Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.C(N(CC)CC)C>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCC4)c23)C1
Temperature: 160 °C
Reaction time: 18 h
Yield: 30.4 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamide (188 mg, 0.602 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (362 mg, 1.81 mmol), and triethylamine (168 μL, 1.20 mmol) in n-BuOH (5 mL) was stirred at 160° C. in a sealed tube for 18 hours. The mixture was allowed to cool to room temperature, and was then diluted with EtOAc (100 mL) and washed with brine (2×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The liquid residue was purified by C-18 reverse phase chromatography (Biotage 25M+) on Biotage SP4 unit eluting with a gradient of 12-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(cyclobutanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (90 mg, 30% yield) as a solid. This material was dissolved in neat TFA (3 mL) and stirred at room temperature for 30 minutes. The mixture was then concentrated in vacuo, and the oily residue was dissolved in a few drops of CH2Cl2 and treated with 2M HCl in ether. The solid formed was crystallized from MeOH and CH3CN to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamide hydrochloride (65 mg, 79% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.81 (s, 1H), 9.19 (s, 1H), 8.29 (br s, 3H), 8.23 (s, 1H), 7.59 (s, 1H), 3.46-3.37 (m, 2H), 3.35-3.26 (m, 3H), 3.08-3.03 (m, 1H), 2.34-2.24 (m, 2H), 2.18-2.11 (m, 3H), 2.01-1.94 (m, 1H), 1.86-1.80 (m, 2H), 1.70-1.60 (m, 1H), 1.50-1.44 (m, 1H); LCMS (APCI+) m/z 392, 394 (M+H)+, Retention time=2.28 minutes (Method 2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]([C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:23][C:24](=[O:31])[C@@H:25]([NH:30][S:50]([C:47]1[CH:48]=[CH:49][C:44]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:45][CH:46]=1)(=[O:52])=[O:51])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(C(C)(C)C)cc1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.20 g, 0.45 mmol) and triethylamine (0.13 mL, 0.90 mmol) in 5 mL of CHCl3 was cooled to 0° C. and treated with 4-tert-butylphenylsulfonyl chloride (0.10 g, 0.45 mmol). The reaction mixture was warmed to room temperature and treated with saturated aqueous NaHCO3. The organic phase was separated from the aqueous phase. The aqueous phase was extracted with additional CHCl3, and the combined organic extracts were dried MgSO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 1:1 heptane/ethyl acetate). The chromatography product was crystallized from hot heptane/ethyl acetate to give the title compound as a white solid 0.20 g 70%), mp=142-143° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)morpholine-4-carboxylate (step 1)(500 mg, 1.154 mmol) and trifluoroacetic acid (3556 μl, 46.2 mmol) in DCM (3.8 ml) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure and the crude product was diluted with EtOAc. The mixture was washed with sat. NaHCO3 and the organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:10](O)=[O:11])([OH:8])(=[O:7])=[O:6]>CN(C)C=O.CCOCC>[S:5]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:10]([Cl:3])=[O:11])([OH:8])(=[O:7])=[O:6]
Reactant: O=C(O)C(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)C(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)O
Yield: 81.3 %

Procedure:
6.58 Grams (5.7 × 10-2M) of thionyl chloride, 2 ml. of ether and 2 drops of dimethylformamide were added to 1.5 g. (5.7 × 10-3M) of α-sulfo-α-(p-nitrophenyl)acetic acid to allow to react for 14.5 hours at room temperature. The reaction product was subjected to the evaporation to dryness under reduced pressure to obtain a crude desired product. Yield 81.3%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(OC([N:33]1[CH2:37][CH2:36][C@H:35]([C:38](O)=[O:39])[CH2:34]1)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:52].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:52].[ClH:52].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:38]([C@H:35]4[CH2:36][CH2:37][NH:33][CH2:34]4)=[O:39])[CH2:20][CH2:19]3)=[O:17])=[CH:24][CH:25]=2)=[N:2]1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(C(=O)[C@H]2CCNC2)CC1
Temperature: 60 °C
Yield: 104.4 %

