Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:16][C@@H:11]2[O:12][C:13](=[O:15])[CH2:14][C@@H:10]2[C@H:9]1/[CH:17]=[CH:18]/[C@@H:19]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:16][C@@H:11]2[O:12][CH:13]([OH:15])[CH2:14][C@@H:10]2[C@H:9]1/[CH:17]=[CH:18]/[C@@H:19]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](COc3cccc(C(F)(F)F)c3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](/C=C/[C@H](COc3cccc(C(F)(F)F)c3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 130.5 %

Procedure:
(3aR,4R,5R,6aS)-5-((tetrahydro-2H-pyran-2-yl)oxy)-4-((3R,E)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-2-one (19.0 g, 35.3 mmol) was dissolved in toluene (200 mL), followed by cooling to −70° C., and DIBAL (1.0M in hexane, 53 mL, 53 mmol) was added dropwisely. Then the reaction was quenched by adding saturated aqueous solution of ammonium chloride (10 mL) at −70° C. The resulting mixture was poured into a 2M sodium bisulfate aqueous solution (200 mL) at room temperature and stirring was continued for 30 minutes. After separation of the organic layers, toluene (200 mL) was added to the aqueous layer. The combined organic layers were concentrated under reduced pressure to give 25.0 g of crude titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].CCN(CC)CC>S(Cl)(Cl)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1cc(F)cc(Br)c1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 3-bromo-5-fluorobenzoic acid (commercially available) (10.0 g, 45.7 mmol) in thionyl chloride (80 mL) was heated at reflux for 2 hours. Thionyl chloride was removed under reduced pressure and the residue was added to solution of N,O-dimethylhydroxylamine hydrochloride (5.32 g, 54.8 mmol) and Et3N (10.1 g, 0.1 mol) in DCM (300 mL) dropwise at 0° C. After the reaction mixture was stirred at r.t. overnight, it was washed with water (3×100 mL), brine, dried over anhydrous Na2SO4 and concentrated. The colorless oil was used in next step without further purification (11.0 g, yield: 95%).
Reaction SMILES: [CH:1](=[CH:10][C:11]([OH:13])=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>CCCCCC>[CH:1](=[CH:10][C:11]([Cl:16])=[O:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=CC=Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: O=C(Cl)C=CC=Cc1ccccc1
Yield: 77.9 %

Procedure:
Preparation of C6H5—CH═CH—CH═CH—CO2PEG—OCH2CH(OC2H5)2: A solution of cinnamylideneacetic acid (1.7 g, 0.01 moles) and thionyl chloride (3 ml, 0.04 moles) in 50ml of hexane were refluxed under N2 for 4 h, then filtered to remove a small amount of dark solid and the filtrate evaporated under vacuum. The residue was dried under vacuum overnight at room temperature to obtain 1.5 g of cinnamylideneacetyl chloride as a yellow solid, m.p. 51-52° C.)
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>>[C:1]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCCC2)cc1
Yield: 82.4 %

Procedure:
2.00 g (7.2 mmol) of trityl chloride was treated with 0.51 g (7.2 mmol) pyrrolidine and 0.72 g (7.2 mmol) triethylamine according to General Method C in Example 6 to give 1.86 g (82%) of 1-tritylpyrrolidine (T7), mp: 126° C.
Reaction SMILES: Cl.Cl.[C:3]1([C@@H:9]2[C@@H:18]3[CH2:19][CH2:20][N:21]([C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])[C@@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:30]([N:38]=[C:39]=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([CH2:31][CH2:30][NH:38][C:39]([N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]2[C:22]([N:21]2[C@@H:17]3[C@@H:18]([C@H:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[NH:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=43)[CH2:19][CH2:20]2)=[O:23])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCCc1ccccc1
Reactant: O=C([C@H]1CCCCN1)N1CC[C@H]2[C@@H](c3ccccc3)Nc3ccccc3[C@H]21
Agent: Cl
Product: O=C(NCCc1ccccc1)N1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21

