Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[N:29]([CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)=[C:30]=S.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:30]([NH:29][CH2:32][CH2:33][NH2:34])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCN)n(CC3CCOCC3)c12
Reaction time: 1 h
Yield: 31 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and 1,1-dimethylethyl (2-isothiocyanatoethyl)carbamate (50 mg). The crude product isolated was treated with TFA (2 ml) in DCM (10 ml), the mixture stirred for 1 h, then evaporated in vacuo. The residue was dissolved in DMSO (1 ml) and purified by MDAP (HpH method) to give the title compound as a beige solid (26 mg, 31%). LCMS (HpH) Rt 0.73 min, MH+ 451
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:10]([C:18]([C:20]2[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:22][O:23][C:24]=2[CH2:25]Cl)=[O:19])[N:9]=[N:8]1.C(N(CC)CC)C.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>ClCCl>[F:38][C:37]([F:39])([F:40])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:41])([F:1])[F:42])[CH:36]=1)[CH2:6][N:7]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:10]([C:18]([C:20]2[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:22][O:23][C:24]=2[CH2:25][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:19])[N:9]=[N:8]1
Reactant: C1COCCN1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CN1CCOCC1
Temperature: 25 °C
Yield: 93 %

Procedure:
Heat a mixture of [1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-chloromethyl-3-(2-chloro-phenyl)-isoxazol-4-yl]-methanone (100 mg, 0.158 mmol), triethylamine (80 mg, 0.790 mL) and morpholine (0.79 mL) at 50° C. for 18 h. Cool to RT, dilute the mixture with dichloromethane (50 mL) and wash with water (4×40 mL). Dry the organic layer with anhydrous MgSO4, filter, and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to give the title compound (93% yield) as a brown oil. MS (ES) 685.2 (M++1); TLC Rf=0.1 (75% EtOAc in hexanes).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:15][C:13]1[CH:12]=[N:11][CH:10]=[C:9]([C:24]#[C:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH:14]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#Cc1cccc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Clc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
Add triethylamine (2.38 mL, 16.88 mmol), copper (I) iodide (80.4 mg, 0.422 mmol) and bis(triphenylphosphine)palladium (II) dichloride (148 mg, 0.211 mmol) to a solution of 3,5-dibromopyridine (1 g, 4.22 mmol) and 1-chloro-3-ethynylbenzene, (prepared as described in PREPARATION 12), (574 mg, 4.22 mmol) in ethyl acetate (4.22 mL). Stir under nitrogen at 50° C. for 18 h. Concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, to give the title compound (571 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:6](I)[C:5]2=[O:19].[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:32]=[CH:33][C:34]([C:6]3[C:5](=[O:19])[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[O:8][C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:35][CH:36]=2)[CH2:28][CH2:29][CH2:30]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=c1c(I)c(-c2ccccc2)oc2ccc(F)cc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Temperature: 125 °C
Yield: 30.2 %

Procedure:
To a microwave vial were added 6-fluoro-3-iodo-2-phenyl-chromen-4-one (55 mg, 0.15 mmol), {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (62 mg, 0.165 mmol, prepared as described in WO2008/070016), sodium carbonate solution (2M in water, 0.26 mL, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) and DME (3 mL). The reaction mixture was purged using argon and heated in a microwave reactor to 125° C. for 30 min. The mixture was partitioned between water (2 mL) and EtOAc (3 mL). The aqueous phase was extracted with ethyl acetate (3 mL). The combined organic extracts were washed with brine (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 30% ethyl acetate in cyclohexane) to afford the title compound (22 mg, 30%). 1H NMR (400 MHz, CDCl3): δ 7.95-7.90 (m, 1H), 7.57-7.52 (m, 1H), 7.46-7.30 (m, 6H), 7.28-7.22 (m, 2H), 7.21-7.16 (m, 2H), 5.03 (s, 1H), 2.64-2.31 (m, 4H), 2.14-2.00 (m, 1H), 1.89-1.77 (m, 1H), 1.48-1.18 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[N:13]=[CH:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[N:13]=[CH:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)=[C:2]([CH:7]=1)[NH2:1]
Reactant: Nc1cc(Cl)ccc1S
Reactant: CCCn1cnc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc(CSc2ccc(Cl)cc2N)c1
Yield: 67 %

