Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40]>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[C:25]([F:33])[CH:26]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:28]=2)[CH:12]=[C:13]([NH:40][C:39]2[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:37]([C:36]([F:35])([F:48])[F:49])[CH:38]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 97 %

Procedure:
The title compound was prepared in 97% yield from 2-(5′-fluoro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 40, step (a)) and 3,5-bis-(trifluoromethyl)aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:24]=[CH:23][C:10]([O:11][CH:12]3[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:14]1[CH2:13][CH:12]([O:11][C:10]2[CH:23]=[CH:24][C:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:8][CH:9]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CCCC3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(OC2CNC2)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.1 %

Procedure:
A solution of 1A (5.2 g, 15.5 mmol) in DCM (50 mL) was treated with TFA (10 g, 88 mmol) and stirred at RT for 17 h. The reaction mixture was concentrated and then co-evaporated using DCM. The residue was dissolved in water and the pH adjusted to pH 10 by adding NaOH. The solution was extracted several times with DCM and the organic solutions were filtered through a phase separator. The solvent was removed by evaporation. There was obtained 3.1 g (85%) of 1B as an oil. 1H NMR (500 MHz, CDCl3): δ 1.69-1.83 (m, 4H), 2.43-2.57 (m, 4H), 3.53 (s, 2H), 3.73-3.81 (m, 2H), 3.87-3.92 (m, 2H), 4.93-5.01 (m, 1H), 6.68 (d, 2H), 7.20 (d, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[S:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: COc1ccc(N2CCCNCC2)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCN(Cc3csc(-c4ccccc4)n3)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole (80 mg, 0.38 mmol, 1 equiv), 1-(2,4-dimethoxyphenyl)-[1,4]diazepane HCl salt (117 mg, 0.38 mmol, 1 equiv) and Cs2CO3 (619 mg, 5 equiv) in 1 mL of DMF was stirred at room temperature overnight. The mixture was diluted with EtOAc (˜30 mL), washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) sequentially and then dried over magnesium sulfate. The residue was purified by flash column chromatograph using 30 to 100% EtOAc in hexane to afford the title compound as light tan solid (50 mg) after evaporation and drying in vacuo. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 2H, J=8.0 Hz), 7.39 (m, 3H), 7.15 (s, 1H), 6.88 (d, 1H, J=8.8 Hz), 6.42 (s, 1H), 6.39 (d, 1H, J=8.8 Hz), 3.91 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.25 (m, 4H), 2.92 (m, 4H), 1.98 (m, 2H). MS (ES) m/z 410.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:13]3[CH:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:13]3[CH:14]=[N:15][C:16]([O:33][CH2:32][CH2:31][NH:30][CH3:29])=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2oc(Cl)cc2c1
Reactant: CNCCO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)nc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 16, step C described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(6-chloropyridin-3-yl)but-1-enyl)phenol (70 mg, 1.0 eq) was reacted with 2-(methylamino)ethanol (128 mg, 10 eq) to give the desired product (Z/E=1/1). m/z=449[M+1]+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([P:18](=[O:21])([OH:20])[OH:19])[NH:9][S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].ClC(Cl)(Cl)C#N>N1C=CC=CC=1>[NH4+:9].[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:21][P:18]([CH:8]([NH:9][S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:12])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:19])[O-:20])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=P(O)(O)C(Cc1ccccc1)NS(=O)(=O)c1cccs1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: N#CC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(OP(=O)([O-])C(Cc2ccccc2)NS(=O)(=O)c2cccs2)cc1
Product: [NH4+]
Temperature: 105 °C
Yield: 107.1 %

