Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].ClC1C=C(C2(CC[N+:34]34[CH2:41][CH2:40][C:37]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)([CH2:38][CH2:39]3)[CH2:36][CH2:35]4)CN(CC3C=C(C(F)(F)F)C=C(C(F)(F)F)C=3)C(=O)N2C)C=CC=1Cl>CN(C=O)C>[C:42]1([C:37]23[CH2:40][CH2:41][N:34]([CH2:35][CH2:36]2)[CH2:39][CH2:38]3)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1(CC[N+]12CCC(c3ccccc3)(CC1)CC2)c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: c1ccc(C23CCN(CC2)CC3)cc1

Procedure:
4-(3,4-Dichlorophenyl)-4-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-methyl-1-[3,5-bis(trifluoromethyl)benzyl]imidazolidin-2-one chloride A mixture of the compound obtained in the previous step and 0.35 g of 4-phenyl-1-azabicyclo[2.2.2]-octane in 1 ml of DMF is heated at 80° C. for 3 hours. After cooling to RT, the reaction mixture is poured into a mixture of 50 ml of water, 50 ml of DCM and 3 ml of concentrated HCl and stirred for 5 minutes. The precipitate formed is wrung, washed with water, with DCM and then with ether and dried to give 0.3 g of the expected product. M.p.=290 C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH2:16])[CH3:15].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH:16][CH2:23][C:21]1[S:22][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH3:15]
Reactant: CC(N)COc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)s1
Product: CC(COc1ccc2ccccc2c1Cl)NCc1ccc(Cl)s1
Yield: 61 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]propan-2-amine and 5-chlorothiophen-2-carbaldehyde in 61% yield as a slightly white oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:32])[CH2:22][CH2:23][S:24][CH2:25][C:26]1[N:27]=[C:28]([NH2:31])[S:29][CH:30]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:32])[CH2:22][CH2:23][S:24][CH2:25][C:26]1[N:27]=[C:28]([NH:31][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[S:29][CH:30]=1)[CH3:19]
Reactant: CCOC(=O)CCSCc1csc(N)n1
Reactant: CC(C)Oc1cc(OC(C)C)cc(C(=O)O)c1
Product: CCOC(=O)CCSCc1csc(NC(=O)c2cc(OC(C)C)cc(OC(C)C)c2)n1

Procedure:
3-[2-(3,5-Diisopropoxy-benzoylamino)-thiazol-4-ylmethylsulfanyl]-propionic acid ethyl ester was prepared from 3,5-diisopropoxy-benzoic acid and 3-(2-amino-thiazol-4-ylmethylsulfanyl)-propionic acid ethyl ester following general procedure A.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[CH2:19][C@H:18]2[C:20]([O:22]CC)=[O:21])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C@@H:17]2[CH2:19][C@H:18]2[C:20]([OH:22])=[O:21])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
4N NaOH solution (4 L) was added to a solution of (trans)-ethyl 2-(4-(benzyloxy)phenyl)cyclopropanecarboxylate (Intermediate R, 250 g, 0.844 mol) in Methanol (1.2 L) at 0° C. and stirred at RT for 4 h. After completion, the solvent was evaporated, the residue was diluted with water (1 L), acidified with 4 N HCl solution, extracted with EtOAc (2×2 L). Combined organic extracts were washed with water (1 L), brine (1 L), dried over anhydrous Na2SO4, filtered and evaporated to afford (trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarboxylic acid (190 g, 84%) as off white solid. The crude was carried to next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(N(C(C)C)C(C)C)C.[CH2:14]=[C:15]([CH2:18][CH3:19])[CH2:16][OH:17]>C1COCC1>[CH3:1][O:2][CH2:3][O:17][CH2:16][C:15]([CH2:18][CH3:19])=[CH2:14]
Reactant: C=C(CC)CO
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=C(CC)COCOC
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.4 %

Procedure:
Chloromethyl methyl ether (103.4 ml, 1363 mmol) and N-ethyldiisopropylamine (247.2 ml, 1419 mmol) were added to a solution of 2-methylene-1-butanol (65.1 g, 757 mmol) prepared in Reference Example 205 in THF (750 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, and the mixture was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford 2-methoxymethoxymethyl-1-butene (98 g, quantitative) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccc(F)cc3)c12

