Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].[CH3:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[CH3:24])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O
Reaction time: 1.67 h
Yield: 29.5 %

Procedure:
500 mg of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine was dissolved in 5 ml of dry pyridine, and the resulting solution was cooled with ice. To the solution was added 710 mg of 2-methylbenzoyl chloride, and the mixture was allowed to stand at room temperature for 100 minutes. The same procedure as in Example 1 gave 200 mg (yield: 29.5%) of 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)uridine as crystals having a melting point of 108° to 109° C. This was identical with the crystals obtained in Example 1 by the mixed examination.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6]>S(Cl)(Cl)=O>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([Cl:1])=[O:6]
Reactant: CC(C)N1CCC(Oc2ccc(C(=O)O)c(Cl)c2)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CC(C)N1CCC(Oc2ccc(C(=O)Cl)c(Cl)c2)CC1
Yield: 199 %

Procedure:
2-Chloro-4-[(1-isopropyl-4-piperidinyl)oxy]benzoic acid hydrochloride (D32) (0.20 g) was dissolved in thionyl chloride (10 ml) and heated under reflux for 1.5 h. The thionyl chloride was removed by evaporation and the residue was evaporated from DCM (3×10 ml) to give the title compound (D33) (0.21 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32]([C:31]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=2)=[CH:27][C:26]=1[Cl:25])=[O:33]
Reactant: COc1ccc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)cn1
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 150, step 2, 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 175, step 3) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=514.4 [M+H+].
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:31]=3[C:30]([F:29])([F:43])[F:44])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(C(F)(F)F)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,4-bis-trifluoromethyl-benzaldehyde. MS (ESI) m/z 602.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[O:19]1[C:23]2([CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.Br[CH2:32][CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.O1CCCC1>[CH2:35]([O:34][CH2:33][CH2:32][C:26]1([C:29]#[N:30])[CH2:27][CH2:28][C:23]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:24][CH2:25]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N#CC1CCC2(CC1)OCCO2
Reactant: BrCCOCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CC1(CCOCc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 8 mL of a tetrahydrofuran solution containing 0.94 mL of diisopropylamine, 4.5 mL of 1.6 mol/L butyllithium/hexane was added dropwise at −78° C., the mixture was stirred at the same temperature for 1 hour, and then thereto was added dropwise 7 mL of a tetrahydrofuran solution containing 0.60 g of 1,4-dioxaspiro[4.5]decane-8-carbonitrile. After stirring at −78° C. for 1 hour, the mixture was added dropwise with 0.85 mL of benzyl 2-bromoethyl ether, and further stirred for 1 hour. The temperature of the reaction mixture was increased to room temperature, and then a 10% aqueous citric acid solution and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=6:1] to obtain 1.1 g of a colorless oily substance, 8-(2-(benzyloxy)ethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile.
