Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]COCC.[Br:13][C:14]1[C:15]([CH3:22])=[C:16]([C:19]([OH:21])=[O:20])[S:17][CH:18]=1.C(O)(=O)C>CO.O1CCCC1>[CH3:8][O:20][C:19]([C:16]1[S:17][CH:18]=[C:14]([Br:13])[C:15]=1[CH3:22])=[O:21]
Reactant: CCOCC
Reactant: Cc1c(Br)csc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1scc(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
The (trimethylsilyl)diazomethane solution in ether (2.0 M, 41.2 mL, 82.3 mmol) was added dropwise to a solution of 4-bromo-3-methyl-thiophene-2-carboxylic acid (13.0 g, 58.8 mmol, purchased from Oakwood Products) in methanol (50 mL) and tetrahydrofuran (50 mL) at ambient temperature. After the reaction mixture was stirred at ambient temperature for 30 min, acetic acid was added to decompose the excess (trimethylsilyl)diazomethane until the yellow color disappeared. Most of the solvent was evaporated and ethyl acetate was added. The organic solution was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to produce 12.8 g of a white solid. 1H NMR (CDCl3, 200 MHz): δ=7.40 (s, 1H), 3.87 (s, 3H), and 2.54 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11])=O.[CH2:24]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11])=[CH2:24]
Reactant: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (11.78 g, 33.0 mmol) in dry THF (100 mL) was added dropwise a solution of NaH (4.79 g, 110 mmol) in THF (100 mL) under nitrogen for 0.5 h. Then a solution of 5-formyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (8 g, 27.5 mmol) in THF (1 mL) was added slowly into the reaction mixture. The mixture was then allowed to warm to room temperature and stirring continued for 2 h. Purification via flash chromatography then afforded the title compound (4 g, 13.83 mmol, 50.3% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:22])(C)(C)C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)C.[Zn]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:22])[NH:13]2
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Reactant: CC(C)(C)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Temperature: 25 °C
Yield: 97 %

Procedure:
4-(2,3-Difluoro-phenyl)-1H-indole 3c (744 mg, 3.25 mmol) was dissolved in 12 mL of ethanol under stirring at room temperature, and 21 mL of tert-butanol, 6.4 mL of glacial acetic acid and pyridinium tribromide (3.12 g, 9.7 mmol) were then added successively to the solution. Upon completion of the addition, the reaction mixture was stirred for 3 hours, and 16 mL of glacial acetic acid and zinc dust (1.1 g, 16.25 mmol) were then added to the mixture. The reaction mixture was stirred for another 1 hour, filtered to remove the residue and concentrated under reduced pressure. The residue was added with 30 mL of ethyl acetate, washed successively with 10 mL of water, 10 mL of saturated sodium bicarbonate solution and 10 mL of saturated brine, dried over anhydrous sodium sulfate and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure to give the title compound 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 3d (780 mg, yield 97%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Agent: Cl
Product: c1cnc2c(NC[C@@H]3CCCNC3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1

