Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:21])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[CH:8]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:31]([C:33]1[O:37][C:36]([C:38](Cl)=[O:39])=[CH:35][CH:34]=1)#[N:32]>C(Cl)Cl>[CH2:1]([N:3]([CH3:21])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:38]([C:36]2[O:37][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[O:39])=[C:9]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[CH:8]=1)[CH3:2]
Reactant: CCN(C)CCCc1ccc(N)c(N2CCC(C)CC2)c1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)CCCc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCC(C)CC2)c1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 4-[3-(ethyl-methyl-amino)-propyl]-2-(4-methyl-piperidin-1-yl)-phenylamine (as prepared in the previous step, 32 mg, 0.11 mmol) in DCM (2 mL) at 0° C. was added DIEA (48 μL, 0.27 mmol) followed by 5-cyano-furan-2-carbonyl chloride (as prepared above, 22 mg, 0.16 mmol). The reaction was allowed to warm to RT overnight, at which time it was diluted with DCM (20 mL), washed with saturated aqueous NaHCO3 (10 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative TLC (10% MeOH—CHCl3) afforded 20 mg (45%) of the title compound as an oily amber solid. 1H-NMR (CDCl3; 400 MHz): δ 9.69 (s, 1H), 8.38 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=3.6 Hz), 7.05 (d, 1H, J=2.0 Hz), 7.00-6.97 (m, 1H), 6.91 (d, 1H, J=4.0 Hz), 3.01-2.98 (m, 2H), 2.78-2.64 (m, 7H), 2.50 (s, 3H), 2.04-1.98 (m, 2H), 1.89-1.85 (m, 2H), 1.63-1.46 (m, 5H), 1.25 (t, 3H, J=4.6 Hz), 1.10 (d, 3H, J=6.4 Hz), 0.93-0.89 (m, 2H). Mass spectrum (ESI, m/z) calcd for C24H32N4O2, 409.2 (M+H). found 409.3.
Reaction SMILES: C(OC(CSC(=O)C)C(O)=O)(=[O:3])C.C(SCC(CSC(=O)C)C(O)=O)(=O)C.C([O:32][C:33](=[O:60])[C@H:34]([CH2:48][CH2:49][CH2:50][CH2:51][NH:52]C(OC(C)(C)C)=O)[NH:35][C:36](=[O:47])[CH:37](OC(=O)C)[CH2:38][S:39]C(=O)C)(C)(C)C.C(OC(CSC(=O)C)C(N[C@H](C(O)=O)CCCCN)=O)(=O)C>>[OH:3][C@@:34]([C:33]([OH:32])=[O:60])([CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])[NH:35][C:36](=[O:47])[CH2:37][CH2:38][SH:39]
Reactant: CC(=O)OC(CSC(C)=O)C(=O)O
Reactant: CC(=O)OC(CSC(C)=O)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(=O)OC(CSC(C)=O)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: CC(=O)SCC(CSC(C)=O)C(=O)O
Product: NCCCC[C@](O)(NC(=O)CCS)C(=O)O

Procedure:
By substituting 2-acetoxy-3-(acetylthio)propanoic acid for the 2-(acetylthiomethyl)-3-(acetylthio)propanoic acid in the procedure of Example 38 and then submitting the product to the procedures of Examples 39 and 40, Nα -[2-acetoxy-3-(acetylthio)propanoyl]-Nε -tert.butyloxycarbonyl-L-lysine tert.butyl ester, Nα -[2-acetoxy-3-(acetylthio)propanoyl]-L-lysine and Nα -(2-hydroxy-3-mercaptopropanoyl-L-lysine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N2C(=O)C=C(O)C2CC2CC2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(N2C(=O)C[C@H](O)[C@@H]2CC2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a mixture of 2-chloro-4-[2-(cyclopropylmethyl)-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]benzonitrile (400 mg) and acetic acid (0.87 mL) in acetonitrile (10 mL) was added sodium borohydride (131 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 310 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:28][CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1ccncc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccncc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-pyridin-4-yl-methylamine (CA [58088-57-6]).
Reaction SMILES: [Na:1].C(C1(CCO[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.[O:47]1[CH2:51][CH2:50][O:49][CH:48]1[CH2:52][OH:53]>>[Na:1].[O:47]1[CH2:51][CH2:50][O:49][CH:48]1[CH2:52][O:53][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[O:25])[C:18]=1[CH3:35]
Reactant: OCC1OCCO1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OCC2OCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 17.2 %

