the title compound (4.28 g, 96%). 1H NMR (500 MHz, CDCl3): δ 8.45 (s, 1H), 7.96 (dd, J=2 Hz, J=8.5 Hz, 1H), 7.16-7.15 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 6.89-6.85 (m, 1H); m/z (337.9, M+ H+)
Reaction SMILES: C([Mg]Cl)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14](\[CH3:20])/[C:15](OCC)=[O:16])=[CH:9][CH:8]=1.Cl.[CH3:22][NH:23][O:24][CH3:25]>C1COCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10](/[CH:13]=[C:14](\[CH3:20])/[C:15]([N:23]([O:24][CH3:25])[CH3:22])=[O:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(F)cc1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)/C(C)=C/c1ccc(F)cc1
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A solution of isopropylmagnesium chloride (2.0 M in THF, 59.1 mL, 118 mmol) was added dropwise via addition funnel to a mixture of Example 1A (5.47 g, 26.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.12 g, 52.5 mmol) in THF (100 mL) at 0° C. Upon complete addition, the reaction was allowed to proceed 2 hr at 0° C. The reaction was quenched by slow addition of saturated aq NH4Cl solution (70 mL). The mixture was stirred 60 min, then partitioned between EtOAc (50 mL) and H2O (100 mL). The separated aqueous phase was extracted with EtOAc, and the combined organic layer was washed with 1 N aq HCl and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash 280; SF65-400 g column; 20% to 60% EtOAc/hexanes; 0-40 min) to give the title compound (5.06 g, 22.7 mmol, 86% yield) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.50-7.40 (m, 2H), 7.29-7.18 (m, 2H), 6.72 (s, 1H), 3.65 (s, 3H), 3.19 (s, 3H), 2.01 (d, J=1.5 Hz, 3H). MS (DCI+) 224 (M+H).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(C)c1ccc2c(c1)CCN2

Procedure:
A solution of (R/S) ethyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)butyrate (3.1 g, Reference Example 6) in dichloromethane (30 ml), cooled in an ice bath, was treated with trifluoroacetic acid (30 ml). After about 30 minutes the reaction mixture was evaporated and traces of trifluoroacetic acid were removed by chasing off with toluene (twice), to give the title compound as a dark viscous gum, which was used immediately without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[Cl:10][CH:11]([C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([Cl:1])=[CH:7][C:6]=1[CH3:8])[C:12]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: Cc1ccc(C)c(Cl)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(Cl)C(=O)c2ccccc2)c(C)cc1Cl
Temperature: 0 °C
Yield: 134.3 %

Procedure:
A mixture of 2-chloro-1,4-dimethyl-benzene (5 g, 35.56 mmol) and chloroacetylchloride (4.0 g, 35.6 mmol) was cooled to 0° C. and treated with aluminum chloride (4.74 g, 35.6 mmol) in small portions. The reaction slurry was diluted with dichloromethane and allowed to warm to room temperature. After 30 min the reaction was poured onto a mixture of ice and 10 mL of concentrated aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate and the organic layers were combined and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried (Na2SO4) and concentrated to give approximately 7 g of pure product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:22])[CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CCNc2ccc(Cl)cc2N1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CN1CCC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
20.4 g 8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one is stirred for 2 hours on a water bath with 12.8 g methyl iodide and 10 g anhydrous potassium carbonate. The inorganic material is removed by filtration under suction and the filtrate is diluted with 200 ml water. The crystalline precipitate is filtered under suction, washed with water, and recrystallized from alcohol. The yield is 20 g of the m.p.=143°-144° C. (93% of the theory).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][CH2:19][CH2:18]3)[CH:14]=[C:13]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O1CCCC1>CO>[N:17]1([C:15]2[CH:14]=[C:13]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:12]=[C:11]([S:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][CH:6]=3)[N:16]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(N3CCC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)O)cc3)n2)[nH]n1
Temperature: 25 °C
Yield: 109.8 %