Procedure:
The title compound, light brown solid (54 mg, 69%), MS (ISP) m/z=313.2 [(M+H)+], mp 239.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3](C#N)=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][CH:7]=1.[C:21](=[O:24])([O-])[O-:22].[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([C:21]([OH:22])=[O:24])=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
3-chloro-2-cyano-6-[3-(trifluoromethyl)phenoxy] pyridine (2.58 g, 0.086 mol) was dissolved in 30 ml of 90% sulfuric acid. The obtained solution was heated and stirred at 120° C. for 1.5 hours. Thereafter, the obtained reaction solution was poured into ice water, and then mixed with sodium carbonate to form a weak-acidic solution, thereby precipitating solids. The precipitated solids were filtered out, washed with water, and then dried.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][NH:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:15]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[CH2:16].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:15][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Clc1ccc2[nH]c3c(c2c1)CNCC3
Reactant: C=Cc1ccc2ccccc2n1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Clc1ccc2[nH]c3c(c2c1)CN(CCc1ccc2ccccc2n1)CC3

Procedure:
The title compound was prepared following the procedure of Example 2 with the exception that 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was used instead of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 2-vinylquinoline was used instead of 2-vinylpyridine. The product was converted to the dihydrochloride salt; mp 187°-190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:13]([C:23]#[N:24])=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)[O:31][C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=O)[O:27]1>>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[C:13]([C:23]#[N:24])=[CH:12][N:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:1][C:28](=[O:27])[CH2:29][C:30]([C:32]3[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[CH:33]=3)=[O:31])[CH:3]=2)[CH:15]=1
Reactant: N#Cc1cn(-c2ccc([N+](=O)[O-])c(N)c2)cc1-c1ccccc1Cl
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cc(C#N)c(-c4ccccc4Cl)c3)ccc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-(3-amino-4-nitro-phenyl)-4-(2-chloro-phenyl)-1H-pyrrole-3-carbonitrile (Example E2) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as an orange-brown solid (203 mg).
Reaction SMILES: [Li].[F:2][CH:3]([F:22])[O:4][C:5]1[CH:6]=[C:7]([C:12]([O-])=[CH:13][C:14](=O)[C:15]([O:17]CC)=[O:16])[CH:8]=[C:9]([F:11])[CH:10]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][NH2:53])[CH:47]=1>>[F:11][C:9]1[CH:8]=[C:7]([C:12]2[N:52]([C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)[N:53]=[C:14]([C:15]([OH:17])=[O:16])[CH:13]=2)[CH:6]=[C:5]([O:4][CH:3]([F:2])[F:22])[CH:10]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(F)cc(OC(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(F)cc(OC(F)F)c2)n(-c2cccnc2)n1

Procedure:
590 mg (1.01 mmol) of the compound of Example 7A is reacted analogously to the synthesis of the compound of Example 20A with 161 mg (1.11 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 150 mg (43% of theory) of the title compound is obtained.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4]([Br:13])=[CH:5][C:6](Br)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].O=O.Cl>[Cu-]=O.C(OCC)(=O)C>[Br:13][C:4]1[CH:5]=[C:6]([NH2:1])[C:7](=[CH:11][C:3]=1[Cl:2])[C:8]([OH:10])=[O:9]
Reactant: N
Reactant: O=C(O)c1cc(Cl)c(Br)cc1Br
Agent: O=[Cu-]
Agent: Cl
Agent: O=O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)c(Cl)cc1C(=O)O
Reaction time: 0.67 h
Yield: 96.2 %

