Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:8]([C:10]([O:12]C)=[O:11])=[CH:7][CH:6]=[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:4]=2[CH:3]=[CH:2]1.O1CCCC1.O.[OH-].[Li+]>CO>[C:17]([O:16][C:14]([C:5]1[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)c2cc[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)O)c2[nH]ccc12
Temperature: 40 °C
Yield: 65.6 %

Procedure:
To a solution of 4-tert-butyl 7-methyl 1H-indole-4,7-dicarboxylate (0.58 g, 2.10 mmol) in a mixture of methanol (20 mL), terahydrofuran (10 mL) and water (10 mL) was added a 2M aqueous solution of lithium hydroxide (2.1 mL, 4.20 mmol), and the reaction mixture was stirred at 40° C. until full consumption of starting material. The organic portion of the solvent was evaporated and the pH of the aqueous solution was adjusted to 3-4 by the addition of 1 M aqueous hydrochloric acid. The acidic aqueous phase was partitioned with ethyl acetate (150 mL), and the organic layer was separated and washed with brine, dried over sodium sulfate, filtered and concentrated to give 4-(tert-butoxycarbonyl)-1H-indole-7-carboxylic acid (0.36 g, 67%). MS (EI) for C14H15NO4: 260 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10](O)[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:45]([SH:47])[CH3:46].O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([S:47][CH2:45][CH3:46])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCS
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(O)c2c1[nH]c1ccccc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(SCC)c2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
To a solution of 3-(4-fluorobenzoyl)-1-hydroxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (60 mg, 0.3 mmol) in DCM (2 mL) was added trifluoromethanesulfonic anhydride (50 mL, 0.6 mmol) at 0° C. and the mixture was stirred for 1 hour at 0° C. Ethanethiol (34 mL, 0.9 mmol) was added and the reaction mixture was stirred overnight at 20° C. Water was added and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was then washed with water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel, eluted with MeOH-DCM (1:19) to give the title compound (2 mg); 1NMR (CDCl3): δ 8.59 (1H, s), 8.77 (1H, d), 7.54 (2H, m), 7.36 (1H), 7.19 (1H, m), 7.06 (2H, m), 6.73 (1H, s), 4.41 (2H, m), 4.21-4.30 (3H, m), 2.59-2.69 (2H, m), 1.28 (3H, t), 1.19 (3H, t). MS (ES): 439 (MH+).
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:62]([CH2:64][CH3:65])[CH3:63])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:11]([NH:13][C@@H:14]([CH2:44][C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=2)[C@@H:15]([C@H:17]2[CH2:26][C:25]3[C:20](=[C:21]([O:27][CH2:28][CH:29]=[CH2:30])[CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[OH:16])=[O:12])[C:6]1=[O:61])(=[O:3])[CH3:2].C(O)(=O)C>CO.[Pd]>[C:1]([NH:4][C@:5]1([C@@H:62]([CH2:64][CH3:65])[CH3:63])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:11]([NH:13][C@@H:14]([CH2:44][C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:26][C:25]3[C:20](=[C:21]([O:27][CH2:28][CH2:29][CH3:30])[CH:22]=[CH:23][CH:24]=3)[CH2:19][NH:18]2)=[O:12])[C:6]1=[O:61])(=[O:3])[CH3:2].[CH2:28]([O:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH2:19][N:18]([CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C@@H:17]([C@@H:15]([OH:16])[C@@H:14]([NH2:13])[CH2:44][C:45]1[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=1)[CH2:26]2)[CH:29]=[CH2:30]
Reactant: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)[C@H](CCc1ccccc1)N1CC[C@](NC(C)=O)([C@H](C)CC)C1=O)C2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)C2
Product: CCCOc1cccc2c1CN[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)[C@H](CCc1ccccc1)N1CC[C@](NC(C)=O)([C@H](C)CC)C1=O)C2
Reaction time: 3.5 h
Yield: 74 %
Yield: 147.4 %

Procedure:
