Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(OC(=O)NC(C(=O)NC1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:58][C:59]([C:61]1([NH:66][C:67]([CH:69]2[CH2:73][CH:72]([O:74][C:75]3[C:84]4[C:79](=[CH:80][C:81]([O:85][CH3:86])=[CH:82][CH:83]=4)[N:78]=[C:77]([C:87]4[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=4)[CH:76]=3)[CH2:71][N:70]2[C:93](=[O:113])[NH:94][CH:95]([C:100](=[O:112])NC2C3C(=CC=CC=3)CC2O)C(C)(C)C)=[O:68])[CH2:63][CH:62]1[CH:64]=[CH2:65])=[O:60])C>>[CH:42]1([C@H:95]([NH:94][C:93]([N:70]2[CH2:71][C@H:72]([O:74][C:75]3[C:84]4[C:79](=[CH:80][C:81]([O:85][CH3:86])=[CH:82][CH:83]=4)[N:78]=[C:77]([C:87]4[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=4)[CH:76]=3)[CH2:73][C@H:69]2[C:67]([NH:66][C@:61]2([C:59]([OH:58])=[O:60])[CH2:63][C@H:62]2[CH:64]=[CH2:65])=[O:68])=[O:113])[C:100](=[O:112])[NH:24][CH2:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: O=C([O-])NCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)NCC1CCCCC1)C1CCCCC1)C(=O)O

Procedure:
N-(tert-butoxycarbonyl)-L-cyclohexylglycine was attached to the resin as described for the preparation of compound 16 followed by reaction with cyclohexanemethylamine as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC>95%. M+H+752.4.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.Br[CH2:51][C:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:53]>C(#N)C.C(OC(=O)C)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:51][C:52](=[O:53])[C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(=O)c5ccccc5)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of (1R,2S,3S,4R,55)-1-(acetoxymethyl)-5-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (260 mg, 0.46 mmol) and DIPEA (0.38 mL, 2.25 mmol) in acetonitrile (2.25 mL), 2-bromo-1-phenylethanone (269 mg, 1.3 mmol) was added at r.t. and stirred overnight. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL) and washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2.2:7.8 acetone:hexane) to afford the title compound (230 mg, 0.33 mmol, 73.6%).
Reaction SMILES: CI.Cl[CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[CH3:10][C:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH3:10][C:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]([CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])([OH:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc2c(=O)c3ccccc3ccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: Cc1cccc2c1C=Cc1ccccc1C2(O)CCCN(C)C
Temperature: 45 °C
Reaction time: 5 h

Procedure:
20 g. of Gilman alloy are covered with 40 ml. of dry ether and treated with 0.5 ml. of methyl iodide. After the vigorous reaction has subsided somewhat, a solution containing 80 ml. of 1chloro-3-dimethylaminopropane in 360 ml. of dry ether is added dropwise in such a way that the reaction mixture is maintained at boiling. The mixture is stirred at 45° C. under reflux conditions for an additional 5 hours. The reaction mixture is then cooled with ice-water and a solution containing 43.6 g. of 1-methyl-5H-dibenzo[a,d]cyclohepten-5-one in 820 ml. of dry ether is added over a one-hour period. Subsequently, the mixture is boiled and stirred at reflux for another 17 hours. After about 12 hours, it is once more cooled with ice water and decomposed with a cold saturated ammonium chloride solution. The organic layer is separated, washed with water, dried over sodium sulfate and evaporated. The 1-methyl-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene obtained is recrystallized from high-boiling petroleum ether and has a melting point of 141°-143° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:36])([F:35])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][OH:34])[CH:28]=4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[O:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:36][C:7]([F:6])([F:35])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])[CH:28]=4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ccnc(CO)c3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1

Procedure:
Methansulfonyl chloride (0.2 mL, 2.46 mmol) is added to a solution of 5-(2-hydroxymethyl-pyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide, Example 25-D, (700 mg, 1.64 mmol) and triethylamine (0.7 mL, 4.92 mmol) in DCM (50 mL) at rt. After 1 h the reaction is partitioned between DCM and saturated aqueous NaHCO3. Organic layer is removed, dried over anhydrous Na2SO4, concentrated and then separated via FCC (EtOAclheptanes 2:4 to EtOAc/heptanes 9:1) to give the title compound. MS (ESI) m/z 506.0 (M+1).
Reaction SMILES: COC(=O)C([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)NC(=O)CN(S(C1C=CC(C)=CC=1)(=O)=O)C.[Na].[C:30]([NH:33][CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])[CH3:31].Cl.N1C=CC(CCl)=CC=1>CCO>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:34]([NH:33][C:30](=[O:32])[CH3:31])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COC(=O)C(Cc1ccncc1)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: ClCc1ccncc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccncc1)(NC(C)=O)C(=O)OCC