Procedure:
The same procedure as in the steps (4f) to (4j) described in Example (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using 1,3-dioxolan-2-ylmethanol obtained in the step (66b) above to obtain the title compound (411 mg, total 17.2% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]1([C:20](=O)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:29][C:30]([NH2:32])=[O:31].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:32][C:30](=[O:31])[NH:29]2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: O=Cc1cc(Cl)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc(Cl)c(O)c([N+](=O)[O-])c2)N1
Temperature: 78 °C
Yield: 41.4 %

Procedure:
A mixture of 3-chloro-4-hydroxy-5-nitrobenzaldehyde (Intermediate 59) (150 mg, 0.74 mmol), 1,2-diphenylethanone (146.0 mg, 0.74 mmol), urea (133.9 mg, 2.23 mmol), concentrated hydrochloric acid (0.5 mL) in ethanol (3 mL) was refluxed at 78° C. for 45 h. After cooling, the mixture was evaporated and the residue was purified by preparative HPLC to give Compound 120 (129.1 mg, yield 41.4%). 1HNMR (DMSO-d6 400 MHz): δ 11.09 (s, 1H), 8.79 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.27-7.21 (m, 5H), 7.05-7.00 (m, 3H), 6.83-6.81 (m, 2H), 5.28 (d, J=2.8 Hz, 1H); MS (ESI): m/z 422.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][C@@H:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:23]([C:30]1[CH:31]=[N:32][C:33]([C:36]2[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=2)=[N:34][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[NH2:1][C:2]1[C:3]([O:14][C@@H:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][C:39]1[CH:38]=[CH:37][C:36]([C:33]2[N:32]=[CH:31][C:30]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:35][N:34]=2)=[CH:41][CH:40]=1)=[O:8]
Reactant: CCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCC[C@@H](C)Oc1cc([N+](=O)[O-])c(C(=O)O)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCc1cnc(-c2ccc(OC(=O)c3cc(N)c(O[C@H](C)CCCCCC)cc3[N+](=O)[O-])cc2)nc1
Yield: 82.7 %

Procedure:
5-Amino-2-nitro-4-[(R)-2-octyloxy]benzoic acid (0.06 g), 0.1 g of 4-(5-heptyl-2-pyrimidinyl)phenol and 0.04 g of 4-(dimethylamino)pyridine were dissolved in 10 ml of dichloromethane and the solution was treated portionwise within 10 minutes with 0.07 g of N,N'-dicyclohexylcarbodiimide while stirring. The mixture was stirred at room temperature for 40 hours, filtered and concentrated. Chromatography of the residue on silica gel with ethyl acetate/dichloromethane (vol. 1:8) and recrystallization from diethyl ether/hexane (vol. 1:1), gave 0.09 g of 4-(5-heptyl-2-pyrimidinyl)phenyl 5-amino-2-nitro-4-[(R)-2-octyloxy]benzoate of melting point 105° C.
Reaction SMILES: [CH:1]([O:14][C:15]([CH:17]([O:38][N:39]=[C:40]([C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)[C:41](O)=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:20]([O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:19]=1)=[O:16])([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.[NH2:69][CH:70]1[C:95](=[O:96])[N:72]2[C:73]([C:79]([O:81][CH:82]([C:89]3[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=3)[C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)=[O:80])=[C:74]([CH2:77][Cl:78])[CH2:75][S:76][C@H:71]12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.Cl>C(Cl)Cl>[CH:1]([O:14][C:15]([CH:17]([O:38][N:39]=[C:40]([C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[S:47][CH:48]=1)[C:41]([NH:69][CH:70]1[C:95](=[O:96])[N:72]2[C:73]([C:79]([O:81][CH:82]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)[C:89]3[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=3)=[O:80])=[C:74]([CH2:77][Cl:78])[CH2:75][S:76][C@H:71]12)=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:20]([O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:19]=1)=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCOCOc1ccc(C(ON=C(C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OCOCCOC
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCCOCOc1ccc(C(ON=C(C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OCOCCOC
Reaction time: 1 h