Procedure:
A 50 ml round bottom flask equipped with a condenser was charged with 4-[4-azetidin-1-yl-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-benzoic acid methyl ester (800 mg, 2.0 mmol), 2M sodium hydroxide aqueous solution (5 ml), tetrahydrofuran (30 ml) and methanol (5 ml). The reaction mixture was heated to reflux for one hour. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The solid residue was taken up in methanol (30 ml) and concentrated hydrochloric acid (1 ml). The solvent was then removed under reduced pressure to give the title compound (0.84 g, 100%) as a mono HCl salt. 1H NMR (DMSO) 2.05-2.10 (3H, s), 2.20-2.30 (2H, m), 3.80-3.85 (2H, t), 4.05-4.10 (2H, S), 7.40-7.45 (2H, d), 7.85-7.90 (2H, d). MS (ES+): 383
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4.[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[CH:22]1([CH2:25][N:20]2[CH2:19][CH2:18][C@@:15]34[C:16]5[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@@H:10]3[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4)[CH2:24][CH2:23]1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCC(=O)C3
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1CCC(=O)C3

Procedure:
A sample of 3-methoxymorphinan-6-one hydrochloride (3.08 g, 10 mmol, prepared in Part IC), was reacted with cyclopropylmethyl bromide in the presence of sodium bicarbonate as described in Example 1D. After chromatography on Silica Gel G using 20:1 V/V chloroform-methanol, 2.5 g of the desired product was isolated as a syrup. This was converted to the hydrochoride salt to yield 2.1 g (58%) of TR-5152, mp 265°-267° C.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15](O)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:29]1[C:33]([NH2:34])=[N:32][N:31]=[N:30]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([NH:34][C:33]2[NH:32][N:31]=[N:30][N:29]=2)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1OC1CCN(C(=O)C(=O)O)CC1
Reactant: Nc1nnn[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1OC1CCN(C(=O)C(=O)Nc2nnn[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A solution of [4-(2-tert-butylphenoxy)piperidin-1-yl](oxo)acetic acid (300 mg, 0.98 mmol) obtained in Example 52 and oxalyl chloride (126 μL, 1.47 mmol) in toluene (5 ml) was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and DMF (1 mL) was added to the residue. The mixture was added to a solution of 1H-tetrazole-5-amine (255 mg, 3.0 mmol) and triethylamine (205 μL, 1.47 mmol) in toluene (10 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was partitioned between ethyl acetate-1N hydrochloric acid, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (317 mg, 87%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:20][CH:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[C:23]([CH:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][C:28]([OH:29])=[C:17]([F:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: NC(Cc1ccc(O)c(F)c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(O)c(F)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-fluoro-4-hydroxy-DL-phenylalanine to provide the title compound in good yield.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[F:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[F:17][C:18]1[C:23]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:28]=[CH:29]/[C:30]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:31]
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1F
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2cccc(C(F)(F)F)c2F)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-fluoro-3-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:18])[C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].CN1CCOCC1.[C:26]([O:29][C@H:30]([CH3:58])[C@H:31]([NH:36][C:37]([C:39]1([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:43][CH2:42][CH2:41][N:40]1[C:44]([C@@H:46]1[CH2:50][CH2:49][CH2:48][NH:47]1)=[O:45])=[O:38])[C:32]([O:34][CH3:35])=[O:33])(=[O:28])[CH3:27]>C(Cl)Cl.CN(C=O)C>[CH3:35][O:34][C:32](=[O:33])[C@@H:31]([NH:36][C:37]([C:39]1([CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:43][CH2:42][CH2:41][N:40]1[C:44]([C@@H:46]1[CH2:50][CH2:49][CH2:48][N:47]1[C:7](=[O:9])[C@@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:18])=[O:45])=[O:38])[C@H:30]([O:29][C:26](=[O:28])[CH3:27])[CH3:58]
Reactant: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)[C@@H]1CCCN1)[C@@H](C)OC(C)=O
Reactant: CC(=O)O[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OC(C)=O)[C@@H](C)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
To a solution of compound (2S,3R)-3-acetoxy-2-(tert-butoxycarbonylamino)-butanoic acid 12 (199 mg, 0.76 mmol) in CH2Cl2 (6 mL) was under inert atmosphere were added IBCF (125 mg, 0.91 mmol) and NMM (154 mg, 1.52 mmol) at −15° C. and stirred for 1 h. A solution of (2S,3R)-methyl 3-acetoxy-2-(2-benzyl-1-((S)-pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamido)-butanoate 8 (350 mg, 0.76 mmol) in DMF (2 mL) was added to the reaction mixture and stirred for 1 h at −15° C. The resultant reaction mixture was allowed to warm to RT and stirred for 19 h. The reaction mixture was extracted with EtOAc and the separated organic layer was washed with water (20 mL), followed by brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford compound 13 (100 mg, 20%).