Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[O:9][C:10]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[O:24][CH2:26][C:27]([O:29][CH3:30])=[O:28])[O:9][C:10]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1cccc(CCc2nc(-c3cccs3)c(-c3cccs3)o2)c1
Reactant: COC(=O)CBr
Product: COC(=O)COc1cccc(CCc2nc(-c3cccs3)c(-c3cccs3)o2)c1

Procedure:
Reaction of 3-[2-[4,5-di(2-thienyl)-2-oxazolyl]-ethyl]phenol with methyl bromoacetate according to the procedure of Example 29 provided the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][N:8]([CH2:26][C:27]([O:29]CC)=O)[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[O:17])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][OH:33]>O1CCOCC1>[OH:33][NH:32][C:27](=[O:29])[CH2:26][N:8]([CH2:7][CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)=[O:17])=[O:10]
Reactant: NO
Reactant: CCOC(=O)CN(CCC1CCCC1)C(=O)N1CCCC1C(=O)Nc1cccc(O)c1
Solvent: C1COCCO1
Product: O=C(CN(CCC1CCCC1)C(=O)N1CCCC1C(=O)Nc1cccc(O)c1)NO
Reaction time: 36 h

Procedure:
To ethyl 2-[N-(2-(cyclopentyl)ethyl)-N-[2-(3-hydroxyphenyl)aminocarbonyl-pyrrolidin-1-carbonyl)amino]acetate (200 μmol) in dioxane (2 mL) was added 50% aqueous hydroxylamine (1 mL), and the reaction stirred for 36 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-{N-[2-(cyclopentyl)ethyl]-N-[2-(3-hydroxyphenyl)aminocarbonylpyrrolidin-1-ylcarbonyl]-amino}acetamide. 1H NMR (DMSO-d6): δ9.33 (br s, 1H), 7.25-7.24 (m, 1H), 7.07-6.99 (m, 2H), 6.45-6.41 (m, 1H), 4.38 (dd, J=8.4, 8.4, 1H), 3.88 (d, J=16.5, 1H), 3.66 (d, J=16.5, 1H), 3.48-3.46 (m, 2H), 3.27-3.22 (m, 1H), 3.20-3.01 (m, 1H), 2.19 (br s, 1H), 1.91 (br s, 1H), 1.73-1.68 (m, 5H), 1.63-1.41 (m, 6H), 1.08-1.05 (m, 2H). ES−MS: calcd. for C21H30N4O5 (418.2); found: 417.7 [M−1].
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6](SC)=[N:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[CH3:21][C:22]1[S:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[N+:26]=1[CH3:27].C(N(CC)CC)C>CN(C)C=O>[I-:1].[CH3:27][N+:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[S:23][C:22]=1[CH:21]=[C:6]1[N:5]=[C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:3]([CH3:2])[C:8]2[CH:9]=[CH:10][S:11][C:7]1=2
Reactant: Cc1sc2ccccc2[n+]1C
Reactant: CSc1nc(-c2ccccc2)[n+](C)c2ccsc12
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(c2ccccc2)=NC(=Cc2sc3ccccc3[n+]2C)c2sccc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
200 mg (0.50 mmol) 1-Methyl-4-methylsulfanyl-2-phenyl-thieno(3,2-d)pyrimidin-1-ium iodide and 145 mg (0.50 mmol) 2,3-dimethyl-benzothiazol-3-ium iodide were dissolved in 2.0 ml dimethylformamide and 202 mg (0.28 ml, 2.00 mmol) triethylamine were added. The green solution was stirred for 1 h at 80° C., filtrated and the residue was washed with methanol. The crude product was purified further by HPLC.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[F:25][B-](F)(F)F.F[B-](F)(F)F.F[N+]1C=CC=CC=1C1C=CC=C[N+]=1F.[Na]>C(#N)C>[F:25][C:12]1[CH:13]=[C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:3][CH:2]2[OH:1])[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: F[B-](F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: F[n+]1ccccc1-c1cccc[n+]1F
Agent: [Na]
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(O)c(F)c2)C(O)C1