Procedure:
(1-propyl-1H-imidazol-4-yl)methanol (535 mg, 3.11 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 4-(chloromethyl)-1-propyl-1H-imidazole. Then following General Procedure A, the title compound (587 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (744 mg, 4.66 mmol), 4-(chloromethyl)-1-propyl-1H-imidazole, K2CO3 (2.1 g, 15.54 mmol) in DMF (10 ml).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:13]=2[O:17][CH2:18][CH2:19][CH3:20])[N:8]1[C:27](=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[CH3:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:21]3[CH2:26][CH2:25][N:24]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23][CH2:22]3)[C:13]=2[O:17][CH2:18][CH2:19][CH3:20])[N:8]1[C:27](=[O:29])[CH3:28]
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1c(C2CCN(S(C)(=O)=O)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Methanesulfonyl chloride (4 μL, 0.05 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (17.0 mg, 0.05 mmol) and triethylamine (0.02 mL, 0.14 mmol) in dichloromethane (1.0 mL), and the reaction stirred at room temperature overnight. The reaction solution was purified directly via column chromatography on silica gel (Biotage 10 g column, gradient elution with 10-0% hexanes in ethyl acetate) to afford (S)-1-(2-methyl-6-(1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (14 mg, 72%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.04 (m, 6H), 1.19-1.26 (m, 1H), 1.58-1.81 (m, 6H), 2.02 (s, 3H), 2.17-2.30 (m, 2H), 2.68-2.85 (m, 3H), 2.89 (s, 3H), 2.89-2.99 (m, 1H), 3.60-3.76 (m, 4H), 4.57 (br d, J=6.45 Hz, 1H), 7.09 (br s, 2H). MS (ESI, pos. ion) m/z 409 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][O:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17]([O:20][CH:21]1[NH:24][C:23](=[O:25])[CH2:22]1)(=[O:19])[CH3:18]>O.C(#N)C.O>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][O:9][C:10]([O:12][CH:13]([CH:22]2[CH:21]([O:20][C:17](=[O:19])[CH3:18])[NH:24][C:23]2=[O:25])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC1CC(=O)N1
Solvent: O
Solvent: CC#N
Product: CC(=O)OC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
Ceric ammonium nitrate (12.1 g) was added to the solution of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethane-4-acetoxy-2-azetidinone (6.06 g) in 10% H2O-acetonitrile (90 ml) in portions over 1 hour at room temperature, followed by stirring for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C(C)=CC=CC=1>O>[CH2:8]([N:17]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCN1C(=O)C=CC1=O
Temperature: 120 °C

Procedure:
One equivalent each of maleic anhydride and n-nonylamine are charged into a 1 liter 3-neck round bottom glass flask containing 300 ml xylene, a reflux condenser with a Dean-Stark attachment, Teflon-coated magnetic stirring bar, and a thermometer. The contents are heated to 120° C. for about 15 hours, the reaction extent being monitored by the amount of water collected. After 1 equivalent of water is collected, the reaction solvent is flash distilled off. The absence of an infrared absorbance at 1830 cm-1 and 1791 cm-1 is evidence of anhydride consumption; the presence of an infrared absorbance at 1772 cm-1 is evidence of imide formation.
Reaction SMILES: C(N(CC)CC)C.[C:8](=[S:10])=S.[CH:11]([C:14]1[C:19]([NH2:20])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:15]=1)([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH:11]([C:14]1[C:19]([N:20]=[C:8]=[S:10])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:15]=1)([CH3:12])[CH3:13]
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N=C=S
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 5.0 g of triethylamine in 10 ml of pyridine is cooled to from -5° C. to -10° C., and 20 ml of carbon disulfide are added dropwise. At -10° C., a solution of 15.0 g of 2,4-diisopropyl-6-(4-chlorophenoxy)-3-aminopyridine in 27 ml of pyridine is slowly added dropwise. The mixture is further stirred at -10° C. for 1 hour. A solution of 10.0 g of N,N'-dicyclohexylcarbodiimide in 10 ml of pyridine is then added. After a further 3 hours at -10° C., the mixture is stirred for 18 hours at room temperature. The reaction mixture is concentrated by evaporation and hexane is added to the residue. Thehhexane solution is filtered off and concentrated by evaporation. 2,4-Diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl isothiocyanate is obtained in the form of a yellow oil, which is used for the next reaction without being further purified; IR (CCl 4): 2090, 1490, 1220 cm-1.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)[C:2]([NH2:4])=[O:3].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=O)[NH:19][CH:20]=1.N1CCCCC1>C(O)C>[NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:21][C:18]1[NH:19][CH:20]=[C:16]([Br:15])[CH:17]=1)[C:2]([NH2:4])=[O:3]
Reactant: NC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc(Br)c[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)Nc1ccc2c(c1)C(=Cc1cc(Br)c[nH]1)C(=O)N2