To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((R)-8-(allyloxy)-2-benzhydryl-1,2,3,4-tetrahydroisoquinolin-3-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamide (Step 3 (A), 50 mg) in MeOH (5 mL) was added a catalytic amount of Pd on activated charcoal (10 wt %) and acetic acid (0.2 mL). The reaction mixture was put on hydrogenator at 50 psi for 3.5 h. The mixture was then filtered and concentrated in vacuo and purified by silica gel Flash chromatography to give 30 mg of the title compound of compound 3 (74% yield). 1H NMR (CD3OD, 500 MHz) δ 0.76 (3H, d, J=5 Hz), 0.97-1.00 (3H, m), 1.04-1.07 (4H, m), 1.64-1.69 (2H, m), 1.78-1.85 (2H, m), 1.94 (1H, s), 1.97-2.03 (4H, m), 2.06-2.20 (3H, m), 2.38-2.44 (1H, m), 2.53-2.59 (1H, m), 2.78 (1H, dd, J=10, 15 Hz), 2.96 (1H, m), 3.10-3.20 (2H, m), 3.26-3.31 (2H, m), 3.42 (1H, dt, J=5, 10 Hz), 3.97 (2H, t, J=5 Hz), 4.01-4.05 (2H, m), 4.12 (1H, m), 4.22 (1H, dt, J=5, 10 Hz), 4.32 (1H, d, J=15 Hz), 6.75 (1H, m), 6.80 (2H, d, J=10 Hz), 6.92 (2H, d, J=5 Hz), 6.95 (2H, d, J=10 Hz), 7.10-7.19 (4H, m). MS (ESI) (M+H)+ 719.37.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH:17]=[CH:18][N:19]4[Si](C(C)C)(C(C)C)C(C)C)=[CH:11][C:10]=2[C:34]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:35])=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl.CSC>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][NH:19]3)=[CH:11][C:10]=1[C:34]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)=[O:35]
Reactant: COc1ccc(COc2ccc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)cc2C(=O)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccnc1)c1cc(-c2cccc3[nH]ccc23)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
To a solution of [2-(4-methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone (42 mg, 0.07 mmol) in dichloromethane (0.5 mL) and dimethylsulfide (0.5 mL) at 0° C. was added TFA (1 mL) dropwise. After stirring at 0° C. for 30 mins, the starting material was gone. Saturated aqueous NaHCO3 was added to adjust the pH of the mixture to around 6, and the reaction mixture was extracted with EtOAc several times. The combined EtOAc layers were washed with brine, dried and concentrated. Purification by silica gel column chromatography, followed by further preparative SFC chromatography afforded 3.1 mg (14%) of [2-hydroxy-5-(1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 11.87 (s, 1H), 9.13-8.89 (m, 1H), 8.88-8.69 (m, 1H), 8.37-8.23 (m, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.91 (dd, J=8.6, 2.1 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.49-7.40 (m, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.27-7.19 (m, 4H), 7.05 (d, J=7.4 Hz, 1H), 6.57 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:35])([C:31]([F:34])([F:33])[F:32])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[O:5][C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[O:8][C:9]([F:22])([F:21])[CH2:10][O:11][CH2:12][C@@H:13]([F:20])[CH2:14][O:15][CH2:16][CH2:17][CH2:18]Cl.FC(F)(C(F)(F)F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COC[C@@H](F)CO.BrCCCCl.[CH2:72]([C:79]1[CH:80]=[N:81][C:82]([C:85]2[CH:90]=[CH:89][C:88]([OH:91])=[CH:87][CH:86]=2)=[N:83][CH:84]=1)[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78]>C(#N)C.CN(C)C=O>[CH2:72]([C:79]1[CH:84]=[N:83][C:82]([C:85]2[CH:86]=[CH:87][C:88]([O:91][CH2:18][CH2:17][CH2:16][O:15][CH2:14][C@H:13]([F:20])[CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:24])([F:23])[C:6]([F:26])([F:25])[O:5][C:4]([F:28])([F:27])[C:3]([F:30])([F:29])[C:2]([F:35])([F:1])[C:31]([F:34])([F:33])[F:32])([F:22])[F:21])=[CH:89][CH:90]=2)=[N:81][CH:80]=1)[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78]
Reactant: F[C@@H](COCCCCl)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: ClCCCBr