Procedure:
A solution of 0.581 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate in 5 ml of acetonitrile is admixed with 0.320 g of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) and the suspension is subsequently heated at reflux over 15 hours. The reaction mixture is poured onto 10 ml of saturated aqueous sodium thiosulpphate solution and the mixture is extracted with 2×50 ml of ethyl acetate. The combined organic phases are washed with 10 ml each of 0.5 M HCl and brine, dried over sodium sulphate and concentrated. The title compound is obtained as a colourless solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (2:1 EtOAc-heptane); Rt=3.80.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:12]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:9])=[C:10]([I:12])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CC(C)(C)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of commercially available 4-tert-butylaniline (2.00 g, 13.4 mmol) in MeOH (10 mL) was added to a mixture of silver sulfate (4.17 g, 13.4 mmol) and iodine (3.39 g, 13.4 mmol) in MeOH (30 mL). The mixture was stirred at room temperature for 4 h. The mixture was filtered. The filtrate was concentrated. The title compound was obtained after flash chromatography using EtOAc:hexane/2:8 as the eluant. 1H NMR (CDCl3, 500 MHz): B7.65 (d, J=2. Hz, 1H), 7.20 (dd, J=8.5, 2.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 1.30 (s, 9H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.C(N(CC)CC)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.O>ClCCl>[C:27]1([C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:25])=[CH:22][CH:23]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.26 g (1.2 mmol) of 4-biphenylcarbonyl chloride was added under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to yield the desired product.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Si:12]([O:19][CH:20]1[CH2:37][N:25]2[C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[CH:28][C:27]=3[N:36]=[C:24]2[CH2:23][N:22]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(Cl)(Cl)Cl.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:61]>>[NH2:61][C:28]1[C:27]2[N:36]=[C:24]3[CH2:23][N:22]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:21][CH:20]([O:19][Si:12]([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14])[CH2:37][N:25]3[C:26]=2[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1Cc2nc3cnc4ccccc4c3n2CC(O[Si](C)(C)C(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1Cc2nc3c(N)nc4ccccc4c3n2CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
mCPBA (3.89 g of 77% pure material, 17.36 mmol) was added to a solution of tert-butyl 11-{[tert-butyl(dimethyl)silyl]oxy}-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (4.07 g, 8.68 mol chloroform, and the reaction was stirred for 30 minutes at ambient temperature. Additional mCPBA (0.5 equivalent) was added, and the reaction was stirred for four hours. Ammonium hydroxide (50 mL) was added with vigorous stirring, and after ten minutes, p-toluenesulfonyl chloride (1.82 g, 9.55 mmol) was added. The reaction was stirred overnight at ambient temperature and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 98.5:1:0.5 and 89:10:1 dichloromethane:methanol:ammonium hydroxide), and the resulting product was dried under high vacuum to provide 2.25 g of tert-butyl 6-amino-11-{[tert-butyl(dimethyl)silyl]oxy}-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:34])([F:33])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C(Cl)Cl>[F:34][C:9]([F:8])([F:33])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][CH2:18][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(C(F)(F)F)cc3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(N2CCC3(CCNC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 ml) was added to a cooled (0° C.) solution of tert-butyl 8-(4-(trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.47 mmol, 1.0 eq.) in methylene chloride (3 ml) and the reaction mixture was stirred at 25° C. for 1 h. When the reaction was complete, the solvent was removed in vacuo in order to obtain the desired amine (AMN-23).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:39][CH2:38][C:21]3([N:25]=[C:24]([C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([OH:36])[CH:27]=4)[NH:23][C:22]3=[O:37])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:9]([CH3:40])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:42]([O:46][C:47]([N:49]([CH3:72])[CH2:50][CH2:51][O:52][CH2:53][C:54]([F:71])([F:70])[C:55]([F:69])([F:68])[C:56]([F:67])([F:66])[CH2:57]OS(C(F)(F)F)(=O)=O)=[O:48])([CH3:45])([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:19][CH2:20][C:21]3([N:25]=[C:24]([C:26]4[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([O:36][CH2:57][C:56]([F:66])([F:67])[C:55]([F:68])([F:69])[C:54]([F:70])([F:71])[CH2:53][O:52][CH2:51][CH2:50][N:49]([C:47]([O:46][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:48])[CH3:72])[CH:27]=4)[NH:23][C:22]3=[O:37])[CH2:38][CH2:39]2)(=[O:16])=[O:17])=[C:9]([CH3:40])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(O)cc(C(F)(F)F)c1)NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCC(F)(F)C(F)(F)C(F)(F)COCCN(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1)NC2=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
4-{2-[2-(3-Hydroxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester (77.0 mg, 0.13 mmol) and trifluoro-methanesulfonic acid 5-[2-(tert-butoxycarbonyl-methyl-amino)-ethoxy]-2,2,3,3,4,4-hexafluoro-pentyl ester (58.0 mg, 0.13 mmol) were dissolved in DMF (1 ml). Potassium carbonate (53.8 mg, 0.39 mmol) was added and the mixture was stirred at 60° C. overnight. The reaction mixture was extracted with ethyl acetate, and the organic layer was then washed with saturated brine, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-{2-[2-(3-{5-[2-(tert-butoxycarbonyl-methyl-amino)-ethoxy]-2,2,3,3,4,4-hexafluoro-pentyloxy}-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester (57 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]1OCC[O:18]1)([CH2:7][CH3:8])[CH2:5][CH3:6]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]=[O:18])([CH2:5][CH3:6])[CH2:7][CH3:8]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(Oc1ccc(Cl)cc1C=O)C(=O)OC
Yield: 93.6 %