Procedure:
(S)-tert-butyl 3-((7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)piperidine-1-carboxylate (0.11 mmol) was treated with HCl solution (in EtOAc, 4 N, 3 mL) at room temperature until the reaction was completed. The precipitates were collected by filtration and further purified by chromatography to afford the title compound. MS (m/z): 405 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[S:15][C:16]([CH3:23])=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:18]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:24])[C:4]=1[CH2:25][CH2:26][C:27](O)=[O:28])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:61]([CH2:63][NH2:64])[OH:62]>C(Cl)Cl.CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[S:15][C:16]([CH3:23])=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:18]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:24])[C:4]=1[CH2:25][CH2:26][C:27]([NH:64][CH2:63][CH2:61][OH:62])=[O:28])[CH3:2]
Reactant: NCCO
Reactant: CCc1cc(-c2noc(-c3cc(CC(C)C)c(C)s3)n2)cc(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)c(C)s3)n2)cc(C)c1CCC(=O)NCCO
Temperature: 0 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a solution of 3-{2-ethyl-4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (42 mg, 100 μmol) and DIPEA (39 mg, 300 μmol) in DCM (2 mL), TBTU (32 mg, 100 μmol) followed by ethanolamine (18 mg, 300 μmol) is added. The mixture is stirred at 0° C. for 16 h before it is diluted with EA, washed with 1 N aq. NaOH solution, dried over Na2SO4 and filtered. The solvent is evaporated and the residue is dried under HV to give 3-{2-ethyl-4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-N-(2-hydroxy-ethyl)-propionamide (39 mg) as a beige solid; LC-MS: tR=1.10 min, [M+1]=456.47.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][C@H:29]([OH:31])[C@@H:28]([OH:32])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:30][C@H:29]([OH:31])[C@@H:28]([OH:32])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@H](O)[C@@H](O)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3S,4S)-pyrrolidine-3,4-diol. MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (s, 1 H), 8.01 (s, 1 H), 7.80-7.78 (d, J=7.6 Hz, 1 H), 7.67-7.63 (m, 2 H), 7.54-7.50 (m, 2 H), 5.83 (s, 1 H), 5.21 (s, 2 H), 4.45 (s, 2 H), 4.22 (s, 2 H), 4.18-4.15 (m, 2 H), 3.67-3.60 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[C:15]([O:17]CC)=[O:16])[CH3:2].C(O)C.O1CCCC1.[OH-].[Na+]>O>[CH2:21]([O:20][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[C:15]([OH:17])=[O:16])[CH3:22]
Reactant: CCOC(=O)c1cc2c(n1CC(OCC)OCC)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(Cn1c(C(=O)O)cc2c1CCCC2)OCC
Temperature: 75 °C
Yield: 77.6 %

Procedure:
To a mixture of 195b (4.7 g, 15.2 mmol) in a mixed solvent of ethanol (20 mL), tetrahydrofuran (20 mL), and water (30 mL) was added sodium hydroxide (3.0 g, 75.0 mmol). The reaction was heated at 75° C. for two days and concentrated under reduced pressure. The residue was suspended in water and neutralized with diluted aqueous citric acid solution. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic phase was concentrated under reduced pressure to afford 195c (3.32 g, 78%). MS-ESI: [M-EtOH+H]+ 236.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15]C)=[O:14])(=[O:8])=[O:7].FC1C=CC=CC=1COC1C=C(C=C([N+]([O-])=O)C=1)C(O)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])(=[O:8])=[O:7]
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2cccs2)c1
Agent: O=C(O)c1cc(OCc2ccccc2F)cc([N+](=O)[O-])c1
Product: O=C(O)c1cccc(NS(=O)(=O)c2cccs2)c1

Procedure:
Methyl 3-(thiophene-2-sulfonamido)benzoate (242a) was hydrolyzed to the acid in an analogous matter to that described in for the formation of 3-(2-fluorobenzyloxy)-5-nitrobenzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[C:17]2[C:12]([C:13](=[O:38])[C:14]([CH3:37])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:41]([F:44])([F:43])[F:42].C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][C:9]1[C:18]([CH:19]([OH:20])[C:41]([F:44])([F:43])[F:42])=[C:17]2[C:12]([C:13](=[O:38])[C:14]([CH3:37])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C2CCN(C(=O)OCc3ccccc3)CC2)oc2c(C=O)c(OCc3ccccc3)ccc2c1=O
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c(C2CCN(C(=O)OCc3ccccc3)CC2)oc2c(C(O)C(F)(F)F)c(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of benzyl 4-[7-(benzyloxy)-8-formyl-3-methyl-4-oxo-4H-chromen-2-yl]piperidine-1-carboxylate (378 mg, 0.74 mmol) obtained in Example 36-1 in dimethyl sulfoxide (10 mL), molecular sieves 4A (1.0 g) and trimethyl(trifluoromethyl)silane (1.09 mL, 7.39 mmol) were added, and then the mixture was stirred at room temperature for 3 hours. Ethyl acetate (80 mL) was added to the reaction solution, and insoluble matter was removed by filtration through celite. The filtrate was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous hydrochloric acid solution (3 mL) and methanol (12 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=80/20→40/60) to obtain 392 mg of the title compound (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.C(N)CCC.O.[N+:17]([CH3:20])([O-:19])=[O:18]>C1C=CC=CC=1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[CH:20][N+:17]([O-:19])=[O:18]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: C[N+](=O)[O-]
Solvent: O
Solvent: CCCCN
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1cc(Cl)ccc1O
Reaction time: 3 h