Procedure:
To a solution 5-ureidoindolin-2-one (326 mg, 1.71 mmol) in ethanol was added 4-bromo-2-pyrrolecarboxaldehyde (297 mg, 1.71 mmol), and piperidine (0.2 mL). The reaction mixture was refluxed for 18 hours. The mixture was cooled and filtered to afford a golden-colored solid which was washed with ethanol and ether to afford 5-ureido-3-[(4-bromopyrrol-2-yl)methylene]indolin-2-one; (453 mg); 1H NMR (400 MHz, DMSO-d6) δ 5.77 (s, 2H); 6.74–6.76 (d, 1H); 6.96 (s, 1H); 7.02–7.04 (dd, 1H); 7.41–7.42 (m, 1H); 7.52–7.53 (m, 1H); 7.73–7.74 (d, 1H); 8.34 (s, 1H); 10.82 (bd, 1H); 13.5 (bs, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[C:17]([CH2:19][C:20](O)=[O:21])#[N:18]>>[C:17]([CH2:19][C:20]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:21])#[N:18]
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: N#CCC(=O)O
Product: N#CCC(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine (prepared as in example 1b) and cyanoacetic acid. Yield after recrystallisation from methanol: 50%. Colorless crystals with mp=164-166° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:15]([CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:16])=[CH:7][CH:8]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[CH2:18]([S:15]([C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([NH2:12])[C:2]([NH2:1])=[CH:3]2)=[CH:8][CH:7]=1)(=[O:17])=[O:16])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CS(=O)(=O)c1ccc2cc([N+](=O)[O-])c(N)cc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)CS(=O)(=O)c1ccc2cc(N)c(N)cc2c1

Procedure:
To 0.025 mole of the 2-amino-7-isobutylsulfonyl-3-nitronaphthalene (prepared in Example 11) in 100 ml of 95% ethanol is added a solution of 3.4 equivalents of sodium hydrosulfite (Na2S2O4) in a solution of 100 ml of water and 15 ml concentrated (28%) ammonium hydroxide. The mixture is refluxed for 5 minutes and an amount of hydrosulfite solution equal to 10% of the original is added to the refluxing mixture. TLC (silica gel, ether) indicates consumption of starting material. The mixture is concentrated to one-half its original volume under vacuum and the residual mixture extracted with two 150 ml portions of chloroform. The combined chloroform extracts are dried (Na2SO4), filtered, and evaporated to dryness to yield the crude title compound which is used without further purification in Example 13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:18][N:19]([CH3:32])[C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)(=O)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH:23]2[CH2:22][CH2:21][C:20]([N:19]([CH3:32])[CH3:18])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)[CH2:14][CH2:13]1
Reactant: CN(C)C1(c2ccccc2)CCCCC1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2[nH]cc(C3CCN(C4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-methoxy-3-piperidine-4-yl-1H-indole (461 mg, 2 mmole) and 4-dimethylamino-4-phenylcyclohexane (435 mg, 2 mmole) were dissolved in dry 1,2-dichloroethane (40 ml). Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg, 2.8 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (20 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The non-polar diastereoisomer was obtained as a colourless oil in a yield of 590 mg (68%) and the polar diastereoisomer was obtained as a colourless oil in a yield of 170 mg (20%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[CH2:3]1.C([O-])=O.[NH4+:17]>C(O)C.[Pd]>[NH2:17][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4](=[O:12])[CH2:3][C:2]([CH3:13])([CH3:1])[C:7]=2[CH:8]=1
Reactant: [NH4+]
Reactant: CC1(C)CC(=O)Oc2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Solvent: CCO
Product: CC1(C)CC(=O)Oc2ccc(N)cc21
Temperature: 80 °C

