Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][O:18][C@@H:19]1[CH2:28][CH2:27][C@H:22]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC3CCCCC3N2C(=O)OC(C)(C)C)cc1
Agent: [Rh]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@@H](OC[C@@H]2CC3CCCCC3N2C(=O)OC(C)(C)C)CC1
Reaction time: 48 h

Procedure:
A mixture of methyl 4-[1-tert-butoxycarbonyl-(2S)-octahydroindolylmethoxy]benzoate (700 mg, 1.8 mmol) and 5% Rh on alumina (400 mg) in EtOH (10.0 ml) and AcOH (1.0 ml) was hydrogenated at room temperature at 5 atm for 48 hr. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (7:1, v/v) as eluent to give methyl cis-4-[1-tert-butoxycarbonyl-(2S)-octahydro indolylmethoxy]cyclohexanecarboxylate (600 mg, 85%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.10-2.35 (m, 20H), 1.44 (s, 9H), 3.45-3.90 (m, 5H), 3.80 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:17]=[CH:16][C:15]3[N:18]=[CH:19][N:20]([C:21]4[S:25][C:24]([C:26]([O:28]C)=O)=[C:23]([O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:38]([F:41])([F:40])[F:39])[CH:22]=4)[C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:42]>CO>[C:26]([C:24]1[S:25][C:21]([N:20]2[C:14]3[CH:13]=[C:12]([C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:11])[N:17]=[CH:16][C:15]=3[N:18]=[CH:19]2)=[CH:22][C:23]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:39])[F:40])(=[O:28])[NH2:42]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 150 mg of methyl 5-{6-[(2-morpholin-4-ylethyl)carbamoyl]-1H-imidazo[4,5-c]pyridin-1-yl}-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B9) and 20 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture was concentrated to dryness, the resulting residue was dissolved in 5 ml of methanol and purified by preparative HPLC (water/acetonitrile, elution gradient 9/1 to 1/9 (v/v)). After lyophilization the title compound was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]2[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[SH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][S:15][CH2:2][C:3]1[O:7][C:6]2[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)=[O:18])[CH3:21]
Reactant: O=[N+]([O-])c1cccc2cc(CBr)oc12
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSCc1cc2cccc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromomethyl-7-nitrobenzo[b]furan (512 mg), ethyl mercaptoacetate (0.24 ml) and potassium carbonate (552 mg) in N,N-dimethylformamide (4 ml) was stirred at ambient temperature for 2 hours. To the reaction mixture was added cold water and the separated solid was collected, washed with water and dried to give 2-ethoxycarbonylmethylthiomethyl-7-nitrobenzo[b]furan (546 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[N:21]([CH3:23])[C:20]5[C:15](=[CH:16][C:17]([O:24][CH3:25])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1.[CH3:31]OC1CC(=O)C2NC3C4N(C)C5C(=CC(OC)=CC=5)C=4C4CN(C)C(=O)C=4C=3C=2C=1.COC1C=CC2NC3C4NC5C(=CC(OC)=CC=5)C=4C4C(=O)N(C)C(=O)C=4C=3C=2C=1.CI.S(OC)(OC)(=O)=O.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[N:21]([CH3:23])[C:20]5[C:15](=[CH:16][C:17]([O:24][CH3:25])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:26](=[O:30])[N:27]([CH3:31])[C:28](=[O:29])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1
Reactant: COC1=Cc2c([nH]c3c2c2c(c4c5cc(OC)ccc5n(C)c34)CN(C)C2=O)C(=O)C1
Reactant: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(C)c35)C(=O)NC4=O)c2c1
Agent: COc1ccc2[nH]c3c4[nH]c5ccc(OC)cc5c4c4c(c3c2c1)C(=O)N(C)C4=O
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(C)c35)C(=O)N(C)C4=O)c2c1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
6,7,12,13-tetrahydro-3,9-dimethoxy-12-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole; yellow crystals; m.p. >330° C. The 6,7,12,13-tetrahydro-3,9-dimethoxy-6,12-dimethyl-5,1-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole used as starting material is prepared by the methylation of 6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole (precursor for Example 7) with methyl iodide or dimethyl sulphate in the following manner: A solution of 1 g (2.5 mmol) 6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole in 50 ml dry dimethylformamide is added dropwise at 20° C. to a suspension of 91 mg (3.0 mmol) sodium hydride (80% in paraffin oil) in 5 ml dimethylformamide under an atmosphere of argon. After stirring for 1 hour at 200° C., 0.2 ml (3.2 mmol) methyl iodide are added thereto and the reaction mixture is stirred for 16 hours at 20° C. It is then evaporated in a vacuum and the residue is partitioned between ethyl acetate and water. The ethyl acetate phase is separated off, dried over anhydrous sodium sulphate, filtered and evaporated. The residue is stirred with 30 ml diisopropyl ether/ethyl acetate (2:1 v/v) and the undissolved product is filtered off. 6,7,12,13-Tetrahydro-3,9-dimethoxy-6,12-dimethyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole is obtained in the form of a pale brown amorphous powder. The methylation can also be carried out in an analogous manner with dimethyl sulphate as alkylation agent.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([NH2:20])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1([CH2:27][C:28](O)=[O:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[N:21]1([CH2:27][C:28]([NH:20][C:17]2([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)=[O:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: NC1(c2ccc(OCCCN3CCCCC3)cc2)CC1