Procedure:
N-(Toluene4-sulfonyl)sarcosyl-β-(pyrid-4-yl)-D,L-alanine methyl ester was employed in this reaction and was prepared as follows. Sodium metal (2 eq.) was dissolved in EtOH containing diethyl acetamidomalonate (1 eq.) and 4-picolylchloride hydrochloride (1 eq.). The mixture was heated to reflux for 6 hr, and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was taken up into saturated aq NaHCO3 and extracted with EtOAc. The solvent was removed and the residue purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to give diethyl 2-(4-pyridylmethyl)-2-acetamidomalonate.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:24](I)([CH3:26])[CH3:25]>C(#N)C.O>[CH:24]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH2:5][CH2:6]1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: O=c1[nH]cc(C2=CCNCC2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)N1CC=C(c2c[nH]c(=O)c3ccccc23)CC1
Temperature: 40 °C

Procedure:
4-(1,2,3,6-Tetrahydropyridin-4-yl)-2H-isoquinolin-1-one (0.4 g) obtained in Example 205 and potassium carbonate (1 g) were suspended in acetonitrile (10 mL) and water (1 mL), and isopropyl iodide (0.35 mL) was added at room temperature. The mixture was stirred under heating overnight at 40° C. After the completion of the reaction, the solvent was evaporated. Aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography (NH silica gel, Fuji Silysia Chemical Ltd.). The fraction eluted with chloroform:methanol=25:1 was concentrated, and the precipitated crystals were collected by filtration to give 4-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-isoquinolin-1-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:14](=[O:15])[NH:13][C:12]3[N:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2(=[O:21])=[O:20])=[N:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25][N:13]1[C:12]2[N:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10](=[O:20])(=[O:21])[N:9]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=2)[C:14]1=[O:15]
Reactant: COc1cc(F)c(CBr)c(F)c1
Reactant: Cc1ccc(N2C(=O)Nc3ncccc3S2(=O)=O)nc1C
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(C)c(C)n3)S(=O)(=O)c3cccnc32)c(F)c1
Yield: 66.7 %

Procedure:
The title compound (182 mg, 0.40 mmol) was prepared from 2-(5,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (IntF1) (181 mg, 0.60 mmol), 2,6-difluoro-4-methoxybenzyl bromide (169 mg, 0.71 mmol) and K2CO3 (123 mg, 0.89 mmol) in DMF (3 mL) using the methods of (115).
Reaction SMILES: [C:1]([N:6]([CH2:8][C:9]([NH2:11])=[S:10])[CH3:7])([O:3][CH2:4][CH3:5])=[O:2].Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[C:1]([N:6]([CH2:8][C:9]1[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1)[CH3:7])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOC(=O)N(C)CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(CN(C)C(=O)OCC)n1

Procedure:
To a solution of (N-carbethoxy-N-methylamino)thioacetamide (30.7 g; 0.17 mole) [prepared in Step B] in 180 ml of absolute ethanol was added a solution of ethyl bromopyruvate (25.0 ml; 0.20 mole) in 130 ml of absolute ethanol. The reaction mixture was heated at reflux temperature for 17 hours and then evaporated under reduced pressure, and the residue was partitioned between ether and water. The organic layer was washed with water and saturated sodium chloride solution, dried, filtered and evaporated under reduced pressure to give an oil which was placed on silica gel and chromatographed using diethyl ether as the eluting solvent. The appropriate fractions yielded the title compound as an oil; TLC [Silica/CH2Cl2 :CH3CN (85:15)] gave Rf=0.50. The NMR spectrum (60 MHz) in d6 dimethyl sulfoxide gave the following resonances δ: 8.49 (s, 1H); 4.79 (s, 2H); 4.23 (m, 4H); 3.00 (s, 3H); 1.30 (q, 6H).
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:29])=[C:18]([CH2:20][NH:21][C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH:19]=1)(OC(C)(C)C)=O.Cl.Cl.CCOCC.CO>O>[ClH:29].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:29])=[C:18]([CH2:20][NH:21][C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)c2ccco2)c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: O=C(NCc1cc(OC[C@@H]2CCN2)cnc1Cl)c1ccco1
Yield: 64 %

