Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C(Cl)=O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[NH2:18].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48].[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:50]([NH:49][C:47](=[O:48])[C:40]2[CH:41]=[CH:42][C:43]([O:45][CH3:46])=[CH:44][C:39]=2[O:38][CH3:37])=[S:51])[CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (53 mg, yield 63%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25]C(C)(C)[C:23](C)(C)[O:22]3)=[C:17](C=O)[CH:16]=2)[CH:7]=1)[CH3:4]>CO.C(Cl)Cl>[CH2:3]([O:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[B:21]([OH:25])[O:22][CH2:23][C:19]=3[CH:20]=2)[CH:7]=1)[CH3:4]
Reactant: CCOc1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ncc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOc1cc(Oc2ccc3c(c2)COB3O)ncc1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of NaBH4 (0.10 g, 2.6 mmol) in anhydrous methanol (20 mL) was added to a solution of 4-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (3.53 g, 8.95 mmol) in CH2Cl2 (80 mL) and stirred at room temperature for 5 minutes. Solid NaBH4 (0.58 g, 15.3 mmol) was then added portionwise over 30 minutes at room temperature. The reaction mixture was stirred for an additional 30 minutes, quenched by the addition 70% aqueous acetic acid (3 mL) then stirred for an additional 1 hour at room temperature. The reaction was concentrated and the residue purified by silica gel flash column chromatography (AcOH/MeOH/CH2Cl2 1:1:100 v/v/v) to give the title compound as a viscous oil. The oil was lyophilized to give a white solid (0.781 g, 29% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[CH:3]=[C:4]([C:9]([O:11]C)=[O:10])[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:8][O:7][C:5]([C:4](=[CH:3][CH:2]([CH3:1])[CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[C:9]([OH:11])=[O:10])=[O:6]
Reactant: COC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)O

Procedure:
Conjugated malonate 3a (10 g, 29.5 mmol) in THF (130 ml) is vigorously stirred with NaOH (4.8 g, 118 mmol) in water (120 ml) at 25° C. for 5 h. After addition of conc. NaHCO3 the mixture is extracted with tert-butyl methyl ether. The organic phase, which contains aldehyde 5, is discarded. The water phase is acidified with conc. HCl to pH 2 and extracted with tert-butyl methyl ether. The organic phase is dried over MgSO4, filtered and evaporated under reduced pressure giving 7.5 g (82%) of crude 1b with Z-configuration, which isomerizes upon standing slowly to an E/Z 1:1 mixture. Analytical data of the Z-isomer: 1H-NMR (400 MHz, CDCl3): δ0.96 (s, 6 H), 1.1 (d, 3 H), 1.4-1.6 (6 H), 1.56 (s, 3 H), 1.85-2.0 (4 H), 3.8 (m, 1 H), 3.9 (s, 3 H), 7.2 (d, 1 H) ppm. 13C-NMR (400 MHz, CDCl3): 19.41 (t), 19.42 (q), 19.8 (q), 26.4 (t), 28.56 (q), 28.57 (q), 32.7 (t), 34.8 (s), 36.0 (d), 36.8 (t), 39.7 (t), 52.6 (t), 124.0 (s), 127.3 (s), 136.7 (s), 161.0 (d), 166.6 (s), 167.3 (s). Z-Configuration determined on freshly prepared 1b by non-decoupled 13C-NMR-(method described in J. Med. Chem. 50, 1322-1334, 2007). HSQC- and HMBC-analysis in DMSO-D6. MS (DIP, El): m/z (%) 308 (M+, 65), 290 (10), 275 (20), 259 (24), 243 (76), 215 (29), 190(27), 175 (32), 158(100), 140 (43), 123 (29), 121 (22).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[C:18]1(S)[CH:23]=[CH:22]C=[CH:20][CH:19]=1>>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([S:16][C:17]2[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=2)[N:3]=1
Reactant: Sc1ccccc1
Reactant: CSc1nc(N)n2nc(-c3cccs3)nc2n1
Product: Nc1nc(Sc2ccccc2)nc2nc(-c3cccs3)nn12