Procedure:
A solution of 2-(4-chloro-2-[1,3]dioxolan-2-yl-phenoxy)-2-ethyl-butyric acid methyl ester (16 g, 48.8 mmol) in trifluoroacetic acid (20 mL) was stirred at room temperature for 3 h. Then the mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was washed with IN NaOH solution, water, dried over anhydrous Na2SO4 and concentrated to give the title compound (13 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:17]C(=O)[O-])[C:5]1[CH:6]=[N:7][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=1.C(OC(=O)C)C.Cl>>[CH3:1][O:2][CH2:3][CH:4]([C:5]1[CH:6]=[N:7][C:8]([O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:9][CH:10]=1)[NH2:17]
Reactant: COCC(NC(=O)[O-])c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCC(N)c1ccc(OCC(F)(F)F)nc1
Yield: 91.5 %

Procedure:
(2-methoxy-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamate (0.046 g, 0.131 mmol, Step-9, single enantiomer) and 4M hydrochloric acid ethyl acetate solution (4 mL) is stirred at room temperature for 2 hours. After removal of the solvent, the residue is diluted with methanol (4 mL) and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix is rinsed with methanol (5 mL). The crude mixture is eluted with 1M ammonia in methanol (5 mL) and concentrated under reduced pressure to give 0.030 g (91% yield) of the title compound as colorless syrup.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:29])[NH:6][C:7](=[O:28])[N:8]([C@@H:10]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@@H:11]2[O:12]C(=O)C)[CH:9]=1)#[C:2][CH3:3]>O1CCOCC1>[C@@H:10]1([N:8]2[CH:9]=[C:4]([C:1]#[C:2][CH3:3])[C:5](=[O:29])[NH:6][C:7]2=[O:28])[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@@H:11]1[OH:12]
Reactant: CC#Cc1cn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)c(=O)[nH]c1=O
Solvent: C1COCCO1
Product: CC#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]c1=O
Reaction time: 18 h
Yield: 82.5 %

Procedure:
Product of stage (b) (0.3 g, 0.73 mmol) was dissolved in 20 ml of dioxan/880 ammonia/water (3:2:1) and left standing at room temperature for 18 hours. The solvent was evaporated and co-evaporated with ethanol and final recrystallisation of the residue from ethanol afforded 0.17 g of the title compound (82%) melting at 225°-227° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:17]([C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:29]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[CH:33][CH:32]=3)=[O:30])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccnc3Nc3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.296 g of 6,11-dihydropyrido[2,3-b][1,5]benzodiazepine, 0.604 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride and 0.232 g of N,N-diisopropylethylamine in 6 ml of dichloromethane is stirred at room temperature for 1.5 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with H2O, saturated NaHCO3, H2O, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is purified on thick layer silica gel plates with hexane-ethyl acetate (1:2) as solvent to give the product as a solid which is crystallized from ethyl acetate to give off-white crystals, m.p. 220° C.-221° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH2:30]([O:37][C:38](=[O:48])[CH2:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:41]([N:40]([CH2:39][C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:48])[C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O=C(CNCc1ccccc1)OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OCc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
To a solution of (2R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid (5.14 g) in dichloromethane (50 ml) was added triethylamine (8.49 ml), N-benzylglycine benzyl ester hydrochloride (5.08 g), and 2-chloro-1-methylpyridinium iodide (4.89 g) under ice-bath cooling. After being stirred at room temperature 90 minutes, the reaction mixture was concentrated under reduced pressure, and ethyl acetate (50 ml) and water (50 ml) were added to the residue with stirring, adjusted pH 1 with diluted hydrochloric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (100 g) using a mixed solvent of toluene and ethyl acetate (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give N-benzyl-N-(benzyloxycarbonylmethyl)-(2R)-2-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propionamide (8.57 g) as a syrup.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH:3]=O.[CH2:15]([NH2:17])[CH3:16].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH2:15]([NH:17][CH2:3][C:2]([CH3:5])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:1])[CH3:16]
Reactant: CCN
Reactant: CC(C)(C=O)c1ccc([N+](=O)[O-])cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CCNCC(C)(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
In a 250 mL round bottom flask was charged 2-methyl-2-(4-nitrophenyl)propanal (2.00 g, 10.4 mmol), absolute ethanol (30 mL), ethyl amine solution (20.7 mL, 1M in THF). Titanium isopropoxide (6.2 mL, 20.7 mmol) was added and the mixture was stirred at ambient temperature for 1 h. Sodium borohydride (1.17 g, 31 mmol) was added and the reaction stirred for an additional 1 h. The reaction was quenched by pouring into 10% ammonium hydroxide solution (25 mL), ethyl acetate was added and the solids were removed by filtration, the pad was washed once with ethyl acetate and the solvent was concentrated in vacuo to give N-ethyl-2-methyl-2-(4-nitrophenyl)propan-1-amine (2.25 g, 98%). LC/MS (ESI+) 223 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:15]([F:24])[C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]1)(=[O:11])=[O:10].C(OCC)(=O)C.[ClH:41]>C(O)C>[ClH:41].[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:15]([F:24])[C:14]([CH2:25][NH:26][CH3:27])=[CH:13]1)(=[O:10])=[O:11]
Reactant: CN(Cc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2cccnc2F)c1F
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
tert-Butyl ({1-[(2,6-difluorophenyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (430 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 283 mg, 75%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:9])[CH3:6].O.[C:24](Cl)(=[O:26])[CH3:25]>>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][C:18]([C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=3)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C(C)=O)cc12
Reaction time: 0.08 h