Procedure:
2.8 g (0.0196 mol) of copper(I) oxide are suspended in 120 ml (corresponding to 1.6 mol of NH3) of 25% aqueous ammonia solution under nitrogen. To this is added dropwise, at 25° C. with stirring and over the course of 40 minutes, a suspension of 63.2 g (0.2 mol) of 5-chloro-2,4-dibromobenzoic acid, 160 ml (corresponding to 2.14 mol of NH3) of 25% strength aqueous ammonia solution and 180 ml of ethyl acetate, with the exclusion of oxygen. The temperature rises to about 35° C. during the addition. Stirring is continued for 21/4 hours at30° C. Finally, 11.6 g (0.04 mol) of ethylenediaminetetraacetic acidis added to the mixture and the pH is adjusted to 3.1 by acidifying with hydrochloric acid. The ethyl acetate is distilled off at 90° C., the suspension is stirred at room temperature, and the anthranilic acid isfiltered off under suction and washed. 48.2 g of 4-bromo-5-chloroanthranilic acid is obtained as a pale-brown powder, corresponding to 96.2% of theory relative to 5-chloro-2,4-dibromobenzoic acid.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:37]#[N:38])=[C:18]([O:19][CH:20]4[CH2:23][N:22](C(C5C=CC=CC=5)C5C=CC=CC=5)[CH2:21]4)[C:13]=3[C:12]3[CH:39]=[C:40]([C:43]4[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=4)[CH:41]=[N:42][C:11]2=3)(=O)=O)C=CC=CC=1.ClC(OC(Cl)C)=O>CO.C(Cl)Cl>[NH:22]1[CH2:21][CH:20]([O:19][C:18]2[C:13]3[C:12]4[CH:39]=[C:40]([C:43]5[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=5)[CH:41]=[N:42][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:37]#[N:38])[CH2:23]1
Reactant: Cn1cc(-c2cnc3c(c2)c2c(OC4CN(C(c5ccccc5)c5ccccc5)C4)c(C#N)ncc2n3S(=O)(=O)c2ccccc2)cn1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2cnc3[nH]c4cnc(C#N)c(OC5CNC5)c4c3c2)cn1
Temperature: 25 °C
Yield: 3.9 %