Reaction SMILES: [Cl-].[Li+].[CH3:3][N:4]1[C@H:13]2[C@@:8]([CH3:19])([C:9]3[CH:17]=[CH:16][C:15](Br)=[CH:14][C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6][C:5]1=[O:20].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Li].C([Li])CCC.[CH3:38][S:39]SC>O1CCCC1>[CH3:3][N:4]1[C@H:13]2[C@@:8]([CH3:19])([C:9]3[CH:17]=[CH:16][C:15]([S:39][CH3:38])=[CH:14][C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6][C:5]1=[O:20]
Reactant: CSSC
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 1140.9 %

Procedure:
Lithium chloride (1.80 grams, 2.46 mmole; 10 equivalents) was rapidly weighed and placed in a 500 ml flask equipped with mechanical stirring, pressure equalizing addition funnel, thermocouple, injection septum and nitrogen inlet. (+)-(4aR)-(10bR)-4-Methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (13.09 grams, 2.46 mmole; 1.0 equivalents) and 100 mL of dry tetrahydrofuran were added and stirred until dissolved (10-15 minutes.). Then, 46.71 mL of lithium hexamethyldisilazide (LiN(TMS)2, 46.71 mmole; 1.1 equivalents) in tetrahydrofuran was added via syringe over 40 minutes (1 degree exotherm). A clear yellow solution resulted and was stirred at room temperature for 1 hour. Methyllithium (1.4M in diethyl ether; 33.36 mL; 46.71 mmole; 1.1 equivalents) was added dropwise via syringe over 50 minutes. Gas evolution was observed and the reaction was exothermic from 23 to 26 degrees. The exothermic reaction was controlled using standard procedures. The reaction mixture was allowed to stir at room temperature for 45 minutes and was then cooled to -70° C. n-butyllithium (1.6M in hexane; 29.2 mL; 46.71 mmole; 1.1 equivalents) was added via syringe over 25 minutes while the reaction temperature was maintained at -71/-70° C. The remaining yellow solution was maintained at -70° C. and stirred for 35 minutes. High pressure liquid chromatography showed nearly complete dianion formation after 15 minutes. Dimethyldisulfide (4.00 grams; 42.46 mmole; 1.0 equivalents) was dissolved in 25 mL of tetrahydrofuran and added over 50 minutes. The mixture was stirred for 30 minutes (-70° C.). High pressure liquid chromatography showed the reaction was complete after 10 minutes. The mixture was quenched with 1N hydrochloric acid (100 mL, -70° C). The reaction was warmed to room temperature and the aqueous layer was extracted with 200 mL of methyl t-butyl ether. The organic layers were combined and washed with 50 mL. of brine. The organic layers were dried over magnesium sulfate and filtered and concentrated on rotovap™@35° C. and house-vac. A white solid formed as the volume decreased. The organics were concentrated from 550 mL to approximately 30-40 mL. of a white slurry. The slurry was stirred at room temperature for a few hours followed by filtration with small portions of methyl t-butyl ether until the washes were colorless. The white solid was dried and afforded 7.73 grams (66%) of (+)-(4aR)-(10bR)-4-methyl-8-methylthio-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.
Reaction SMILES: C(O)C.C([O:6][C:7](=O)[CH:8]([CH3:23])[CH:9]([N:11]([C:15]1[C:20]([NH2:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=1)[CH:12]1[CH2:14][CH2:13]1)[CH3:10])C>C(O)(=O)C>[Cl:22][C:17]1[N:18]=[CH:19][C:20]2[NH:21][C:7](=[O:6])[CH:8]([CH3:23])[CH:9]([CH3:10])[N:11]([CH:12]3[CH2:14][CH2:13]3)[C:15]=2[N:16]=1
Reactant: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1N)C1CC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1C(=O)Nc2cnc(Cl)nc2N(C2CC2)C1C
Yield: 89.1 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 0.616 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopropyl-amino]-2-methyl-butyric acid ethyl ester (V-46), prepared in the previous step, was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, water and then dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 0.468 g of (rac)-2-chloro-9-cyclopropyl-7,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-46).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[F:10][C:11]1([F:23])[O:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:19](B(O)O)[C:13]=2[O:12]1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:11]1([F:10])[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[C:16]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=3)[C:14]=2[O:15]1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Reactant: CSc1nccc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nccc(-c2cccc3c2OC(F)(F)O3)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