Procedure:
400 mg of AlCl3 was suspended in 10 ml of acetyl chloride at 0° C. and 600 mg of beta-carboline-3-carboxylic acid ethyl ester was added. After 5 minutes, 600 mg of AlCl3 was added and the mixture was stirred for 1 hour. Alcohol was added and the pH adjusted to 7-8. 50 ml of water was added and the filtered mixture yielded 450 mg of raw product, which was recrystallized from ethanol/water (1:1). Mp: 290°-305° C.
Reaction SMILES: C1(N)CCCCC1.[CH:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[Na]>CO>[CH:11]1([NH:10][CH:8]=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=CNc1ccccc1
Agent: [Na]
Solvent: CO
Solvent: NC1CCCCC1
Product: O=CNC1CCCCC1
Temperature: 100 °C
Yield: 79 %

Procedure:
To the reactor described in Example 1, there is placed 99 grams cyclohexylamine, 14 grams (0.1 mole) of sodium formanilide and 150 grams of methanol. The autoclave is closed and purged with carbon monoxide, the temperature raised to 100° C. with atmospheric steam and carbon monoxide introduced at 28 kg/cm2 for about an hour. The reaction mixture is then cooled and vented, 10 milliliters of concentrated hydrochloric acid is added and the solvent is removed by distillation. Benzene is then added and the benzene solution filtered through a bed of filter acid. Distillation gives N-cyclohexyl formamide, boiling point 118°-130° C. at 3 milliliters. The expected yield is about 79%.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][C@@H:10]3[C@H:14]([CH3:15])[C@@H:11]3[C:12]=2[CH:13]=1)=[O:5])C.[OH-].[Na+]>>[CH3:15][C@H:14]1[C@H:10]2[CH2:9][C:8]3[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:13][C:12]=3[C@@H:11]12
Reactant: CCOC(=O)c1cc2c([nH]1)C[C@@H]1[C@H](C)[C@H]21
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1[C@H]2Cc3[nH]c(C(=O)O)cc3[C@@H]12

Procedure:
The title compound was synthesized from ±(1S,1aS,5aR)-1-methyl-1a,4,5,5a-tetrahydro-1H-4-aza-cyclopropa[α]pentalene-3-carboxylic acid ethyl ester (0.12 g, 0.585 mmol) and sodium hydroxide (1.5M, 3.1 mL) according to General Procedure 7 to afford the title compound. LC-MS: MS m/z: 178 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([CH:16]1[CH2:21][CH2:20][N:19](CC2C=CC=CC=2)[CH2:18][CH2:17]1)=[O:15]>CC1C=CC=CC=1C>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:18][CH2:17]1)=[O:15]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccccc1C(=O)C1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)N1CCC(C(=O)c2ccccc2C)CC1

Procedure:
A mixture of 12 parts of ethyl carbonochloridate, 31 parts of (2-methylphenyl)[1-(phenylmethyl)-4-piperidinyl]methanone and 270 parts of dimethylbenzene is stirred and refluxed for 4 hours. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is washed with a dilute hydrochloric acid solution. The organic phase is separated, dried, filtered and evaporated, yielding 20 parts of ethyl 4-(2-methylbenzoyl)-1-piperidinecarboxylate as an oily residue.