Procedure:
To a stirred solution of 9-benzenesulfonyl-5-(1-benzhydrylazetidin-3-yloxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (238 mg, 0.37 mmol) in methanol (10 mL) at 0° C. was added a solution of 1-chloroethyl chloroformate (120 μL, 1.1 mmol) in DCM (10 mL). The reaction mixture was allowed to warm to ambient temperature then heated at 40° C. for 4 h. The reaction was cooled to ambient temperature and then concentrated in vacuo. Purification of the residue by flash chromatography (silica, 11 g column, SPE NH2, 0-20% methanol in DCM) afforded the title compound as a white solid (5 mg, 5%). 1H NMR (CDCl3 plus CD3OD, 400 MHz): 8.85 (s, 1H), 8.74-8.69 (m, 2H), 8.08 (s, 1H), 7.93 (s, 1H), 5.73-5.64 (m, 1H), 4.19-4.05 (m, 4H), 4.01 (s, 3H). LCMS (Method G): RT=5.59 min, M+H+=346.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH:24]4[CH2:26][CH:25]4[C:27]([O:29][CH3:30])=[O:28])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CCOC(C)=O.CCCCCC>CO>[OH:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH:24]4[CH2:26][CH:25]4[C:27]([O:29][CH3:30])=[O:28])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C1CC1CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1CC1CCC12CCC(c3cccc(O)c3)(CC1)OC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of methyl 2-(2-(1-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropanecarboxylate (61A; 8.8 g, 21.2 mmol), and PPTS (1.07 g, 4.25 mmol) in MeOH (50 mL) was stirred at 50° C. for 3 h, then was cooled to rt and concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient with 0% to 30% EtOAc/hexane over 20 min to give methyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropanecarboxylate (racemate; 7.0 g, 21.2 mmol, 100% yield) as a white solid. LCMS [M+H]+=331.1; 1H NMR (CDCl3) δ: 7.18 (t, J=7.9 Hz, 1H), 6.99-6.86 (m, 2H), 6.69 (ddd, J=8.0, 2.6, 1.0 Hz, 1H), 5.32 (s, 1H), 3.82 (d, J=1.1 Hz, 2H), 3.69 (s, 3H), 2.07-1.95 (m, 4H), 1.71-1.57 (m, 4H), 1.45-1.14 (m, 7H), 0.73 (ddd, J=8.1, 6.3, 4.2 Hz, 1H). This racemate was separated by chiral preparative HPLC (Instrument=Berger Multigram II SFC; Column: CHIRALPAK® AD-H, 30×250 mm, 5μ; Mobile Phase: 20% MeOH/80% CO2; Flow Conditions: 85 mL/min, 150 Bar, 40° C.; Detector Wavelength: 220 nm; Injection Details: 1.0 mL of ˜150 mg/mL) to give Example 65A (2.35 g, 7.11 mmol, 45% yield; [α]=+60.6° (1.8% in DCM) @589 nm) and Example 65B (2.34 g, 7.08 mmol, 45% yield; [α]=−72.2° (1.0% in DCM) @589 nm) as oils.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=1.[H-].[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[N:15]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: c1ccc(-c2ccccc2Sc2nc3ccccc3[nH]2)nc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)n1c(Sc2ccccc2-c2ccccn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-[2-(2-Pyridyl)-phenyl thio]-1H-benzimidazole (0.825 mmole) in anhydrous dimethylformamide (15 ml) was treated under nitrogen with sodium hydride (0.90 mmole). The mixture was stirred for 20 minutes at room temperature, cooled to 5° and benzyl chloroformate (0.90 mmole) was added. The mixture was allowed to attain room temperature, then stirred for 18 hours after which it was poured into ice/water and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to an oil. The oil was flash chromatographed on silica gel using 10% ethyl acetate in dichloromethane as eluant to give the sub-title compound as a brown oil, MW 437 Base Peak 91.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.O=[C:22]1[CH2:27][CH:26]2[CH2:28][CH:23]1[CH2:24][CH:25]2[O:29][C:30](=[O:32])[CH3:31].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:22]3[CH2:27][CH:26]4[CH2:28][CH:23]3[CH2:24][CH:25]4[O:29][C:30](=[O:32])[CH3:31])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CC(=O)OC1CC2CC1CC2=O
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CC(=O)OC1CC2CC1CC2Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-acetic acid 5-oxo-bicyclo[2.2.1]hept-2-yl ester (prepared as in J. Meinwald et al., Tetrahedron 1962, 18, 815-820) using decaborane yielded a mixture of isomers of the title compound as a white foam. MS (ESI): m/z=431.4 [M+H]+.
Reaction SMILES: N(C(OC(C)C)=O)=N[C:3](OC(C)C)=O.[F:15][C:16]([F:58])([F:57])[C:17]1[CH:18]=[C:19]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[CH2:20][N:21]([C:45]1[N:46]=[N:47][NH:48][N:49]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:24]2[CH:36]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:38]([CH3:40])=[CH:39][C:23]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C1(C)C=CC=CC=1>[F:54][C:53]([F:56])([F:55])[C:51]1[CH:50]=[C:19]([CH:18]=[C:17]([C:16]([F:57])([F:15])[F:58])[CH:52]=1)[CH2:20][N:21]([C:45]1[N:46]=[N:47][N:48]([CH3:3])[N:49]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[C:24]2[CH:36]=[C:37]([C:41]([F:42])([F:43])[F:44])[C:38]([CH3:40])=[CH:39][C:23]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Add diisopropyl azodicarboxylate (0.56 mL, 3.94 mmol) to a solution of (S)-tert-butyl 5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.10 g, 3.29 mmol) and triphenylphosphine (1.03 g, 3.94 mmol) in methanol (0.20 mL, 4.94 mmol) and toluene (30 mL) at 0° C. under nitrogen. Warm the mixture to room temperature and stir for 12 h. Add silica gel, remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:3), to provide the title compound as a colorless oil (2.04 g, 95%). APCI MS m/z 653 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[NH:22][CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4.Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:22]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4
Reactant: BrCc1ccccc1
Reactant: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1ccccc1)CC3
Temperature: 50 °C
Yield: 87 %

Procedure:
To a stirred solution of 3-(3-chloropropyloxy)morphinan.HCl 54 (3 mg, 0.008 mmol) in dry DMF (0.15 mL) was added potassium carbonate (7 mg, 0.024 mmol), benzylbromide (2 μL, 0.032 mmol) sequentially and the mixture was stirred at 50° C. After starting material disappeared on TLC, solvent was concentrated and column chromatography gave 3 mg (87%) of the title compound: 1H NMR (300 MHz, CDCl3) δ7.15˜7.35 (5H, m); 7.05 (1H, d); 6.80 (1H, s); 6.73 (1H, d); 4.10 (2H, t); 3.55˜3.85 (4H, m); 3.05 (1H, m); 2.80 (1H, m); 2.56 (1H, m); 2.40 (1H, m); 2.00˜2.30 (4H, m); 1.00˜1.90 (10H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])=[CH:8][CH2:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C>CCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[C@H:7]([C@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])[CH2:8][CH2:9]2
Reactant: CC[C@H](C(=O)O)C1=CCc2cc(OC)ccc21
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CC[C@H](C(=O)O)[C@@H]1CCc2cc(OC)ccc21
Yield: 95 %