Procedure:
In the same manner as in Example 135 and using (3aS,4S,9bS)-4-phenyl-1-[(2R)-piperidin-2-ylcarbonyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline dihydrochloride and phenethylisocyanate, the title compound was synthesized.
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:19])=[C:6]([C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:7][S:8][C@H:3]12.[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][CH2:67][C:68]([O:70][CH:71]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)=[O:69])/[C:62](O)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][CH2:67][C:68]([O:70][CH:71]([C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)[C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)=[O:69])/[C:62]([NH:1][CH:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[S:19])=[C:6]([C:9]4[S:10][C:11]5[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=5[N:13]=4)[CH2:7][S:8][C@H:3]23)=[O:63])[N:60]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Yield: 70.6 %

Procedure:
165 mg of diphenylmethyl 7-amino-3-(benzothiazol-2-yl)thio-3-cephem-4-carboxylate as synthesized in the same manner as in Example 1 (b) above were dissolved in 4 ml of methylene chloride, and to the resulting solution were added 243 mg of (Z)-2-(2-tritylaminothiazol-4-yl)-2-diphenylmethoxycarbonylmethoxyiminoacetic acid, 0.10 of pyridine and 35 μl of phosphorus oxychloride. Next, the acylation reaction and the post-treatment of the reaction solution were carried out in the same manner as in Example 1 (b), and the resultant residue was then purified through a column chromatography on 30 g of silica gel (as developed with mixed solvents of toluene and ethyl acetate, 10:1) to afford 260 mg of the titled compound (yield, 73%).
Reaction SMILES: Br.[CH2:2]([C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:16])[C:7](=[O:23])[NH:6][C:5]1=[O:24])[CH3:3].[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH2:33][CH2:32]1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl.ClCCl>[C:34]([CH2:33][CH2:32][C:31]([N:20]1[CH2:21][CH2:22][N:17]([C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]([CH2:2][CH3:3])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5](=[O:24])[NH:6][C:7]2=[O:23])=[O:16])[CH2:18][CH2:19]1)=[O:37])([OH:36])=[O:35]
Reactant: O=C1CCC(=O)O1
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)N(CCCCC(=O)N2CCNCC2)C1=O
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCC1(c2ccccc2)C(=O)NC(=O)N(CCCCC(=O)N2CCN(C(=O)CCC(=O)O)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The amine of step 5 (4.8 g, 0.01 mole), succinic anhydride (1.2 g, 0.012 mole), and triethylamine (2.2 g, 0.02 mole) in chloroform (150 mL) were heated for 30 min at 50°-60° C. (hot water) and allowed to stir at ambient temperature for 16 hrs. Dichloromethane (200 mL) was added, the mixture was washed with 10% hydrochloric acid solution (3×100 mL). saturated sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed on a rotary evaporator in vacuo to give a white solid, 3.3 g (66%). This material was chromatographed using a SiO2 column to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2.Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[N:3]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:22])=[O:12])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc2c(C=O)c(Cl)n(-c3ccccc3)c2c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc2c(C(=O)O)c(Cl)n(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.8 %

Procedure:
The compound of step 2 (365 mg, 1.27 mmol) was dissolved in tert-butanol (15 ml) and 2-methyl-2-butene (3 ml), and a solution of sodium chlorite (1.06 g, 11.7 mmol) and sodium dihydrogenphosphate (1.06 g, 8.82 mmol) in water (6 ml) was added. The reaction mixture was stirred at room temperature for 48 h. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give 394 mg of the crude title compound.
Reaction SMILES: [Na].[N+:2]([CH:5]=[C:6](SC)[S:7]([CH3:9])=O)([O-:4])=[O:3].Br.[Br:13][CH2:14][CH2:15][CH2:16][NH2:17]>CO>[N+:2]([CH:5]=[C:6]([S:7][CH3:9])[NH:17][CH2:16][CH2:15][CH2:14][Br:13])([O-:4])=[O:3]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCCCBr
Agent: Br
Agent: [Na]
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCCCBr
Reaction time: 5 h
Yield: 39.2 %