Procedure:
To sealed tube containing phosphonic acid (xiii) (50 mg; 0.14 mmol) and sublimed 4-nitrophenol (24 mg; 0.17 mmol) was added pyridine (0.7 mL) and trichloroacetonitrile (100 μL; 1.0 mmol). The reaction was heated to 105° C. for 6 hrs then was cooled and concentrated. The residue was purified by flash chromatography (chloroform-methanol-concentrated ammonium hydroxide; 8:2:0.25) to yield the ammonium salt 44 (36.4 mg, 52%) as a colorless solid: 1H NMR (400 MHz, CD3OD) δH 2.83 (td, J=9, 14 Hz, 1H, CHPh), 3.23-3.29 (m, 1H, CHPh), 3.95-4.02 (m, 1H, NCHP), 6.85 (dd, J=4, 5 Hz, 1H, Ar—H), 7.08-7.20 (m, 6H, Ar—H), 7.27-7.31 (m, 2H, Ar—H), 7.52 (dd, J=1.5, 5 Hz, 1H, Ar—H), 8.12-8.16 (m, 2H, Ar—H); 31P NMR: (162 MHz, CD3OD) δP 16.7; 13C NMR: (100 MHz, CD3OD) δP 38.1, 122.0, 125.9, 127.3, 128.3, 129.2, 130.6, 132.2, 132.3, 144.4, 144.5.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N(Cl)C(=O)C1.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36](=[O:45])[N:37]([CH3:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:31][CH:30]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36](=[O:45])[N:37]([CH3:44])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:33][CH:34]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Reactant: O=S([O-])c1ccc(OCCN2CCCC2)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCNS(=O)(=O)c2ccc(OCCN3CCCC3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (6.72 g, 25 mmol) in THF (45 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (14 mL, 22.4 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min. Then gaseous sulphur dioxide (ca. 6 g) was added causing an immediate precipitation. The mixture was allowed to warm to room temperature and stirred for 1 h. The precipitated lithium sulfinate was isolated by filtration under N2 (g), washed with THF (40 mL) and dried in vacuo providing 5.04 g (78%) of lithium; 4-(2-pyrrolidin-1-yl-ethoxy)-benzenesulfinate as a solid. This lithium sulfinate (179 mg, 0.69 mmol) was suspended in CH2Cl2 (2 mL) and stirred with NCS (80 mg, 0.60 mmol) for 10 min at rt. A solution of N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.55 mmol) in CH2Cl2 (3 mL) was added together with DIPEA (2.0 mmol). The mixture was stirred at rt for 16 h and evaporated to dryness. It was then redissolved in MeCN and purified by preparative HPLC (Gilson). This gave 89 mg (25%) of the title compound as its TFA salt as a crystals.
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[CH2:21]([NH2:23])[CH3:22]>O1CCCC1>[CH2:21]([NH:23][C:2]1[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[CH3:22]
Reactant: CCN
Reactant: COCOCc1nc(OC)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1ccc(OC)nc1COCOC
Yield: 73.7 %

Procedure:
A solution of 3-bromo-6-methoxy-2-[(methoxymethoxy)methyl]pyridine (1.50 g, 5.72 mmol), tris(dibenzylideneacetone)(chloroform)dipalladium(0) (592 mg, 0.572 mmol), (2-biphenyl)di-t-butylphosphine (680 mg, 2.28 mmol), sodium t-butoxide (1.65 g, 17.2 mmol) and ethylamine (2.0 M solution in tetrahydrofuran, 15 mL, 30 mmol) in tetrahydrofuran (15 mL) was warmed to 135° C. over 3 minutes under microwave irradiation (500 W). The reaction mixture was cooled, then filtered through Celite, and washed with ethyl acetate. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (954 mg, 74%) as yellow oil.
Reaction SMILES: [Pd:1].[NH+]([O-])=O.[C:5]([OH:8])(=[O:7])[CH3:6]>>[C:5]([O-:8])(=[O:7])[CH3:6].[C:5]([O-:8])(=[O:7])[CH3:6].[Pd+2:1]
Reactant: CC(=O)O
Reactant: [Pd]
Agent: O=[NH+][O-]
Product: CC(=O)[O-]
Product: [Pd+2]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Palladium diacetate was prepared from palladium sponge, acetic acid and HNO2 by adding 0.295 g. of palladium sponge and 45 ml. of glacial acetic acid in the apparatus described in example 1. The resulting mixture was stirred at ambient temperature for about 2 hours with an occasional addition of gaseous HNO2 to the mixture. The mixture was stirred overnight at ambient temperature and was then heated to 115° C. for one hour while being purged with argon. The resulting brown-red solution was filtered and the filtrate was concentrated to yield orange-red crystals of trimeric, hydrocarbon-soluble palladium diacetate in 96% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[NH2:17])(=[O:4])=[O:3].[F:18][C:19]1[CH:32]=[CH:31][C:22]2[S:23][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:25]([CH3:26])[C:21]=2[CH:20]=1.[H-].[Na+]>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:17][S:27]([C:24]1[S:23][C:22]2[CH:31]=[CH:32][C:19]([F:18])=[CH:20][C:21]=2[C:25]=1[CH3:26])(=[O:29])=[O:28])(=[O:4])=[O:3]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Yield: 5.2 %

Procedure:
This compound was prepared in analogy to Example 20f starting from 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (cf. Example 20c, 0.27 g) in tetrahydrofurane (10 ml) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (0.265 g) with sodium hydride (0.10 g) at rt for 18 h to obtain the title compound (0.025 g) as a yellow foam. MS (ISN): 475.0 (M−H)−
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CN(C)C=O.N1C=CN=C1.[CH3:19][C:20]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])[CH3:21]>O>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:1][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Yield: 95.1 %