Procedure:
5-Chloro-2-hydroxybenzaldehyde (15.6 g.) and n-butylamine (9.12 g) were refluxed in dry benzene (125 ml.) using Dean-Stark water separator for 3 hours. The benzene phase was concentrated to get the oily intermediate (23 g.). It was refluxed in glacial acetic acid (70 ml.) along with nitromethane (23 ml.) for 1 hour. The crude product was obtained by adding ice-water into the reaction mixture. The crude product was crystallised from benzene. The title product melted at 163-5° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:36])[CH:12]([C:19]2[N:20]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:21]=[C:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]=23)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([F:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=3[F:37])=[O:36])=[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:22]3=[N:21]2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 2, 4-{2-[2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid methyl ester (example 12) was hydrolysed using aqueous lithium hydroxide solution in THF and MeOH to give the title compound as white solid. MS: m/e=524.2 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:37]1([CH2:43][C:44]2[CH:45]=[C:46]([CH:60]=[CH:61][CH:62]=2)[O:47][CH2:48]/[CH:49]=[CH:50]\[CH2:51][NH:52][C:53](=[O:59])[CH2:54][S:55][CH2:56][CH2:57][NH2:58])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl>[N:37]1([CH2:43][C:44]2[CH:45]=[C:46]([CH:60]=[CH:61][CH:62]=2)[O:47][CH2:48]/[CH:49]=[CH:50]\[CH2:51][NH:52][C:53](=[O:59])[CH2:54][S:55][CH2:56][CH2:57][NH:58][C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CSCCNC(=O)c1ccc([N+](=O)[O-])o1)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
There was suspended 1.67 g (0.011 mol) of 5-nitro-2-furoic acid in 85 ml of dichloromethane and added 1.62 g (0.011 mol) of HOBt and 2.26 g (0.011 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes. Thereto was added 4.0 g (0.011 mol) of N-[4-[3-(piperidinomethyl) phenoxy]-cis-2-butenyl]-2-(2-aminoethylthio)acetamide and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 10% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by ilica gel column chromatography (chloroform:methanol=10:1) to give 0.60 g of the titled compound as oily matter.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1>ClCCl.[O-2].[Mn+2]>[CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: Cc1ncccc1CO
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ncccc1C=O
Temperature: 25 °C
Yield: 69.1 %

Procedure:
A mixture of (2-methylpyridin-3-yl)methanol (1.0 g, 8.12 mmol) in dichloromethane (10 mL) and manganese oxide (7.06 g, 81.2 mmol) was stirred at room temperature for sixty hours and then heated at 45° C. for 4 h. The reaction was filtered through celite and a plug of silica gel (5×7 cm) using ethyl acetate as eluent. The filtrate was then concentrated to give 2-methyl nicotinaldehyde as an oil (680 mg). 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.67 (dd, 1H), 8.09 (dd, 1H), 7.31 (dd, 1H), 2.88 (s, 3H).
Reaction SMILES: F[C:2]1(F)[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.I[C:19]1[CH:20]=C(C=C[CH:27]=1)C(O)=O.C1C2C(=CC=CC=2)CCN1>>[I:16][C:12]1[CH:11]=[C:10]([C:8]([N:5]2[CH2:4][C:3]3[C:7](=[CH:2][CH:27]=[CH:19][CH:20]=3)[CH2:6]2)=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(I)c1
Reactant: O=C(c1cccc(I)c1)N1CCC(F)(F)CC1
Agent: c1ccc2c(c1)CCNC2
Product: O=C(c1cccc(I)c1)N1Cc2ccccc2C1