Procedure:
A solution of sodium (0.09 g, 0.004 mol) in methanol (10 ml) was added dropwise to a stirred solution of 1-nitro-2-methylthio-2-methylsulphinyl-ethylene (0.5 g, 0.003 mol) and 3-bromopropylamine hydrobromide (0.9 g, 0.004 mol) in methanol (30 ml). The mixture was stirred for 5 hours, and then the solvent was removed in vacuo. The residue was dissolved in water (20 ml) and extracted with chloroform (2×30 ml). The extracts were combined, dried, and concentrated in vacuo. The solid residue was recrystallised from propan-2-ol to give 1-nitro-2-methylthio-2-(3-bromopropylamino)ethylene (0.3 g, 43%) m.p. 92°-92.5°.
Reaction SMILES: CN(C)C(=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].[CH2:32]([CH:37]1[CH2:42][CH2:41][CH:40]([CH:43]=[CH2:44])[CH2:39][CH2:38]1)[CH2:33][CH2:34][CH2:35][CH3:36]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:44]=[CH:43][CH:40]3[CH2:41][CH2:42][CH:37]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:38][CH2:39]3)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18]
Reactant: COC(=O)C1CCC(c2ccc(Br)cc2)CC1
Reactant: C=CC1CCC(CCCCC)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCCC1CCC(C=Cc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Yield: 61.8 %

Procedure:
180 mL of N,N-dimethylacetamide (DMA) solution including 12.8 g (60.1 mmol) of potassium phosphate, 14.3 g (48 mmol) of 4-(4-bromophenyl)cyclohexanecarboxylic acid methyl ester produced in Example 1-1, and 8.33 g (40 mmol) of 1-pentyl-4-vinyl-cyclohexane was poured to flask filled with Argon gas. Then, 0.17 g (catalytic amount) of palladium acetate was added to the flask and reacted in oil bath at 120° C. for 32 hours. After reaction, 100 mL of distilled water was added to the reaction mixture, extracted by ethyl acetate, and then the aqueous layer was extracted by chloroform. The organic layer was dried by Na2SO4, concentrated under reduced pressure, and then recrystallized from ethanol to obtain 9.8 g (62%) of 4-{4-[2-(4-pentyl-cyclohexyl)-ethenyl]-phenyl}cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:20][O:21]C1C=CC(C=O)=CC=1.C(=O)C1C=CC=CC=1>>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:21][CH3:20])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc(NCc2ccccc2)cc1
Reactant: COc1ccc(C=O)cc1
Solvent: O=Cc1ccccc1
Product: COc1ccc(CNc2ccc(NNC(C)=O)cc2)cc1

Procedure:
Procedures (5) and (6) above were repeated, but with 4-methoxybenzaldehyde substituted for benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.I[CH2:11][CH3:12].[H-].[Na+]>CN(C=O)C.[Cl-].[NH4+]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:11][CH3:12])=[CH:4][N:3]=1
Reactant: OCc1cnc(Cl)nc1
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOCc1cnc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of the (2-chloropyrimidin-5-yl)methanol (1 g, 6.92 mmol) in anhydrous DMF (6.92 ml) was cooled at ice-bath temperature and iodoethane (2.236 ml, 27.7 mmol) added. The solution was stirred for 10 minutes at 0° C. Sodium hydride (0.304 g, 7.61 mmol) was added and the resulting mixture stirred at 0° C. for 0.5 hours and RT for 60 minutes. The mixture was diluted with saturated ammonium chloride (100 mL) and extracted with EtOAc (3×50 mL). The organic fractions were combined, washed with brine (100 mL), dried over Na2SO4, filtered and the volatiles removed in vac. The mixture was purified on a 50 g Biotage KP-SiO2 cartridge using a gradient eluant of 0-100% EtOAc:Hexanes, to afford the title compound. LC/MS (m/z): 173 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][CH:10]([CH3:12])[CH2:11][C:5]2=[N:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:9]2[CH:10]([CH3:12])[CH2:11][C:5]3=[N:4][N:3]=[C:2]([CH3:1])[N:6]3[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]2=3)=[CH:20][CH:19]=1
Reactant: Cc1nnc2n1-c1ccccc1NC(C)C2
Reactant: Clc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(C)C2
Temperature: 90 °C
Yield: 10.6 %