Procedure:
The product obtained using Compound 18 (300 mg, 0.90 mmol), (S)-pyrrolidin-1,3-dicarboxylic acid 1-tert-butyl ester (162 mg, 0.76 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg, 1.06 mmol) and N-methylmorpholine (0.17 mL, 1.52 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 124 (278 mg, 61%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:14][CH2:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][CH:17]=1>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:26][CH:27]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 2 g (15 mmol) of 4-tert-butylbenzoyl chloride with 2.9 g (15 mmol) of allyl 4-hydroxymethylbenzoate, 4 g (77%) of allyl ester are obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:25][C@H:24]([CH2:26][O:27]C(=O)C3C=CC(Cl)=CC=3)[C@@H:13]([O:14]C(=O)C3C=CC(Cl)=CC=3)[CH2:12]2)=[C:4]([NH:37][Si](C)(C)C)[N:3]=1.CO[Na].CO>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH2:37])[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=1)[C@@H:11]1[O:25][C@H:24]([CH2:26][OH:27])[C@@H:13]([OH:14])[CH2:12]1
Reactant: C[Si](C)(C)Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Agent: CO[Na]
Solvent: CO
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
To the above prepared mixture of 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofurano syl]-purine (IVa) and 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2′-deoxy-β-D-ribofuranosyl]-purine (IVb) (179 g, >95.4% HPLC purity) in MeOH (895 mL, 5 P) was added 29% MeONa/MeOH solution (5.25 g, 0.1 eq.) at 20-30° C. The mixture was stirred at 20-30° C. for 6 hours, the solid was filtered, washed with MeOH (60 mL, 0.34 P) and then dried in vacuo at 50° C. for 6 hour to give 72 g white to off-white crude cladribine with 98.9% HPLC purity in ca. 93% yield.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)=[C:9]1C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(Sc2cccc(Br)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Clc1ccc2c(Sc3cccc(Br)c3)cn(Cc3ccccc3)c2c1
Reaction time: 0.17 h

Procedure:
1-Benzyl-3-(3-bromo-phenylsulfanyl)-6-chloro-1H-indole-2-carboxylic acid (from the previous step) was dissolved in quinoline (5 mL) then copper (0.120 g, 2 mmol) was added and the reaction was placed in the microwave for 10 minutes at 150° C., and this heating was repeated 3 additional times. The reaction was submitted to standard workup procedures then purified by silica gel chromatography (0-20% EtOAc in hexanes) to provide the title compound.
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:10])=CC=1)([O-])=O.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:50]=[C:49]4[C:44]([CH2:45][CH2:46][NH:47][CH2:48]4)=[CH:43][CH:42]=3)[N:38]=[C:37]([NH2:51])[N:36]=2)[CH2:31][CH2:30]1.C(N(CC)CC)C>C(#N)C.O>[NH2:51][C:37]1[N:38]=[C:39]([C:41]2[CH:50]=[C:49]3[C:44]([CH2:45][CH2:46][N:47]([C:9]([O:11][CH:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]4)=[O:10])[CH2:48]3)=[CH:43][CH:42]=2)[CH:40]=[C:35]([N:32]2[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]2)[N:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)OC(C)(C)C)CC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
tert-Butyl 4-{[(4-nitrophenoxy)carbonyl]oxy}piperidine-1-carboxylate (0.093 g, 0.25 mmol) was added to a solution of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (0.10 g, 0.23 mmol) and triethylamine (0.13 mL, 0.92 mmol) in acetonitrile (5.0 mL). The reaction mixture was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethane (0-10%) to afford the desired product (0.10 g, 79%). Analytic LCMS (M+H)+: m/z=552.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:25][C:4]1([CH3:26])[CH2:5][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][O:24][S:34]([C:31]4[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=4)(=[O:36])=[O:35])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][C:2]([CH3:27])([CH3:1])[NH:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCCO)cc3)n2)CC(C)(C)N1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1

Procedure:
The title compound was prepared from 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propan-1-ol (Example 189) and p-toluenesulfonyl chloride in pyridine. Yield: 140 mg (45%).