Procedure:
80.89 g of p-bromophenol, 400 ml of dimethylformamide, 31.18 g of imidazole and 125.89 g of 1,1-dimethyl-ethyl-diphenylchlorosilane were stirred for 2 hours at ambient temperature and the reaction medium was poured into 2 liters of water. Extraction was carried out with ethyl acetate, followed by decanting, drying and evaporating under reduced pressure. After crystallization from pentane, separation was carried out, followed by drying to obtain 179.24 g of the expected product with a Rf=0.53 (thin layer chromatography, support: silica, eluant: cyclohexane/AcOEt 95/5) and a melting point of 56° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[H-].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH:14](C)[CH2:13][C:12]2=[O:29].C(OCC)=O>C1C=CC=CC=1.C(O)C>[OH:1][CH:2]=[C:3]1[C:12](=[O:29])[C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([O:8][CH3:7])[CH:10]=2)[N:15]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH:14]1[CH3:13]
Reactant: CC[O-]
Reactant: CCCCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCOC=O
Product: CCCCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To sodium ethoxide freshly prepared from 4.8 g. of sodium hydride and 6.0 ml. of ethanol is added 16.0 g. of butyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate and 19.8 ml. of ethyl formate in 150 ml. of benzene over a 30 min. period. The reaction mixture, after stirring at room temperature for 4 hrs., is poured onto 250 ml. of ice-water. The aqueous layer is retained and the organic layer extracted with 1N aqueous sodium hydroxide. The base extracted is combined with the separated aqueous and backwashed with benzene. The aqueous layer is then added to 250 ml. of 12N hydrochloric acid. The resulting yellow oil is extracted with chloroform and the chloroform layer dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual product used in subsequent reactions without further purification.
Reaction SMILES: [C:1]12([C:11]([C:13]3[C:18]([OH:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=3[Cl:21])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:23][OH:24].N1C=CC=CC=1>CCOC(C)=O.C1(C)C=CC=CC=1>[C:1]12([C:11]([C:13]3[C:18]([OH:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=3[Cl:21])=[N:23][OH:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(c1c(O)cc(O)cc1Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: ON=C(c1c(O)cc(O)cc1Cl)C12CC3CC(CC(C3)C1)C2

Procedure:
1-adamantyl-(2-chloro-4,6-dihydroxyphenyl)methanone (1.9 g, 6.2 mmoles), hydroxylamine hydrochloride (100 g) and pyridine (50 ml) were refluxed for 4 h. The mixture was concentrated under vacuum, poured into water, extracted with ethyl acetate, washed with HCl 1N, dried over Na2SO4 and concentrated under vacuum to give the crude product. Flash chromatography (AcOEt/toluene 3/7) gave the pure oxime (1 g as a solid, 50%).
Reaction SMILES: C([N:11]([CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:43]([OH:51])(=[O:50])[CH:44]([CH2:46][C:47]([OH:49])=[O:48])[OH:45].[H][H]>O1CCCC1.[Pd].CCOCC>[CH2:21]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:50][C:43](=[O:51])[CH:44]([CH2:46][C:47]([OH:49])=[O:48])[OH:45])=[O:17])=[CH:19][CH:20]=1)[CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35]
Reactant: [H][H]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: C=CCCCCCCCCC=CCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCCCCCCCCC=CCCCNc1ccc(C(=O)OC(=O)C(O)CC(=O)O)cc1

Procedure:
To a warm solution of N-carbobenzyloxy-4-(4,14-pentadecadienylamino)benzoyl chloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is wahsed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops. The catalyst is filtered. The solution is evaporated and the residue is crystallized from acetic acid to yield the title compound as white crystals.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[F:16][C:17]1[N:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[CH:19][CH:18]=1.Cl.[CH3:27][O:28][NH:29][CH3:30]>C(Cl)Cl>[CH3:27][O:28][N:29]([CH3:30])[C:23]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[N:22]=1)=[O:25]
Reactant: CNOC
Reactant: O=C(O)c1cccc(F)n1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1cccc(F)n1
Reaction time: 17 h
Yield: 19.6 %