Procedure:
4.87 g (5.19 mmol) of 2-[α-benzhydryloxycarbonyl-3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(tritylaminothiazol-4-yl)acetic acid (syn-isomer) and 2.34 g (5.64 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate were dissolved in 90 ml of methylene chloride, and 3.2 ml (25.4 mmol) of N,N-dimethylaniline and 0.63 ml (6.77 mmol) of phosphorus oxychloride were dropwise added at 0° C. The mixture was stirred for 1 hour. The reaction solution was poured into 1N hydrochloric acid, and extracted with 1N methylene chloride aqueous solution. The organic phase was washed with 1N sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain a crude benzhydryl 7-{2-[α-benzhydryloxycarbonyl-3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(tritylaminothiazol-4-yl)acetamido}-3-chloromethyl-3-cephem-4-carboxylate (syn-isomer), which was used for the next reaction without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH2:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]([NH:16][C@@H:17]([CH3:18])[C:19]([OH:21])=[O:20])=[O:8])([O-:15])=[O:14]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O

Procedure:
As shown in scheme 1,2,6-dinitrobenzoyl chloride prepared from 2,6-dinitrobenzoic acid is treated with L-alanine in the presence of sodium carbonate to yield (S)-2-(2,6-dinitrobenzamido)propanoic acid (intermediate 13). Treatment of intermediate 13 either with K18F or K19F gave (S)-2-(2-fluoro-6-nitrobenzamido)propanoic acid, which on reduction with iron powder in the presence of acetic acid gave (S)-2-(2-amino-6-fluorobenzamido)propanoic acid (compound 12). In an analogous manner, treatment of 2,6-dinitrobenzoyl chloride with D-alanine gave (R)-2-(2,6-dinitrobenzamido)propanoic acid (intermediate 14), which on treatment either with K18F or K19F and further reduction with iron powder gave (R)-2-(2-amino-6-fluorobenzamido)propanoic acid (compound 13).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[CH:42][C:43]([F:50])=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[CH:45]=1>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:50][C:43]1[CH:42]=[CH:41][C:40]([C:33]2[CH:34]=[CH:35][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=3)[CH:3]([CH3:5])[CH3:4])=[CH:31][CH:32]=2)=[CH:45][C:44]=1[NH:46][C:47](=[O:49])[CH3:48]
Reactant: CC(=O)Nc1cc(Br)ccc1F
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1cc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)ccc1F
Yield: 45.2 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.50 g), N-(5-bromo-2-fluorophenyl)acetamide (1.17 g) and tetrakis(triphenylphosphine)palladium(0) (0.17 g), the title compound (1.39 g); was obtained as a colorless amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:32])[C:15](=[O:31])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18](SC3COC3)[CH:17]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.O[O:36][S:37]([O-:39])=O.[K+].[O-]S([O-])(=S)=O.[Na+].[Na+].C[CH2:49][O:50][C:51]([CH3:53])=O>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:32])[C:15](=[O:31])[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([S:37]([CH:53]3[CH2:49][O:50][CH2:51]3)(=[O:39])=[O:36])[CH:17]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: O=S([O-])OO
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SC2COC2)cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2COC2)c1
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
To an ice-cold solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(oxetan-3-ylthio)-5-(trifluoromethyl)benzamide (0.042 g, 85.3 μmol, example 251) in MeOH (2 mL) and water (0.5 mL) was added Oxone® (131 mg, 213 μmol) and the reaction mixture was stirred at room temperature for 2.75 hours. The reaction mixture was poured on 10% aqueous Na2S2O3 solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless gum (0.021 g; 46%). MS (ESI): m/z=525.11 [M+H]+.
Reaction SMILES: [C:1]([C:3](=[CH:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([I:28])[CH:20]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=O)#[N:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:16][C:8]1[CH:9]=[C:10]([Cl:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=1[NH:6][C:4]1[C:24]2[C:19](=[CH:20][C:21]([I:28])=[C:22]([O:25][CH2:26][CH3:27])[CH:23]=2)[N:18]=[CH:17][C:3]=1[C:1]#[N:2]
Reactant: CCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1I
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1I
Temperature: 25 °C
Yield: 76 %