Procedure:
Using a similar procedure to that described in Example 2 but starting from 7-amino-5-methylthio-2-(2-thienyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine and using thiophenol, there was obtained 7-amino-5-phenylthio-2-(2-thienyl)-[1,2,4]triazolo[1,5-a][1,3,51triazine as a solid, m.p. >300° C. (decomposition); microanalysis, found: C, 51.9; H, 3.1; N, 25.6%; C14H10N6S2 requires: C, 51.5; H, 3.1; N, 25.8%; NMR 7.20(dd, 1H, thienyl-4H), 7.4-7.8(complex, 1H, phenyl-H, thienyl-3H,5H) and 8.83(d, 2H, NH2).
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1.[CH3:16][O:17]C(Cl)Cl.Cl>C(Cl)Cl>[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[CH:16]=[O:17]
Reactant: COC(Cl)Cl
Reactant: Cc1cc2ccccc2s1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1sc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
SnCl4 (20 mL, 67 mmole) was added over 5 min to a stirred solution of 2-methylbenzo[b]thiophene (5.0 g, 33.7 mmole) in CH2Cl2 (75 mL) at 0° C. under argon. After 15 minutes, dichloromethyl methyl ether (3.7 mL, 41 mmole) was added. The reaction became a yellowish colored suspension. The reaction was allowed to warm to RT and stirred for 16 h, then was poured onto ice water (200 mL). The aqueous mixture was acidified with 1.0 N HCl (100 mL) and stirred until the suspension dissolved. The organic phase was separated, dried (MgSO4), and concentrated under vacuum. Purification by flash chromatography on silica gel (10% ethyl acetate/hexane) gave the title compound (5.83 g, 98%) as a white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.48 (t, 1H), 7.39 (t, 1H), 2.93 (s, 3H)
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](=[O:74])[NH:14][C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])[C:18]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]3[C:54](=[O:55])[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:47]3=[O:56])=[C:17]([CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][N:63]3[C:71](=[O:72])[C:70]4[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:64]3=[O:73])[CH:16]=2)=[CH:11][C:10]([CH:75]=[CH:76][C:77]([O:79][CH2:80][CH3:81])=[O:78])=[C:9]1[C:82]#[C:83][C:84]([OH:97])([C:91]1[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1)[C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O>[CH2:1]([N:8]1[C:12]([C:13](=[O:74])[NH:14][C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:28](=[O:37])[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:35]3=[O:36])[C:18]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]3[C:54](=[O:55])[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:47]3=[O:56])=[C:17]([CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][N:63]3[C:71](=[O:72])[C:70]4[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:64]3=[O:73])[CH:16]=2)=[CH:11][C:10]([CH2:75][CH2:76][C:77]([O:79][CH2:80][CH3:81])=[O:78])=[C:9]1[C:82]#[C:83][C:84]([OH:97])([C:91]1[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=1)[C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1cc(C(=O)Nc2cc(CCCCCCN3C(=O)c4ccccc4C3=O)c(OCCCCCCCN3C(=O)c4ccccc4C3=O)c(CCCCCCN3C(=O)c4ccccc4C3=O)c2)n(Cc2ccccc2)c1C#CC(O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(C(=O)Nc2cc(CCCCCCN3C(=O)c4ccccc4C3=O)c(OCCCCCCCN3C(=O)c4ccccc4C3=O)c(CCCCCCN3C(=O)c4ccccc4C3=O)c2)n(Cc2ccccc2)c1C#CC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
To a stirred solution of 9 (0.07 g, 0.06 mmol) in EtOAc (20 mL) was added dry powdered 10% Pd—C (0.007 g). The resulting mixture was stirred at room temperature for 48 hours under H2 balloon. Pd—C was filtered off and the filtrate was concentrated to give 10 as colorless oil (0.07 g, 80%). The crude product was subjected to the next reaction without further purification. 1H NMR (CDCl3) δ 7.78-7.80 (m, 6H), 7.65-7.69 (m, 7H), 7.14-7.33 (m, 14H), 6.76 (d, J=7.2 Hz, 1H), 6.61 (s, 1H), 5.52 (s, 2H), 4.05 (q, J=6.8 Hz, 2H), 3.62-3.67 (m, 8H), 2.62 (m, 2H), 2.45-2.54 (m, 8H), 2.19-2.22 (m, 2H), 1.56-1.67 (m, 12H), and 1.22-1.35 (m, 17H),
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C:10]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:20]=[C:21]([C:25]#[N:26])[N:22]([CH3:24])[CH:23]=2)[N:18]=1)([CH3:12])[CH3:11].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.O.C(OCC)(=O)C>O1CCCC1>[CH3:11][C:10]1([CH3:12])[CH2:9][O:8][C:28](=[O:30])[N:13]1[C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:20]=[C:21]([C:25]#[N:26])[N:22]([CH3:24])[CH:23]=2)[N:18]=1
Reactant: Cn1cc(-c2csc(NC(C)(C)CO)n2)cc1C#N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2csc(N3C(=O)OCC3(C)C)n2)cc1C#N
Reaction time: 16 h
Yield: 35.4 %