Agent: OC[C@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCCCc1cnc(-c2ccc(OCCCOC[C@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The starting material, 3-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropoxy)propyl chloride, was prepared by combining 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropanol (20 g, 39.4 mmol) and 1-bromo-3-chloropropane (18.6 g, 118 mmol). The resulting compound (2.0 g, 3.4 mmol) was then combined with 5-heptyl-2-(4-hydroxyphenyl)pyrimidine (0.9 g, 3.4 mol) in acetonitrile/dimethyl formamide (1:1, 20 mL) using essentially the procedure of Example 8 of International Patent Publication No. WO 96/33251. The resulting crude product was further purified by chromatography, eluting with 30:1 toluene/ethyl acetate, followed by Kugelrohr distillation (180-90° C. at 0.01 torr; yield 0.96 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[N:7]/[S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[N:2]1.[CH3:14][Mg]Br>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH3:14])=[N:2]1
Reactant: CC(C)(C)S(=O)/N=C/c1ccon1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)c1ccon1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
In a round-bottomed flask, 2-methyl-propane-2-sulfinic acid 1-isoxazol-3-yl-meth-(E)-ylideneamide (584 mg, 2.92 mmol) was dissolved in dichloromethane (10 ml). The reaction mixture was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether, 1.1 ml, 3.3 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h then quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford 655 mg of 2-methyl-propane-2-sulfinic acid (1-isoxazol-3-yl-ethyl)-amide as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[OH:16][C@@H:17]1[CH2:21][NH:20][CH2:19][C@H:18]1[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCO>[C:27]1([CH2:26][O:25][C:24](=[O:33])[NH:23][CH2:22][C@H:18]2[C@H:17]([OH:16])[CH2:21][N:20]([CH2:2][CH2:1][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=4)[N:6]=[CH:5][C:4]=3[F:15])[CH2:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NC[C@@H]1CNC[C@H]1O)OCc1ccccc1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2n1
Yield: 97.9 %

Procedure:
To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (2.55 g, 12.5 mmole) in EtOH (10 mL) was added phenylmethyl(±)-{[trans-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (3.12 g, 12.5 mmole). After 24 h at 80° C. the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (5.56 g, 98%) as a light yellow foam: LC-MS (ES) m/e 455 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][Br:32])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1CBr
Yield: 79.9 %

Procedure:
A solution of Example 33A (1.02 g, 4.47 mmol) in CCl4 (22 mL) was treated with AIBN (0.065 g, 0.4 mmol) and NBS (0.955 g, 5.4 mmol), heated to reflux for 4 hours, washed with water, dried (Na2SO4), filtered, and concentrated to provide the desired product (1.1 g, 79%).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([Br:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>CC(C)=O>[Br-:19].[CH2:10]([N+:6]1[CH:7]=[CH:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH:5]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: c1cc2sccc2cn1
Solvent: CC(C)=O
Product: O=C(C[n+]1ccc2sccc2c1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of thieno[3,2-c]pyridine (13.5 g; 0.10 mole) and phenacyl bromide (19.9 g) (0.10 mole) in acetone (200 ml) is stirred for two hours at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][C:29]([NH2:32])=[N:30][OH:31])[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[Cl:34][C:35]([Cl:40])([Cl:39])[C:36](O)=O.ClC(Cl)(Cl)C(Cl)=O.[OH-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][C:29]3[N:32]=[C:36]([C:35]([Cl:40])([Cl:39])[Cl:34])[O:31][N:30]=3)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CC(N)=NO)c1Cl
Agent: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(C(Cl)(Cl)Cl)n2)c1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