Procedure:
A disposable tube was charged with 1,5-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (69 mg, 0.322 mmol), 1-chloro-4-iodobenzene (100 mg, 0.419 mmol), RuPhos precat. (11.73 mg, 0.016 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (7.51 mg, 0.016 mmol), sodium 2-methylpropan-2-olate (61.9 mg, 0.644 mmol), and a stirbar before being evacuated and purged with nitrogen three times. Toluene (1 mL, 0.4 M) was added, and the mixture was stirred at 90° C. 36 h. The mixture was cooled, diluted with ethyl acetate, filtered, and concentrated before being purified by silica gel chromatography (eluting with methylene chloride/methanol/1% ammonium hydroxide) and reverse phase HPLC to yield the title compound as a white amorphous solid (0.011 g, 0.034 mmol, 11%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:31])/[CH:22]=[CH:23]\[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25]>C1(C)C=CC=CC=1>[NH2:7][C:6]1[C:8]([CH3:13])=[CH:9][C:10]([S:12][CH:22]([CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[C:21]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC(Sc1cc(C)c(N)c(C(C)(C)C)c1)C(=O)OCCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
To a stirred solution of 1.00 g (5.1 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline and 0.05 g (0.5 mmol) of triethylamine in 5 mL of toluene at room temperature is added dropwise a solution of 1.16 g (5.1 mmol) of di-n-butyl maleate in 5 mL of toluene. The reaction mixture is stirred for 18 hours at room temperature. The solvent is removed in vacuo and the crude product is purified by flash column chromatography (silica gel, 85:15, heptane:ethylacetate eluent) to give 0.60 g (28%) of the title compound as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4]1>CCO>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4]1
Reactant: COC1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Solvent: CCO
Product: COC1CCN(CCCN)CC1
Temperature: 5 °C
Yield: 54.2 %