Reaction SMILES: C1CO[C:3]2([CH2:7][CH2:6][CH:5]([S:8][CH2:9][C:10]([OH:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:4]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[O:2]1.C(CCCCCCC1C(=O)CCC=1)(O)=O.OC(CCCCC)CS.CC(=C)C.C1COC2(CCC(SCC(=O)CCCCC)C2CCCCCCC(OC(C)(C)C)=O)O1.C[Mg]Br>CCOCC.C(O)CO>[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:4]1[CH:5]([S:8][CH2:9][C:10]([OH:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][C:3]1=[O:2])([OH:26])=[O:25]
Reactant: CCCCCC(C)(O)CSC1CCC2(OCCO2)C1CCCCCCC(=O)OC(C)(C)C
Agent: C=C(C)C
Agent: CCCCCC(=O)CSC1CCC2(OCCO2)C1CCCCCCC(=O)OC(C)(C)C
Agent: CCCCCC(O)CS
Solvent: OCCO
Solvent: CCOCC
Product: CCCCCC(C)(O)CSC1CCC(=O)C1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.7 g. of 1,1-ethylenedioxy-2-(6-tert.-butoxycarbonylhexyl)-3-(2-hydroxy-2-methylheptylthio)-cyclopentane (obtainable from 2-(6-carboxyhexyl)-2-cyclopentenone, addition of 2-hydroxyheptanethiol, subsequent ketalization with ethylene glycol, as well as oxidation with CrO3 in ether, addition to isobutylene, and reaction of the thus-obtained 1,1-ethylenedioxy-2-(6-tert.-butoxycarbonylhexyl)-3-(2-oxoheptylthio)-cyclopentane with methylmagnesium bromide) is agitated for 2 hours at room temperature in 60 ml. of 2N aqueous HCl, extracted, after cooling, three times with CH2Cl2 ; the organic phase is washed with water, dried over Na2SO4, the solvent is distilled off, and chromatographic purification of the residue (silica gel/chloroform) yields 2-(6-carboxyhexyl)-3-(2-hydroxy-2-methylheptylthio)-cyclopentanone. Rf = 0.25 (silica gel/chloroform : methanol = 95 : 5).
Reaction SMILES: [Cl:1]CCl.[Br:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10]2.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Br:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH3:14])[C:11]([C:15]([Cl:1])=[O:17])=[CH:10]2
Reactant: Cn1c(C(=O)O)cc2cccc(Br)c21
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Cl)cc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane (2 mL) solution of 7-bromo-1-methyl-1H-indole-2-carboxylic acid (200 mg), oxalyl dichloride (0.10 mL) and N,N-dimethylformamide (5 mL) were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, azeotroped twice with toluene to obtain a crude product of 7-bromo-1-methyl-1H-indole-2-carboxylic acid chloride. Separately, a solution was prepared by dissolving 2M trimethylsilyldiazomethane (0.60 mL) and trimethylamine (0.16 mL) in tetrahydrofuran (2 mL)-acetonitrile (2 mL) and a tetrahydrofuran (1 mL)acetonitrile (1 mL) solution of 7-bromo-1-methyl-1H-indole-2-carboxylic acid chloride was added thereto, and then the mixture was stirred at room temperature for 4 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 85:15) to obtain the titled compound having the following physical properties (72 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[C@@H:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=2)[CH2:27][CH2:26]1)[CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:38][CH:36]([C:33]1[N:32]=[C:31]([N:28]2[CH2:27][CH2:26][CH:25]([C@@H:23]([O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH3:24])[CH2:30][CH2:29]2)[O:35][N:34]=1)[CH3:37]
Reactant: CC(C)c1noc(N2CCC([C@@H](C)OS(C)(=O)=O)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC([C@H](C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Step 2, 1.3 g, 5.19 mmol), (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (2.23 g, 7.0 mmol, 70% ee) and K2CO3 (1.45 g, 10.4 mmol) in DMF (35 mL) was stirred at 100° C. in a preheated oil bath overnight. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (75 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown oil, which was by chromatography on a silica gel column eluted with 50% EtOAc/hexanes followed by chromatography on an ISCO silica gel column using 0 to 60% EtOAc/hexanes to give 2-[((1S)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (0.73 g, 70% ee, 30%) as a white solid. The solid was subjected to chiral separation (similar to conditions used above for Example 158) to yield 0.30 g of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H, J=1.3 Hz), 8.25 (d, 1H, J=1.3 Hz), 8.10 (d, 2H, J=8.3 Hz), 8.02 (d, 2H, J=8.5 Hz), 5.20-5.10 (m, 1H), 4.35-4.20 (m, 2H), 3.15-3.00 (m, 5H), 2.90 (septet, 1H, J=7.0 Hz), 2.00-1.80 (m, 3H), 1.60-1.40 (m, 2H), 1.34 (d, 3H, J=6.3 Hz), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 472 (M+H).