4-Iodo-2-methylsulfanyl-pyrimidine (453 mg, 1.79 mmol), 2,2-difluoro-benzo[1,3]dioxole-4-boronic acid (727 mg, 3.59 mmol), Na2CO3 (380 mg, 3.59 mmol), 2-(dicyclohexylphosphino)biphenyl (125 mg, 0.36 mmol) were suspended in degassed DME-water solution (5-1, 6.5 ml). After bubbling N2 into the mixture for 20 minutes, Pd(PPh3)4 (413 mg, 0.36 mmol) was added and the mixture was stirred at 90° C. for 3 hours. The solvent was evaporated under vacuum and the crude was dissolved in DCM and washed with water and brine. The organic phase was dried (Na2SO4) and evaporated; the crude was purified by flash chromatography with hexane-ethyl acetate (8-2) to give the title compound (326 mg, 65% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (80 mg, 0.1886 mmol), 4-dimethylaminopyridine (12 mg, 0.0983 mmol) and piperidine (32 mg, 0.3764 mmol) were dissolved in methylene chloride (10 ml), WSC-HCl (109 mg, 0.5685 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (45 mg, 0.0918 mmol, 49%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([C:23]([C:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][C:26]=3[CH2:34][CH2:35][CH2:36][CH3:37])=[O:24])[CH3:22])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[Br:38].O.Cl>CO>[Br:38][C:9]1[CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][N:21]([C:23]([C:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][C:26]=3[CH2:34][CH2:35][CH2:36][CH3:37])=[O:24])[CH3:22])=[CH:18][CH:19]=2)[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]([OH:39])=[O:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OCC(=O)OC)c(Br)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OCC(=O)O)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
1 N NaOH (2.14 mL, 2.14 mmol) was added under nitrogen to a solution of methyl[(3-bromo-4′-{[[(2-butyl-1-benzofuran-3-yl)carbonyl](methyl)amino]methyl}-1,1′-biphenyl-4-yl)oxy]acetate (1.00 g, 1.78 mmol), prepared in the previous step, in 50 mL of methanol plus 5 mL of water at room temperature. After the addition the reaction was stirred at room temperature for 4 h. The reaction was acidified by the addition of 2.5 mL of 1 N HCl and then concentrated under reduced pressure to remove most of the methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (932 mg, 100%) as a light brown solid, mp 72-78° C. Elemental Analysis for C29H28BrNO5.0.15 H2O. Calc'd: C, 62.97; H, 5.16; N, 2.53. Found: C, 62.71; H, 5.19; N, 2.39
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9]([OH:11])=[O:10])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]1[CH2:19][C:20]1[CH:21]=[C:22]([Br:33])[CH:23]=[C:24]2[C:28]=1[N:27]([CH3:29])[C:26](=[O:30])[C:25]2(Br)Br>C(O)(=O)C.[Zn]>[Br:33][C:22]1[CH:23]=[C:24]2[C:28](=[C:20]([CH2:19][N:3]3[C:4]4[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=4[N:6]([CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9]([OH:11])=[O:10])[C:2]3=[O:1])[CH:21]=1)[N:27]([CH3:29])[C:26](=[O:30])[CH2:25]2
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2N(C)C(=O)C3(Br)Br)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2N(C)C(=O)C3)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of 3-[2-Oxo-3-(3,3,5-tribromo-1-methyl-2-oxo-2,3-dihydro-1H-indol-7-ylmethyl)-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (20 mg, 0.031 mmol) in acetic acid (5 mL) was added Zinc powder (10 mg, 0.16 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes. The mixture was filtered and the filtrate was concentrated. The residue was cool in an ice bath and water was added. The solid that precipitate out from the solution was collected by filtration and was washed with water. The white solid was dried in an oven and was confirmed to be the desirable product (8.9 mg, 59%). LCMS (ESMS): m/z 488.12 (M+H+).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][O:10][CH3:11].CCN(CC)CC.[N-:27]=[N+:28]=[N-:29].[Na+]>C(Cl)Cl.CCOC(C)=O>[N:27]([CH2:7][C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][O:10][CH3:11])=[N+:28]=[N-:29]