Procedure:
To a mixture of triethylamine (0.42 mL, 3 mmol) and 4-[2-(2-hydroxy-1,1-dimethyl-ethylamino)-thiazol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile (0.75 g, 2.71 mmol), prepared in the previous step, in dry tetrahydrofuran (10 mL) was added triphosgene (0.83 g, 2.8 mmol) at room temperature. After 16 h, the mixture was poured into water/ethyl acetate. The organic layer was washed with water, dried (anhydrous sodium sulfate) and evaporated. The product was purified by silica gel column chromatography (ethyl acetate:hexanes, 1:4) to afford the title compound (0.29 g, 36%) as a white powder. HRMS: calcd for C14H14N4O2S [M+H]+, 303.09102; found (ESI, [M+H]+), 303.0914; ANLC 99.6% at 210-370 nm, 9.0 min; 99.5% at 260 nm, 9.0 min, the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(N(CC)CC)C>C(O)C>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00g, 20 mmoles) and N-[4-(bromo)butyl]phthalimide (6.21 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour and heated at reflux for 45 minutes. After the solvent was distilled off, chloroform was added to the residue, which was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.50 g of the desired product (64.1%, pale yellow crystals).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])=[CH:36][CH:35]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with 4-chlorobenzylamine (19 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was then slurried in a 1:1 methanol-dichloromethane solution, and the solid collected by vacuum filtration to afford the title compound as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:28]=[CH:27][C:13]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]1([C@H:68]([NH2:70])[CH3:69])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24]([NH:70][C@@H:68]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH3:69])=[O:25])=[CH:27][CH:28]=2)=[CH:7][CH:8]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a suspension of 4-{(R)-2-[4-(4-chloro-phenyoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyric acid HCl salt (220 mg, 0.5 mmol, 1 eq.) in dichloromethane (5 ml) was added PyBrOP (280 mg, 0.6 mmol, 1.2 eq.), DIPEA (200 mg, 1.5 mmol, 3 eq.) and (R)-1-phenyl ethylamine (80 mg, 0.6 mmol 1.2 eq.). The mixture was stirred at room temperature overnight. The volatile material was removed under reduced pressure and the residue was purified by preparative TLC using dichloromethane/MeOH (15:1) as mobile phase (twice) followed by a column chromatography on silica gel using dichloromethane/MeOH (15:1) as eluent to give the desired product (12 mg, 5%); LCMS (UV, ESI), m/z 493 (M); HPLC: 99%.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>CN(C)C=O.O>[CH:19]1([S:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[O:11][CH3:12])[C:5]([OH:7])=[O:6])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C(=O)O)cc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)O)cc1SC1CCCC1
Temperature: 50 °C
Yield: 13.2 %

Procedure:
A solution of 3-mercapto-4-methoxybenzoic acid (that is prepared as described in Reference Example 45 from 58 g of 3-chlorosulfonyl-4-methoxybenzoic acid) in dimethylformamide (400 mL) is treated with potassium carbonate (120 g) and cyclopentyl bromide (60 g). The solution is heated at 50° C. for 3 hours, and then it is cooled and poured into water (3 L) containing concentrated hydrochloric acid (250 mL). The resulting solid is filtered off and dried, to give 3-cyclopentylthio-4-methoxybenzoic acid (10.5 g), in the form of a white crude solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1(=[N:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:10][CH2:9][CH2:8]1>C(Cl)Cl.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:5]([C:7]1([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:8][CH2:9][CH2:10]1)#[N:6]
Reactant: CC(C)(C)S(=O)N=C1CCC1
Reactant: C[Si](C)(C)C#N
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC1(C#N)CCC1
Reaction time: 16 h
Yield: 81.5 %

Procedure:
Titanium (IV) ethoxide (3.03 g, 13.3 mmol) was added to a stirring solution of trimethylsilyl cyanide (7.12 mL, 53.1 mmol) and N-cyclobutylidene-2-methylpropane-2-sulfinamide (4.6 g, 27 mmol) in DCM (100 mL) at rt. The reaction was allowed to stir for 16 h. An additional 1.7 mL of TMS-CN was added followed by 1.5 g of TiOEt4. The reaction was allowed to stir at rt for an additional 16 h. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give N-(1-cyanocyclobutyl)-2-methylpropane-2-sulfinamide (4.5 g, 22 mmol, 85% yield) consistent by NMR. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.82-2.67 (m, 2H), 2.62-2.34 (m, 2H), 2.26-2.02 (m, 2H), 1.26 (s, 9H).
Reaction SMILES: CS([O-])(=O)=O.[CH2:6]([C@@:9]1([CH2:35][CH3:36])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N+:11]2[C@@H:29]([CH:32]3[CH2:34][CH2:33]3)[CH2:30][O:31][C:10]1=2)[CH:7]=[CH2:8].[CH2:37]([S-:39])[CH3:38].[Na+]>>[CH2:6]([C@@:9]1([CH2:35][CH3:36])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH:32]2[CH2:34][CH2:33]2)[CH2:30][S:39][CH2:37][CH3:38])[C:10]1=[O:31])[CH:7]=[CH2:8]
Reactant: CC[S-]
Reactant: C=CC[C@@]1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C1CC1
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Product: C=CC[C@@]1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSCC)C2CC2)C1=O