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4](=[O:10])[CH2:3]2.Br[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:10]=[C:4]1[CH2:3][CH:2]2[N:9]([CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH:6]([CH2:7][CH2:8]2)[CH2:5]1
Reactant: O=C1CC2CCC(C1)N2
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN2C3CCC2CC(=O)C3)cc1
Reaction time: 96 h
Yield: 75.5 %

Procedure:
A slurry of 8-azabicyclo[3.2.1]octan-3-one hydrochloride salt (0.52 g, 3.2 mmol) and methyl 4-(bromomethyl)benzoate (0.75 g, 3.3 mmol) in 30 mL of acetonitrile was stirred as solid potassium carbonate (1.9 g, 13.6 mmol) was added. After 4 days, the reaction was filtered. The filtrate was concentrated. Purification by chromatography on silica gel using hexane gave 0.66 g of methyl 4-[(3-oxo-8-azabicyclo[3.2.1]oct-8-yl)methyl]-benzoate.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][CH:12]([F:26])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][C:20]=2[CH2:24][CH3:25])=[CH:15][CH:14]=1.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:27][C:22]1[O:23][C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:12]([F:11])[F:26])=[CH:18][CH:17]=2)=[C:20]([CH2:24][CH3:25])[N:21]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCc1ncoc1-c1ccc(C(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc(Cl)oc1-c1ccc(C(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
LiHMDS (1.0 M in THF, 24 mL, 24 mmol) was added to a solution of Example 54A (4.90 g, 21.9 mmol) in THF (73 mL) at −78° C. The reaction was stirred at −78° C. for 30 min, and then solid hexachloroethane (5.20 g, 21.9 mmol) was added in one portion. The reaction was allowed to stir overnight while warming to room temperature. The reaction was quenched with water and the product extracted with EtOAc. The combined organic extract was washed with water and brine, and filtered through celite. The filtrate was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was dissolved in toluene and loaded on silica gel (Analogix® 25×115 column), and eluted with 2 column lengths of hexanes then 5% to 50% EtOAc/hexanes. The result was 4.1 g (73%) of the title compound as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=8.5, 2H), 7.58 (d, J=8.7, 2H), 6.68 (t, J=56.5, 1H), 2.77 (q, J=7.5, 2H), 1.31 (t, J=7.5, 3H). MS (DCI+) m/z 258 (M+H).
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:12][NH2:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.O>CCO>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[N:13][NH:12][C:10]([C:9]1[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1cccnc1Nc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Nc1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of 2-anilino-nicotinic acid hydrazide (0.31 g, 1.05 mmol) in 20 mL EtOH was added 3-trifluoromethyl-benzaldehyde (0.182 g, 1.05 mmol) in 5 mL EtOH at room temperature. The mixture was refluxed for 4 h and cooled to room temperature, then diluted by 100 mL water. The precipitate was collected by filtration, washed with MeOH, and dried to yield the title compound (0.343 g, 85%). 1H NMR (acetone-d6): 11.40 (S, 1H), 11.80 (S, 1H), 8.56 (s, 1H), 8.37 (d, J=4.8 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.80 (m, 3H), 7.12 (m, 1H), 7.32 (m, 2H), 7.0 (t, J=8.1 Hz, 1H), 6.86 (q, J=4.5 Hz, 1H).