Procedure:
A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-ethoxy-3-iodophenyl)amino]prop-2-enamide (2.0 g, 3.76 mmol) in 100 mL of toluene was heated to reflux and phosphorous oxychloride (3.5 mL, 37.6 mmol) was added dropwise via syringe. This suspension was heated at reflux for 6 hours and additional phosphorous oxychloride (3.5 mL, 37.6 mmol) was added to slowly give a dark solution. After 72 hours the mixture was cooled to room temperature, the solid was filtered and washed with toluene and ether. The light brown solid was dried under reduced pressure at ˜40° C., overnight, to provide 1.47 g (76%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-iodo-3-quinolinecarbonitrile as a yellow solid, mp 213-215° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.48 (t, 3H, J=6.9 Hz), 4.32 (q, 2H, J=6.9 Hz), 3.88 (s, 3H), 7.53 (s, 1H), 7.87 (s, 1H), 8.06 (s, 1H), 8.49 (s, 1H), 9.02 (s, 1H), 11.14 (bs, 1H); MS (ES) m/z514.1 (M+H)+
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH3:34][O:35][C:36]1[C:47]2=[C:48]3[N:43]([CH2:44][CH2:45][CH2:46]2)[CH2:42][CH2:41][CH2:40][C:39]3=[CH:38][C:37]=1[CH:49]=O.O>O1CCCC1.C(OCC)(=O)C>[CH3:34][O:35][C:36]1[C:47]2=[C:48]3[N:43]([CH2:44][CH2:45][CH2:46]2)[CH2:42][CH2:41][CH2:40][C:39]3=[CH:38][C:37]=1[CH:49]=[CH:14][C:9]1[S:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(C=O)cc2c3c1CCCN3CCC2
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C=Cc2cccs2)cc2c3c1CCCN3CCC2
Reaction time: 1.5 h
Yield: 63.9 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 3.2 g of phenyllithium (19% solution in dibutylether) (7.23 mmol), and 2.6 g (6.58 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under ice cooling. Next, 1.5 g (6.49 mmol) of 8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-carboaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 1.29 g of an orange oily matter (yield: 63.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[I:12]C1CC(=O)NC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: O=C1CC(I)C(=O)N1
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cc1c(F)cc(C(=O)O)cc1I
Temperature: -20 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
A solution of 3-fluoro-4-methylbenzoic acid (149.7 g) in trifluoromethanesulphonic acid (1050 ml) at −22° C. under nitrogen was treated portionwise over 1.25 h with iodosuccinimide (203.5 g). The mixture was stirred at −20° C. for and further portions of iodosuccinimide were added after 2.5 h (46.5 g) and 20.5 h (30 g). The mixture was stirred at −20° C. for a further 24 h then added slowly to a mixture of aqueous sodium thiosulphate (10%, 1.5 L) and ice (3 kg). The resultant precipitate was collected by filtration and stirred with ethyl acetate (5 L) and aqueous sodium thiosulphate (10%, 1.5 L). The organic phase was dried (MgSO4) and concentrated to ˜1.5 L then left overnight. The precipitate was collected by filtration and further material was obtained through concentration of the filtrate to give the title compound as a white solid (133.9 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])(C)(C)C.[CH3:21][C:22]1[C:23]([CH:29]=O)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:21][C:22]1[C:23]([CH2:29][N:11]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:13])[CH2:10][CH2:9][CH2:8][NH2:7])=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: CC(NCCCNC(=O)OC(C)(C)C)c1ccccn1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCN)C(C)c2ccccn2)c(C)c1

Procedure:
Using General Procedure B: Reaction of [3-(1-pyridin-2-yl-ethylamino)-propyl]-carbamic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-propane-1,3-diamine as a colorless oil. 1H NMR (CDCl3) δ 1.45-1.66 (m, 7H), 2.25 (s, 3H), 2.26 (s, 3H), 2.42-2.65 (m, 4H), 3.75 (d, 1H, J=12.6 Hz), 3.81 (d, 1H, J=12.6 Hz), 4.01 (q, 1H, J=6.6 Hz), 7.11-7.16 (m, 1H), 7.22 (br s, 1H), 7.38 (d, 1H, J=7.8 Hz), 7.62 (dt, 1H, J=7.8, 1.8 Hz), 8.18 (br s, 1H), 8.55 (d, 1H, J=4.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H].C1(C2C=CC(O)=CC=2)C=CC=CC=1>>[C:2]1([OH:1])[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Oc1ccc(C2=CCC(O)CC2)cc1
Agent: Oc1ccc(-c2ccccc2)cc1
Product: Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
It was found that a novel compound 4-(4-hydroxyphenyl)-3-cyclohexene-1-ol can be obtained in good yield by conducting a decomposition reaction in the initial stage of a reaction in the absence of a dehydrogenation catalyst and a hydrogen acceptor, and that by-products such as p-phenylphenol can be virtually inhibited by conducting the dehydrogenation reaction of the novel compound to give 4,4'-biphenol of high purity.