Procedure:
The product of step 213a (0.20 g, 0.50 mmol) was deprotected and isolated as the free base in 64% yield according to the procedure of Example 20b, followed by conversion to the hydrochloride with HCl/Et2O. [α]D23 +21.67 (c 0.7, MeOH); 1H NMR (D2O, 300 MHz) δ 2.66 (dd, J=8.5, 16.5 Hz, 2H), 4.02-4.17 (m, 2H), 4.42 (d, J=4.0 Hz, 2H), 4.64 (s, 2H), 4.88 (m, 1H), 6.68 (dd, J=1.5, 5.5 Hz, 1H), 7.23 (dd, J=1.0, 3.5 Hz, 1H), 7.52 (d, J=3.0 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H); MS (CI/NH3) m/z 322 (M+H)+. Anal. Calcd for C15H16ClN3O3.1.2 HCl.0.2 H2O: C, 48.81; H, 4.81; N, 11.38. Found: C, 48.70; H, 4.76; N, 11.03.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:28][CH:17]2[C:18]3[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[CH:22][C:23]=3[C:24](=O)[CH:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:7]([N:14]1[CH2:15][CH:16]2[C:24](=[CH2:1])[C:23]3[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[CH:19][C:18]=3[CH:17]2[CH2:28]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1c2ccc(OC)cc2C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (18.1 g, 50.7 mmol) and potassium tert-butoxide (5.7 g, 50.7) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.9 g, 33.8 mmol) in anhydrous ether (68 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (200 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 8.1 g (82%−two steps) of the subtitle compound. MS calculated for C20H21NO+H: 292, observed: 292.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[C:10]([CH2:11][N:12]2[CH:16]=[C:15]([C:17]([NH:19][NH2:20])=[O:18])[CH:14]=[N:13]2)=[C:9]([CH3:21])[O:8][N:7]=1>C(O)(=O)C>[CH3:5][C:6]1[C:10]([CH2:11][N:12]2[CH:16]=[C:15]([C:17]([N:19]=[N+:20]=[N-:1])=[O:18])[CH:14]=[N:13]2)=[C:9]([CH3:21])[O:8][N:7]=1
Reactant: O=N[O-]
Reactant: Cc1noc(C)c1Cn1cc(C(=O)NN)cn1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1noc(C)c1Cn1cc(C(=O)N=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
Sodium nitrite (450 mg, 6.5 mmol, in H2O) (10 mL) was added dropwise, over 10 minutes, to a suspension of 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbohydrazide (example 10-1b) (1 g, 4.3 mmol) in 10% aqueous acetic acid (50 mL) and cooled to 0° C. via an ice water bath. The reaction was stirred for an additional 15 minutes then extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were washed with aqueous saturated sodium carbonate (100 mL) followed by H2O (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The solid product was triturated with ethyl acetate/hexanes (1/9) and dried en vacuo to afford 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbonyl azide (1 g, 93%) as a white solid. 1H NMR (CDCl3, 400 MHz)): δ2.20 (s, 3H), 2.44 (s, 3H), 5.07 (s, 2H), 7.81 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.CO.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]2=O)=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH:36]([N:20]3[CH2:21][CH2:22][C@@H:18]([NH:17][C:2](=[O:1])[CH2:3][NH:4][C:5](=[O:16])[C:6]4[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:14])([F:15])[F:13])[CH:7]=4)[CH2:19]3)[CH2:35][CH2:34]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(N2CCCCC2=O)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (306 mg, 0.97 mmol; prepared according to WO2004/050024A2) in methanol (757 μL, 1.87 mmol) at room temperature was added 1-(6-methoxypyridin-3-yl)piperidinone (200 mg, 0.971 mmol) followed by sodium triacetoxyborohydride (247 mg, 1.16 mmol); the reaction mixture was stirred for 16 hours. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (465 mg, 95%) as a white solid. 1H-NMR (CD3OD) δ: 1.59-1.86 (m, 3H), 2.00-2.14 (m, 2H), 2.21-2.48 (m, 2H), 2.64-2.84 (m, 4H), 2.95-3.10 (m, 2H), 3.26-3.38 (m, 2H), 3.49-3.60 (m, 2H), 3.84 (s, 3H), 4.03 (s, 2H), 4.36-4.48 (m, 1H), 6.73 (d, J=9.3 Hz, 1H), 7.46 (dd, J=9.0, 3.0 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 8.14 (d, J=8.1 Hz 1H), 8.22 (s, 1H). MS m/z: 506 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH:32][C:10]([C:7]1[CH:6]=[C:5]([CH2:4][C:3]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c2ccc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Yield: 62.7 %

Procedure:
A solution of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.080 g, 0.334 mmol), 2-(5-chloro-2-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.090 g; 0.368 mmol), HATU (0.127 g; 0.334 mmol) and N,N-diisopropylethylamine (0.144 mL; 0.836 mmol) in DMF (5 mL), was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and a solution of sodium hydrogen sulfate. The organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.090 g (62%) of the title compound as a pink solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl>O>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: ClCCCCCCCl
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)NC(=O)N(CCCCCCCl)C1=O
Reaction time: 0.42 h