N-(5—Chloropyridin-2-yl)-2-[((4-(2-amino-2-(hydroxyimino)ethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (3.06 g, 5.8 mmol) was dissolved in trichloroacetic acid (3.8 g, 23 mmol) and the mixture heated to 85° C. Trichloroacetyl chloride (1.3 mL, 11.6 mmol) was added, and the temperature was increased to 94° C. After one hour the reaction mixture was allowed to cool to room temperature, diluted with water (150 mL) and a small amount of ethyl acetate, and adjusted to basic pH with 1 N NaOH. The aqueous layer was extracted with ethyl acetate (300 mL). The organic phase was washed with 1 M sodium bicarbonate (150 mL), dried over magnesium sulfate, concentrated in vacuo, and dried under vacuum. The crude product was purified by flash chromatography on silica gel eluting with 25% ethyl acetate/hexanes to afford N-(5-chloropyridin-2-yl)-2-[((4-((5-trichloromethyl-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[NH:21][C:22]([C:24]2[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:23])=[CH:6][CH:5]=1.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CCN(CC)CC>C1COCC1>[Cl:33][C:31]1[C:30]([Cl:34])=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([C:22]([NH:21][C:12]2[CH:13]=[C:14]([C:17]([F:19])([F:20])[F:18])[CH:15]=[CH:16][C:11]=2[NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:41]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:42])=[CH:9][CH:8]=2)=[O:23])[CH:32]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCc1ccc(Nc2ccc(C(F)(F)F)cc2NC(=O)c2cc(Cl)c(Cl)cc2C(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1Nc1ccc(CNC(=O)N2CCOCC2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Into a vial are placed 2-({[2-{[4-(aminomethyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid hydrochloride (100 mg, 0.187 mmol), 4-morpholine-carbonylchloride (28 mg, 0.187 mmol), Et3N (0.08 mL, 0.573 mmol), and THF (10 mL). The mixture is heated with efficient stirring at 40° C. for 4 h. The solution is concentrated and purified by preparative thin layer chromatography. The yield is 31 mg of 4,5-dichloro-2-({[2-[(4{[(morpholin-4-ylcarbonyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)phenyl]amino}carbonyl)benzoic acid, 27%. 1H NMR (400 MHz, DMSO-d6): □ 13.88 (s, 1 H), 10.14 (s, 1 H), 8.09 (s, 2 H), 7.77 (s, 1 H), 7.70 (s, 1 H), 7.44-7.42 (m, 1 H), 7.26-7.23 (m, 3 H), 7.14-7.09 (m, 3 H), 4.22-4.21 (m, 2 H), 3.56-3.54 (m, 4 H), 3.30-3.28 (m, 4 H) 7.44-7.42 (m, 1 H), 7.26-7.23 (m, 3 H), 7.14-7.09 (m, 3 H), 4.22-4.21 (m, 2 H), 3.56-3.54 (m, 4 H), 3.30-3.28 (m, 4 H). HRMS for C27H23Cl2F3N4O5 m/z 611.1071 M+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[C:14]([N:6]1[CH:7]=[C:3]([CH2:2][OH:1])[N:4]=[CH:5]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 14 h
Yield: 99.8 %

Procedure:
4-hydroxymethylimidazole (4.53 g, 34 mmol) and triphenylmethylchloride (10.54 g, 38 mmol) were dissolved in DMF (50 mL). To this was added with stirring DIEA (13.46 g, 104 mmol) and the reaction mixture was stirred for 14 hrs. The reaction mixture was poured into water (750 mL) and stirred for about 30 min. The resulting solid was collected, washed with water (3×25 mL) and diisopropyl ether (3×25 mL), and dried in vacuo to yield 11.55 g (99%) of (1-trityl-1H-imidazol-4-yl)methanol. Purity (HPLC): 93%; retention time, 6.37 min.; column: Phenomenex Luna C18(2) (5 μm, 50×4.6 mm); gradient: 10% to 100% B in A over 10 min. at 1.25 mL/min. Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in AcCN. ES-MS: (M+H)+=341.