Procedure:
Add N-methylmorpholine (6 mL, 52 mmol) and isobutylchloroformate (3.5 mL, 26.9 mmol) to a solution of 6-fluoropyridine-2-carboxylic acid (3.8 g, 26.9 mmol) in methylene chloride at 0° C. After 15 minutes add O,N-dimethylhydroxylamine hydrochloride (2.6 g, 26.9 mmol) and N-methylmorpholine (3 mL, 26.9 mmol). Stir the reaction at 0° C. for 15 minutes and then room temperature for 17 hours. Dilute the reaction with methylene chloride and wash sequentially with water (1×50 mL), 10% aqueous citric acid (1×50 mL), brine (1×50 mL), saturated aqueous sodium bicarbonate (1×50 mL), and brine (1×50 mL). Dry the resulting organic solution with Na2SO4, filter, and purify by flash column chromatography (Silica Gel, 20% acetone/hexanes) to provide the title compound 0.97 g (18% from 2-fluoro-5-methylpyridine) as a clear, yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[CH:12]2[CH2:13][C:14](=O)[CH2:15][CH2:16][CH:11]2[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.C(O)C>[CH2:1]([N:8]1[C:18](=[O:19])[CH:12]2[CH:11]([CH2:16][CH2:15][C:14]3[NH:31][C:25]4[C:30]([C:13]=32)=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: O=C1CCC2C(=O)N(Cc3ccccc3)C(=O)C2C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1C2CCc3[nH]c4ccccc4c3C2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Yield: 29 %

Procedure:
To 7 ml of anhydrous ethanol were added 510 mg of N-benzyl-4-oxocyclohexane-1,2-dicarboximide, 490 mg of concentrated sulfuric acid and 220 mg of phenylhydrazine. The mixture was refluxed for 2 hours and then cooled to room temperature. Thereto were added 30 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: benzene/ethyl acetate =50/1 to 20/1) to obtain two fractions. The first obtained fraction was concentrated to dryness under reduced pressure, and the residue was recrystallized from isopropyl alcohol to obtain 190 mg (yield: 29%) of N-benzyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide as colorless needles. The later obtained fraction was concentrated to dryness under reduced pressure to remove the solvent, and the residue was recrystallized from isopropyl alcohol to obtain 120 mg (yield: 18%) of N-benzyl-1,2,3,4-tetrahydrocarbazole-2,3-dicarboximide as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O-:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:23]1([C:26]([OH:28])=O)[CH2:25][CH2:24]1.[CH:29](N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:23]1([C:26]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:29])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=[CH:6][CH:7]=2)=[O:28])[CH2:25][CH2:24]1
Reactant: O=C(O)C1CC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)Cc2cc(C(=O)[O-])ccc2NC1c1cccc(N)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)C3CC3)c1)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
To an ice-cold mixture of 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (150 mg, 0.48 mmol), cyclopropanecarboxylic acid (86.1 mg, 0.73 mmol), N,N-diisopropyl ethylamine (0.16 mL, 0.96 mmol) in dichloromethane (10 mL) was added a solution of phosphorus oxychloride (0.08 mL, 0.82 mmol). Then the reaction mixture was stirred at room temperature for 2.5 h. LC-MS indicated that the starting material was consumed completely. Solvent was removed in vacuo and the residue was purified by Prep. thin layer chromatography (petroleum ether/ethyl acetate=2:1) to afford 109 mg of methyl 2-(3-(cyclopropanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; Yield: 59.8%;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][NH:14][C:15]2[C:16]3[C:21]([N:22]=[C:23]4[C:28]=2[C:27](=[O:29])[CH2:26][CH2:25][CH2:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]2[C:16]3[C:21]([N:22]=[C:23]4[C:28]=2[CH:27]([OH:29])[CH2:26][CH2:25][CH2:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccc(OCc4ccccc4)cc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccc(OCc4ccccc4)cc3)c21
Reaction time: 1 h

Procedure:
To a cooled suspension of 4.75 g of 3,4-dihydro-9-[4-(benzyloxy)benzylamino]acridin-1(2H)-one in 75 ml of tetrahydrofuran was added 6 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. This was stirred for 1 hour.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.Cl.[CH3:10][O:11][C:12](=[O:24])[CH:13]([N:21]=[N+]=[N-])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C.C(OC)(=O)C.[Re]([O-])(=O)(=O)=O.[Na+]>[CH3:10][O:11][C:12](=[O:24])[C:13]([N:21]=[C:2]=[O:1])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(Cc1ccccc1)N=[N+]=[N-]
Agent: O=[Re](=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(=Cc1ccccc1)N=C=O

Procedure:
27.3 mg (0.1 mmole) of sodium perrhenate and 1.04 grams (5.25 mmoles) of diphosgene were present at 80° C. in 1 ml of ethyl acetate saturated with hydrogen chloride. Then there were added within 20 minutes with vigorous stirring 2.05 grams (10 mmoles) of 2-azido-3-phenylpropionic acid methyl ester dissolved in 5 ml of methyl acetate. After reaction for 1 hour at 80° C., the mixture was worked up analogous to Example 1. The crude produce was distilled in a high vacuum (0.0013 mbar) at 90° to 110° C. apparatus temperature in a bulbed tube. There resulted 1.08 grams (53.2% of theory) of analytically pure 2-isocyanato-3-phenylpropenoic acid methyl ester.