Reactant: COC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Methanesulfonyl chloride (4.0 g, 35 mmol) in DCM (50 mL) was slowly added to a solution of (R)-tert-butyl 1-hydroxy-3-methoxypropan-2-ylcarbamate (6.0 g, 29 mmol) and Et3N (3.64 g, 36 mmol) in DCM (150 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The organic phase was washed with water and saturated aq NaHCO3, concentrated, and dissolved in DMF. Sodium azide (2.34 g, 36.0 mmol) was added, and the reaction mixture was stirred at 75° C. for 4 h. The reaction mixture was diluted by EtOAc and washed with water. The crude product was purified by column chromatography on silica gel eluting with EtOAc and petroleum ether (EtOAc/PE=2/1) to give the title compound (4.3 g, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 4.92 (s, 1H), 3.91 (m, 1H), 3.53-3.48 (m, 2H), 3.45-3.40 (m, 2H), 3.38 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[Mg].II.[O:15]=[C:16]([CH3:22])[CH2:17][CH2:18][CH2:19][C:20]#[N:21].Cl>O1CCCC1.O>[OH:15][C:16]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1)([CH3:22])[CH2:17][CH2:18][CH2:19][C:20]#[N:21]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CC(=O)CCCC#N
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(CCCC#N)c1cccc(C(F)(F)F)c1
Temperature: 35 °C
Yield: 49 %

Procedure:
A mixture of 7.0 mL (0.05 mole) of 3-trifluoromethylphenyl bromide, 1.2 grams (0.05 mole) of magnesium and a crystal of iodine in about 70 mL of tetrahydrofuran was warmed to 35° C. to initiate the formation of the Grignard reagent. Upon formation of the Grignard reagent, the reaction mixture was cooled to ambient temperature and, with stirring, a solution of 5.8 mL (0.05 mole) of 5-oxohexanenitrile in 10 mL of tetrahydrofuran was added dropwise. The reaction mixture temperature increased to about 35° C., at which time the rate of addition was slowed to keep the reaction mixture temperature at about 35°-40° C. The complete addition required about 15 minutes. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for 2 hours. After this time, the reaction mixture was poured into 200 mL of water and was acidified with aqueous 2N hydrochloric acid. The mixture was then extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.3 grams of 5-hydroxy-5-(3 -trifluoromethylphenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37].C(N(CC)C(C)C)(C)C.CO>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:14][CH2:15][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(Cl)c(Cl)c4)CCCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 36 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)piperidine (0.71 g, 1.32 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.38 g, 1.32 mmol), and N,N-diisopropylethylamine (0.37 g, 2.9 mmol) in acetonitrile (15 mL). Heat to reflux. After 36 hours, partition the residue between ethyl acetate and saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 15% methanol/2% triethylamine/ethyl acetate to give the title compound. Elemental Analysis calculated for C39H49Cl2N5O5: C 63.40; H 6.68; N 9.48; Found: C 63.68; H 6.69; N 9.57.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C@@H:11]([CH2:14][OH:15])[O:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:15][CH2:14][C@H:11]2[O:10][C:9]3[CH:16]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc2c(c1)O[C@H](CO)CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Yield: 87.5 %

Procedure:
Preparation according to Preparation 5 using [[(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (2.1 g, 8.6 mmol), p-toluenesulfonyl chloride (2.5 g, 12.8 mmol), TEA (1.8 ml, 12.8 mmol) and 4-DMAP (1.0 g, 8.6 mmol) and DCM (dry, 20 ml). DCM (50 ml) was added and the solution was washed with HCl (100 ml, 1 N), water (100 ml) and brine (100 ml) and was evaporated to dryness to give the title compound (3.0 g). MS m/z (rel. intensity, 70 eV) 398 (M+, 49), 226 (bp), 225 (24), 213 (30), 91 (68).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:7]2[C:8]3[CH:9]=[CH:10][NH:11][C:12]=3[CH:13]=[CH:14][C:6]=2[CH2:5][CH2:4]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC([O-])(C)C.[K+]>C1COCC1>[CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:7]2[C:8]3[CH:9]=[CH:10][N:11]([S:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:25])=[O:24])[C:12]=3[CH:13]=[CH:14][C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C1CCc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C1CCc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine (32 mg, 0.2 mmol) in THF is treated with benzenesulfonyl chloride (29.1 mg, 0.22 mmol) followed by KOtBu (19.8 mg, 0.22 mmol), stirred at room temperature for 18 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson preparative HPLC1 to give the title compound, [M+H] 369, retention time (RT) 2.067 minutes. 1Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.