Procedure:
A solution of phthalimide 305 (6.0 g, 19.8 mmol) and N2H4.H2O (1.9 mL, 40 mmol) in EtOH (100 mL) was stirred at reflux temperature for 2 h. The solution was cooled to 5° C. for 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated to half volume. The solution was cooled at 5° C. for a further 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated. The residue was dissolved in 1 M HCl (50 mL), washed with Et2O (2×50 mL) and the pH of the aqueous fraction adjusted to 10 with dilute aqueous NH3 solution. The mixture was extracted with CHCl3 (4×50 mL), the combined organic fraction dried and the solvent evaporated to give diamine 306 (1.85 g, 54%) as a pale yellow oil: 1H NMR δ 3.33 (s, 3H, OCH3), 3.17-3.24 (m, 1H, CHO), 2.71-2.78 (m, 4H, 2×CH2N), 2.37 (dd, J=7.5, 7.2 Hz, 2H, CH2N), 2.08-2.13 (m, 2H, CH2N), 1.85-1.93 (m, 2H, CH2), 1.50-1.67 (m, 6H, 2×CH2, NH2); MS m/z 172 (M+, 5%), 128 (60), 57 (100); HRMS calcd for C9H20N2O (M+) m/z 172.1576, found 172.1571.
Reaction SMILES: [N:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]([O:19][C:20]([NH:22][C@H:23]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:24]([N:10]1[CH2:11][CH2:12][C:7]([CH2:13][OH:14])([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)=[O:25])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: OCC1(N2CCCCC2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(CO)(N2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a round bottom flask equipped with a stirring bar is charged [1,4′]bipiperidinyl-4′-yl-methanol, 22, (2.2 g, 11.1 mmol, 1.0 eq.) 2-(R)-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionic acid (3.648 g, 12.2 mmol), 1-hydroxybenzotriazole (2.552 g, 18.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.71 g, 18.9 mmol) in anhydrous N,N-dimethylformamide (80 mL). The mixture is cooled to 0° C. and N,N-diisopropyl-ethylamine (4.1 mL, 37.7 mmol) is added. The ice bath is removed and the reaction mixture allowed to stir overnight. The mixture is concentrated under reduced pressure and purified by preparative HPLC to afford 2.83 g (43% yield) of the desired compound as the trifluoroacetic acid salt. 1H NMR (CD3OD, 300 MHz) δ 0.85–2.13 (m, 19H), 2.65–3.82 (m, 8H), 3.90–4.10 (m, 3H), 4.48 (m, 1H), 4.76 (m, 1H), 7.22–7.48 (m, 4H). MS (ESI) m/z 480 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:15])[CH:3]=1.[Cl:16][C:17]1[S:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>C(O)C.CO.C(O)(=O)C>[Cl:15][C:4]1[CH:3]=[C:2]([NH:1][CH2:22][C:20]2[S:21][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13]
Reactant: O=Cc1ccc(Cl)s1
Reactant: Nc1ccc(NC(=O)C(F)(F)F)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(Nc1ccc(NCc2ccc(Cl)s2)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of N-(4-Amino-2-chlorophenyl)-2,2,2-trifluoroacetamide (4.567 g, 19.14 mmol) and 5-chloro-thiophene-2-carboxaldehyde (3.97 g, 27.1 mmol) in anhydrous ethanol (50 mL) was heated to reflux for 15 minutes and evaporated in vacuo at 70° C. (0.1 mbar, 30 min). The obtained crude imine as a crystalline solid was dissolved in methanol followed by addition of sodium cyanoborohydride (NaBH3CN) in methanol (50 mL) and acetic acid (9 mL) by portions. The obtained reaction mixture was stirred at room temperature for 60 minutes and evaporated in vacuo to small volume. The concentrated solution was quenched with water and filtered after 30 minutes to give 6.98 g (99% yield) of the title compound as a brown-yellow solid. 1H NMR (DMSO-d6): 4.43 (d, 2H), 6.63 (dd, 1H), 6.77 (d, 1H), 6.79 (t, 1H, NH), 6.94 (d, 1H), 6.97 (d, 1H), 7.10 (d, 1H), 10.85 (br. s, 1H, NHCO). LC/MS (m/z) 367.9 (M+); RT=3.36, (UV, ELSD) 99%, 100%.
Reaction SMILES: Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Li+]>C(O)C.O.O1CCCC1.CN(C)C=O>[C:13]([C:10]1[CH:11]=[CH:12][C:5]2[O:4][C:3]([CH:2]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:7]([CH3:8])[C:6]=2[CH:9]=1)#[N:14]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccc(C#N)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(C#N)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a mixture of 2-[chloro(cyclohexyl)methyl]-3-methyl-1-benzofuran-5-carbonitrile (868 mg) synthesized above, methyl 4-aminobenzoate (546 mg), sodium iodide (902 mg) and N,N-dimethylformamide (10 mL) was added sodium carbonate (638 mg), and the mixture was stirred at 80° C. overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give a pale-brown solid. To a mixture of the obtained solid, tetrahydrofuran (20 mL), water (8 mL) and ethanol (10 mL) was added 1N lithium hydroxide aqueous solution (3.38 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (3.50 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (621 mg, 53%) as a white solid.