Procedure:
According to Step 77-1 in the synthetic method for compound 77-1, 3-iodobenzoic acid 1 and morpholine 2 were used to obtain compound 85-1.
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.B([O-])([O-])[O-].[Na+].[Na+].[Na+].[CH2:18]([N+:22]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21].[CH3:35][O:36][C:37]1([NH:46]C(OCC2C=CC=CC=2)=O)[CH2:40][N:39]([S:41]([O-:44])(=[O:43])=[O:42])[C:38]1=[O:45]>CO.[Pd]>[CH2:31]([N+:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:32][CH2:33][CH3:34].[NH2:46][C:37]1([O:36][CH3:35])[CH2:40][N:39]([S:41]([O-:44])(=[O:42])=[O:43])[C:38]1=[O:45]
Reactant: COC1(NC(=O)OCc2ccccc2)CN(S(=O)(=O)[O-])C1=O
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1(N)CN(S(=O)(=O)[O-])C1=O
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
A 4% sodium borate decahydrate in methanol solution (100 μl) is added to a suspension of 10% palladium on charcoal (30 mg) in methanol (2 ml), and the mixture is stirred under an atmosphere of hydrogen for 15 minutes. 3-Methoxy-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt (60 mg; see Example 49) in methanol (2 ml) is added and the mixture is vigorously stirred for 15 minutes under a hydrogen atmosphere. Catalyst is removed by filtration through Celite on a millipore filter (0.5 mμ), and solvent is removed from the filtrate in vacuo, and the residue is extracted with methylene chloride. Removal of solvent under reduced pressure yields 35 mg of the title compound, as an oil.
Reaction SMILES: O.[N+:2]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=4)=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[CH:34][CH:35]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CCc3ccc(Cc4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cc2ccc(CCc3ccc(Cc4ccc(N)cc4)cc3)cc2)cc1
Yield: 62.9 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 2.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 25.1 g of 1,2-bis(4-(4-nitrobenzyl)phenyl)ethane in 400 milliliters of tetrahydrofuran were introduced and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Crystals were dissolved in chloroform, subjected to a column chromatography treatment with active alumina and silica gel, and thereafter the solution was reconcentrated to give a concentrate, which was then recrystallized from a toluene solvent, to obtain 13.7 g of 1,2-bis(4-(4-aminobenzyl)phenyl)ethane. Melting point was from 138.8° to 140.4° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl.[Cl:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:10]=[CH:11][CH:12]=1)N.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:10]=[CH:11][CH:12]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: Cc1c(N)cccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
Sodium cyanide (58 g, 1.18 mol) in 90 ml of water is added to cuprous chloride (44 g, 0.44 mol) in 180 ml of water while stirring mechanically in a 5 l. 3-necked flask. Evolution of heat results and the cuprous chloride dissolves. This is then cooled in an ice bath to 0° C. A milky suspension of cuprous cyanide results. To this is added 90 ml of toluene. 6 N Hydrochloric acid (125 ml) is added slowly to 3-chloro-2-methylaniline (50 g, 0.35 mol) in a 2 l. erlenmeyer flask, while cooling and swirling. A solution of sodium nitrite (25 g, 0.36 mol) in 70 ml of water is added dropwise to the hydrochloride suspension. Ice is added when required, keeping the temperature at 0° C. Anhydrous sodium carbonate is added until the diazonium hydrochloride solution is neutral to pH paper. This is then added slowly to the cold stirring cuprous cyanide suspension, the temperature not being allowed to rise above 5° C. The reaction is then stirred at 0°-5° C. for 0.5 hr, allowed to reach room temperature over a 2 hr period and then heated to 50° C. on the steam bath. After remaining at room temperature overnight, the product is steam distilled off. The distillate is extracted with benzene, washed with 10% hydrochloric acid, dried and evaporated to afford 28 g of the title compound that solidified on standing.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=1>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][O:5][C:15]1[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
3,3,3-Trifluoropropanol (0.338 g, 2.96 mmol) was dissolved in THF (5 mL) and cooled to 0 C under nitrogen. Potassium tert-butoxide (0.332 g, 2.96 mmol) was added and the mixture stirred for 5 min. Ethyl 6-chloronicotinate (0.500 g, 2.69 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h. Brine (10 mL) was added and the mixture extracted with EtOAc (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a yellow oil. This was purified by FCC, eluting with a gradient of 0-10% EtOAc in heptane to afford the title compound as a colourless oil (0.240 g, 34%), which was used in the next step without further purification. NMR shows approximately 15% unreacted ethyl 6-chloronicotinate. 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.75 (1H, d), 8.11 (1H, dd), 6.71 (1H, d), 4.55 (2H, t), 4.31 (2H, q), 2.57 (2H, m) and 1.33 (3H, t).