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]([CH3:17])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]([C:14]([Cl:22])=[O:15])=[CH:12][N:11]([CH3:17])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1C=C(C(=O)O)[C@H](c2ccc(F)cc2)NC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C=C(C(=O)Cl)[C@H](c2ccc(F)cc2)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10 mL dichloromethane and 1 drop of DMF was added 150 mg of (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid. To this mixture was added 70 μl oxalyl chloride. When the bubbling stopped another drop of oxalyl chloride was added but as no bubbling was observed the solution was stirred at room temperature for 30 minutes after which the solvent was removed in vacuo to afford crude (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid chloride (not shown in Scheme H). This acid chloride was taken up in propionitrile and added to a solution of 125 mg 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine, 3 ml propionitrile, and 0.1 ml di-iso-propylethylamine. The solution was stirred at room temperature for 18 hours, then diluted with ethyl acetate and aqueous pH 2 buffer. The layers were separated and the organic layer dried over Na2SO4, filtered and the solvent removed in vacuo to give (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-amide, which was used directly in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCCl>[OH:23][C:19]1[CH:18]=[C:17]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:22]=[CH:21][C:20]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Oc1cccc(N2CCCC2)c1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1ccc(N2CCCC2)cc1O
Temperature: 60 °C
Yield: 36.3 %

Procedure:
A mixture of 14.8 g (0.1 mole) of phthalic anhydride, 16.3 g (0.1 mole) of 100 percent 3-pyrrolidinophenol and 50.0 ml of 1,2-dichloroethane was maintained at approximately 40° C. for approximately twenty-four hours, at approximately 60° C. for approximately twenty-four hours and at reflux temperature for approximately twelve hours. After cooling the reaction mixture to ambient temperature, the solid which precipitated was collected by filtration and washed with 500.0 ml of 1,2-dichloroethane. The solid was dissolved in dilute aqueous soduim hydroxide, the resulting mixture was filtered to remove insolubles. The filtrate was adjusted to pH 7.0 with the addition of glacial acetic acid and the solid tar-like material which formed was collected by filtration. To the filtrate an additional amount of glacial acetic acid was added. The solid which precipitated was collected by filtration, washed with water and dried to obtain 11.3 g of 2-(2-hydroxy-4-pyrrolidinophenyl)carbonylbenzoic acid, a pale pink-colored solid which melted at 190°-192° C. To the filtrate there was added an additional portion of glacial acetic acid and the solid which was collected by filtration, washed with water and dried to obtain 0.3 g a pale yellow-colored crystals of the desired product which melted at 193°-195° C. The infrared spectra of the two solids were identical having significant maxima at 1100 cm-1 (C=O;m). The nuclear magnetic spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(O)(=O)C>[C:8]([NH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(N)C(=O)O
Solvent: CC(=O)O
Product: CCC(NC(C)=O)C(=O)O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
163 g (1.58 mol) 2-aminobutanoic acid are dissolved in acetic acid, and 242 g (2.37 mol) acetic anhydride are added dropwise. The mixture is stirred for 2 h at 100° C. until completion of reaction, then the solution is evaporated to dryness in vacuo. The solid residue is suspended in ethyl acetate, filtered and washed with diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>O1CCCC1>[C:39]([N:36]1[CH2:37][CH2:38][CH:33]([O:32][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(F)c2)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(F)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reaction time: 4 h

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.1 mmol), acetyl chloride (9.4 mg, 0.12 mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.027 mL, 0.2 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was triturated in dichloromethane and hexanes to give the title compound as a off white solid (Yield: 43 mg).