Procedure:
The title compound was prepared from (3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-ethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium methanesulfonate (Example 357, Step A) and sodium ethanethiolate by the method described in Example 339.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:11].[Li+].[OH-].Cl>O1CCCC1>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])=[O:11]
Reactant: COC(=O)CCCCCNC(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCNC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
(Method J5B) The crude 6-[(naphthalene-2-carbonyl)amino]hexanoic acid methyl ester (3/53) was dissolved in tetrahydrofuran (5 ml) and 1 N LiOH (5.5 ml, 5 mmol) was added. The reaction mixture was stirred for three hours at room temperature and acidified with 2N HCl up to pH 3. The mixture was extracted with ethyl acetate (3×20 ml) the organic layer was washed with saturated NaCl (3×10 ml) and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel with ethyl acetate as eluent to give pure title compound (0.618 g, 79%). 1H NMR (CDCl3, HMDSO), δ: 1.11-1.77 (6H, m); 2.22-2.39 (2H, m); 3.47 (2H, dd, J=7.0 Hz); 6.26 (1H, br s); 7.17(1H, s); 7.33-7.57 (2H, m); 7.64-7.93 (4H, m); 8.22 (1H, s).
Reaction SMILES: [NH2:1][C@H:2]([CH3:20])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[N:5]1.[C:21]([C:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:28]=[C:27]([C:29]([NH:1][C@H:2]([CH3:20])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[N:13][C:12]([C:15]#[N:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]
Reactant: C[C@@H](N)Cn1ccc(-c2cnc(C#N)c([N+](=O)[O-])c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)N[C@H](C)Cn2ccc(-c3cnc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1
Yield: 18.5 %

Procedure:
(R)-5-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-3-nitropicolinonitrile (0.62 g, 1.14 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (0.39 g, 2.50 mmol) using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-10% MeOH in DCM; 2nd column: C-18, eluent: 0-100% MeCN in water) to yield 86 mg (19%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.56 (s, 3H), 4.33 (dd, 1H), 4.55 (dd, 1H), 4.58-4.67 (m, 1H), 6.83-6.86 (m, 1H), 7.29-7.31 (broad s, 1H), 7.65 (d, 1H), 8.91-8.94 (broad s, 1H), 9.64-9.67 (m, 1H).
Reaction SMILES: [AlH4-].[Li+].[N:3]1[CH:4]=[CH:5][N:6]2[CH:11]=[CH:10][C:9]([C:12](OCC)=[O:13])=[CH:8][C:7]=12>C1COCC1>[N:3]1[CH:4]=[CH:5][N:6]2[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=12
Reactant: CCOC(=O)c1ccn2ccnc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Lithium tetrahydroaluminate (0.50 g, 13.2 mmol) was slowly added in small portions to an ice-cooled solution of ethyl imidazo[1,2-a]pyridine-7-carboxylate (2.20 g, 11.6 mmol) in THF (150 mL). The mixture was slowly warmed to II and stirred at rt overnight. The solution was cooled to 0° C. and quenched carefully with 1N aq. HCl (10 mL). Solid K2CO3 and anhydrous Na2SO4 were added and the mixture was stirred at rt for 30 min. The mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated to yield the crude product as a solid (1.68 g, 80% purity) which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([OH:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2].[CH2:16]([O:18][CH:19]=[CH2:20])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([O:14][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(C)C(O)CC=C(C)C
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: CCOC(C)OC(CC=C(C)C)C(C)CCOC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene (2.27 g, 10.6 mmole), ethyl vinylether (0.82 g. 11.4 mmole), p-toluenesulfonic acid monohydrate (catalytic amount) and ether (50 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (150 ml) and washed with 5% sodium bicarbonate solution (2×100 ml). The organic phase is dried (Na2SO4), and evaporated in vacuo to give the crude product. The crude material is further purified by column chromatography on silica gel (25 g, 5% ethyl acetate in hexane) to give 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene as a colorless oil.