Procedure:
128 g of 5,5-dimethyl-hydantoin (1.0 mol), 69 g of anhydrous potassium carbonate (0.5 mol) and 775 g of 1,6-dichlorohexane are reacted at 132°-150° C internal temperature (external temperature 160° C) and the resulting water of reaction is removed continuously by azeotropic circulatory distillation. After 6 hours 25 minutes, the reaction is complete and the reaction mixture is filtered hot to remove the potassium chloride formed. The filtrate is concentrated on a rotary evaporator and dried to constant weight at 100° C and 10-1 mm Hg.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][N:7]=1.[S:16]([O:21]C)([O:19][CH3:20])(=[O:18])=[O:17]>C(OCC)(=O)C>[CH3:20][O:19][S:16]([O-:21])(=[O:18])=[O:17].[CH3:1][N+:2]([CH3:20])([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][N:7]=1
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])cn1
Reactant: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COS(=O)(=O)[O-]
Product: C[N+](C)(C)CCOc1ccc([N+](=O)[O-])cn1

Procedure:
4.4 g (21 mol) of the compound from Step 12.1 was dissolved in 50 mL of ethyl acetate and to the resulting mixture was added 2.65 g (21 mmol) of dimethyl sulfate over a period of 5 min with agitation. A precipitate was formed as a result of a slightly exothermic reaction. The mixture was allowed to agitate for an additional hour after which it was suction-filtered. The filter cake was then washed with ethyl acetate and dried at 40° C. under vacuum which gave 6.5 g (92% of the theoretical) of colorless crystals.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C@H:17]3[C@H:15]([O:16]3)[C@H:14]([CH3:18])[C@H:13]([OH:19])[C@@H:12]([CH3:20])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[Si:29](OS(C(F)(F)F)(=O)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CO>C(Cl)Cl>[C:1]1([S:7]([C:10]2[C@H:17]3[C@H:15]([O:16]3)[C@H:14]([CH3:18])[C@H:13]([O:19][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@@H:12]([CH3:20])[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=C(S(=O)(=O)c2ccccc2)[C@@H]2O[C@H]12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: C[C@H]1[C@H]2O[C@H]2C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Yield: 95.6 %

Procedure:
A mixture of alcohol α36 (62 mg, 0.21 mmol) and 2,6-lutidine (50 μL, 0.43 mmol) in CH2Cl2 (2 mL) was cooled to −78° C., and 63 μL (0.27 mmol) of TBSOTf was added. The stirred cold solution was warmed to 0° C. over 5 h. MeOH (40 μL, 1 mmol) was then added to quench the excess TBSOTf. The resulting mixture was concentrated via rotary evaporation, and the crude residue was purified by flash column chromatography (EtOAc/hexanes; 1:5) to afford 82 mg (95%) of α37 as a white solid. mp 89.0-90.0° C.; [α]20D=−30.5 (c=0.61, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.93-7.97 (m, 2H), 7.55-7.70 (m, 3H), 7.09 (d, J=5.1 Hz, 1H), 3.70 (dd, J=8.4 Hz, 2.1 Hz, 1H), 3.67 (d, J=4.8 Hz, 1H), 3.37 (dd, J=7.2 Hz, 4.2 Hz, 1H), 2.60 (m, 1H), 2.49 (m, 1H), 1.26 (d, J=7.2 Hz, 3H), 0.90 (s, 9H), 0.74 (d, J=7.2 Hz, 3H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 146.0, 140.2, 136.1, 133.7, 129.3, 128.4, 74.5, 56.8, 48.7, 40.9, 36.9, 25.9, 18.4, 18.1, 9.7, −4.3, −4.4; Analytical. Calculated for C21H32O4S: C, 61.72; H, 7.89. Found: C, 61.39; H, 7.59.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F-:21].[K+].C(O)CO>O>[F:21][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [F-]
Reactant: CCOC(=O)C(Br)c1ccc(C2CCCCC2)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: CCOC(=O)C(F)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 118 g. (0.33 moles) of ethyl α-bromo-3-chloro-4-cyclohexylphenylacetate is vigorously stirred at 130°-140° C with 29 g. (0.5 moles) of potassium fluoride in 100 ml. of ethylene glycol for 12 hours. The reaction mixture is cooled and 400 ml. of water is added and the crude product separates. The aqueous glycol mixture is extracted with ether, the ether is then dried, evaporated to dryness and upon distillation results in ethyl α-fluoro-3-chloro-4-cyclohexylphenylacetate.