Procedure:
A solution of the product obtained in Example 3 (105 g, 453 mmol), ClRh(PPh3)3 (21.0 g, 5% eq.) and triethylamine (68.8 g, 679.5 mmol) in EtOH (945 mL) and THF (105 mL) was shaken in a 2-L pressure bottle under 60 psi H2 for 16 hours. The solvents were removed at a reduced pressure. The resulting mixture was stirred in 1.5 L of 1N HCl solution and 1.5 L CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined CH2Cl2 layers were washed with 1 L of 1N HCl solution and stirred with 1 L of 1N NaOH solution. The organic layer was extracted with 1N NaOH solution (2×0.5 L). The combined aqueous layer was washed with CH2Cl2 (2×250 mL), and acidified (pH 2.0–3.0) by a slow addition of conc. HCl solution at below 15° C. The acidic mixture was extracted with CH2Cl2 (2×1.5 L), and washed with water (2×0.5 L) until pH 5.0–6.0. After washing with brine and drying over anhydrous Na2SO4, solvent was evaporated under a reduced pressure. The product (101.0 g, 95% yield, 96.8% ee) was obtained as a light yellow oil. 1H NMR (DMSO-d6) δ12.20(s, 1H), 7.04(d, 1H), 6.78(d, 1H), 6.66(dd, 1H), 3.70(s, 3H), 3.28(m, 1H), 2.72(m, 2H), 2.32(m, 1H), 2.06(m, 1H), 1.80(m, 1H), 1.50(m, 1H), 1.36(m, 1H), 0.82(t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:17][OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[CH:36][O:35][N:34]=2)=[CH:29][CH:28]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCC[C@H]2CO)(=O)=O)=CC=1>>[O:35]1[CH:36]=[N:37][C:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][N:11]([C@@H:12]3[CH2:16][CH2:15][CH2:14][C@@H:13]3[CH2:17][OH:18])[S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:28][CH:29]=2)=[N:34]1
Reactant: O=S(=O)(N[C@@H]1CCC[C@@H]1CO)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ncon2)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCC[C@@H]1CO
Yield: 13.4 %

Procedure:
The title compound was synthesized from 4-chloro-N-(cis-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide 145 mg, 0.50 mmol), cesium carbonate (326 mg, 1.0 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (143 mg, 0.60 mmol) according to the procedure described for 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 2) to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(cis-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (30 mg, 13%). 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (1H, s), 8.04 (2H, d, J=8.31 Hz), 7.68-7.73 (2H, m), 7.40-7.46 (4H, m), 4.66 (1H, d, J=16.87 Hz), 4.38 (1H, d, J=16.87 Hz), 4.23 (1H, q, J=7.22 Hz), 3.55 (1H, dd, J=11.21, 7.18 Hz), 338 (1H, dd, J=11.33, 5.04 Hz), 2.13-2.28 (1H, m), 1.49-1.83 (5H, m), 1.19-1.29 (1H, m). LC/MS R.T.=2.15 min; [M+H]+=448.14. HRMS [M+H]+ calc'd 448.1098, found 448.1108.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:13]([CH2:15][C:16]([NH2:18])=[S:17])#[N:14]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:18]=[C:16]([CH2:15][C:13]#[N:14])[S:17][CH:2]=2)=[CH:6][CH:7]=1
Reactant: N#CCC(N)=S
Reactant: COc1ccc(C(=O)CBr)cc1
Product: COc1ccc(-c2csc(CC#N)n2)cc1
Yield: 75 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-methoxyphenyl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (1.5 g, yield 75%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.9 Hz, 2H), 7.35 (s, 1H), 6.98 (d, J=8.9 Hz, 2H), 4.17 (s, 2H), 3.86 (s, 3H). MS (ESI) m/z: Calculated for C12H10N2OS: 230.05. found: 231.2 (M+H)+.