Procedure:
To a suspension of 1.5 g 10% Pd-C in 300 ml ethanol were added under an atmosphere of argon 29.2 g (132.0 mmol) 3,4-dihydro-4,4-dimethyl-6-nitro-2-oxo-2H-1-benzopyran (prepared by nitration of 3,4-dihydro-4,4-dimethyl-2-oxo-2H-1-benzopyran according to J. Am. Chem. Soc. 1970, 92, 4377, the disclosure of which is incorporated herein by reference) and 21.4 g (339.4 mmol) ammonium formate. The temperature raised for approximately 1 hour to 50° C. accompanied by a gas evolution, and it was heated for additional 3 hours at 80° C. The catalyst was filtered through Celite, which was washed with 500 ml hot ethanol. The combined filtrates were concentrated under reduced pressure to a volume of 100 ml, and the formed precipitate was filtered with suction. A second crop of the crude 6-amino-3,4-dihydro-4,4-dimethyl-2-oxo-2H-1-benzopyran was obtained after further concentration. Both crops were combined and dissolved in 80 ml THF followed by addition of 80 ml water, 25.3 g (183 mmol) potassium carbonate, and 29.2 g (133.8 mmol) Boc2O. After 8 hours stirring at room temperature another 2.9 g Boc2O and 2.5 g potassium carbonate were added, and stirring was continued overnight. The mixture was poured into 300 ml water and extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. A first crop of the title compound crystallized from the oily residue with diisopropylether. An additional amount was obtained from the concentrated mother liquid by chromatography on silica gel with toluene crystallizing from the oily pure fractions with diisopropylether.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][C:2]1=[O:8].[Br:9]Br.ClCCl>C(O)(=O)C>[Br:9][CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][NH:1][C:2]1=[O:8]
Reactant: O=C1CCNC(=O)C1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1CCNC(=O)C1Br
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a mixture of piperidine-2,4-dione (0.072 g, 0.637 mmol) in acetic acid (1.591 mL) was added bromine (0.033 mL, 0.637 mmol) dropwise. The reaction mixture was stirred at rt 70 min. Dichloromethane was added and the cloudy mixture was concentrated in vacuo. The residual solution was treated with ethyl ether. A white solid crashed out and the AcOH/ether was decanted. The white solid, presumed to be product was carried forward. The white solid started liquifying and turning red rapidly upon exposure to light and standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([N:14]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]2)=[O:13])[CH2:11][CH2:10]1.CC(C)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([N:14]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]2)=[O:13])[CH2:11][CH2:10]1
Reactant: O=C(N1CCC(O)C1)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3Cl)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol (3.05 g, 0.0102 mol) in acetone (50 mL, 0.7 mol) was added Jone's oxidant in water (8.00 M, 2.54 mL) at 0 degrees celsius and the resulting solution was stirred at rt for 1 hour. The mixture was flustered through celite and the filtrate was concentrated. The resulting residue was dissolved in AcOEt, washed with water and brine successively, dried with MgSO4, and concentrated in-vacuo. The crude product was purified by Combiflash eluting with 40% AcOEt in hexanes.
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([CH3:33])[CH:20]=[CH:19][C:18]([CH:21]([NH2:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[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:32][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([CH3:33])=[CH:20][CH:19]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(N)c2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: Cc1ccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2cccc(C(F)(F)F)c2)cc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-p-tolyl-C-(3-trifluoromethyl-phenyl)-methylamine (example 4.6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:5][CH:4]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:49]([O:53][C:54]([CH2:56][O:57][C:58]1[CH:59]=[C:60]([CH:68]=[C:69]([O:71][CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:70]=1)[CH2:61][NH:62][CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[O:55])([CH3:52])([CH3:51])[CH3:50]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:26])[N:62]([CH2:61][C:60]2[CH:59]=[C:58]([O:57][CH2:56][C:54]([O:53][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:55])[CH:70]=[C:69]([O:71][CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:68]=2)[CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)COc1cc(CNCCC(=O)O)cc(OCC(=O)OC(C)(C)C)c1
Reactant: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)O)cc1
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)O)Cc2cc(OCC(=O)OC(C)(C)C)cc(OCC(=O)OC(C)(C)C)c2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hexadecanedioic acid mono-(4-methoxy-benzyl)ester (0.4 g, 0.98 mmol) was dissolved in ethyl acetate (10 mL). N-Ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.187 g, 0.98 mmol) and 1-hydroxy-7-azabenzotriazole (0.134 g, 0.98 mmol) was added and the mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, diisopropylethylamin (0.50 mL, 2.95 mmol) was added followed by 3-(3,5-Bis-tert-butoxycarbonylmethoxybenzylamino)propionic acid (0.432 g, 0.98 mmol). The mixture was stirred overnight under nitrogen at room temperature. The mixture was separated between ethyl acetate (200 mL) and water (2×100 mL). The organic phase was dried (Na2SO4), solvent removed in vacuo. The crude product was purified by RP-HPLC on C18-column, buffer A: 0.1% TFA, buffer B: MeCN+0.1% TFA; gradient 80-100% B to yield the title compound.