Reactant: O=C(O)CN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(CN1CCOCC1)NC1(c2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-cyclopropylamine (0.195 g, 0.72 mmol) and morpholin-4-yl-acetic acid (0.125 g, 0.86 mmol) are dissolved in DMF, and diisopropylethylamine added (0.15 mL), followed by EDC (0.165 g, 0.86 mmol) and HOBt (0.116 g, 0.86 mmol). The reaction mixture was stirred overnight at room temperature. The residue is purified by chromatography [SCX-MeOH wash, elute 2M NH3/MeOH; then Biotage 12M SiO2, elute 10% (25/5/1 CHCl3/MeOH/NH4OH)/90% (10% MeOH/CHCl3)] to give the title compound as a yellow oil. HRMS 402.2765 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@H:7]([CH2:18][CH2:19][S:20][CH3:21])[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([O:40][CH:41]([CH2:49][O:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:42][S:43][CH2:44][CH2:45][C:46](O)=[O:47])(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[C@H:7]([CH2:18][CH2:19][S:20][CH3:21])[NH:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:46](=[O:47])[CH2:45][CH2:44][S:43][CH2:42][CH:41]([O:40][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:49][O:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCSC)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 4-aminobenzoylmethionine t-butyl ester (160 mg) in pyridine (5 ml), phospholic trichloride (0.022 ml) was added, followed by stirring at room temperature for 2 hours. After addition of 6,7-bis(palmitoyloxy)- 4-thiaheptanoic acid (164 mg) as obtained in Reference Example 4, the reaction mixture was stirred at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to yield the title compound (163 mg, yield 68%) as a colorless wax-like substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.C([O:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])C.[O-]CC.[Na+].Cl>C(O)C.O.O1CCCC1>[F:19][C:18]([F:21])([F:20])[C:17](=[O:16])[CH2:11][C:10]([C:6]1[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:13])=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1cc(C)c(C(C)=O)cc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(C)c(C(=O)CC(=O)C(F)(F)F)cc1C
Yield: 88.4 %

Procedure:
At room temperature, to a mixture of 1-(4-methoxy-2,5-dimethylphenyl)-ethanone (described in Reference Preparation example 82) 5 g and tetrahydrofuran 200 ml was added trifluoroacetic acid ethyl ester 7.9 g and 20% sodium ethoxide solution in ethanol 19 g. The resulting mixture was stirred with heating under reflux for seven hours, and then to the reaction mixture was added water 70 ml, and the resulting mixture was acidified with 6N aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4,4,4-trifluoro-1-(4-methoxy-2,5-dimethyl-phenyl)-butane-1,3-dione 6.8 g.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1([C:9]([OH:25])([CH2:18][N:19]2[C:23]([SH:24])=[N:22][CH:21]=[N:20]2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7]1.C(N(CC)CC)C>O1CCCC1>[Cl:5][C:6]1([C:9]([OH:25])([CH2:18][N:19]2[C:23]([S:24][C:3](=[O:4])[NH:2][CH3:1])=[N:22][CH:21]=[N:20]2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7]1
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)Sc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
At room temperature, a solution of 0.3 ml (5 mmol) of methyl isocyanate in 5 ml of absolute tetrallydrofuran is added dropwise with stirring to a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol, 0.1 ml of triethylamine and 20 ml of absolute tetrahydrofuran. After the addition, the reaction mixture is stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product that remains is chromatographed over silica gel using a mixture of petroleum ether/ethyl acetate=1:1. Concentration of the eluate gives 1.3 g (65% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-[5-(N-methyl-carbamoylthio)-1,2,4-triazol-1-yl]-propan-2-ol in the form of an oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]1.C(O)(=O)C>O>[NH2:3][N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1
Reactant: CCOC(=O)c1cn(N)c2cc3c(cc2c1=O)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Temperature: 90 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a solution of 4.4 g (0.11 mole) of sodium hydroxide in 350 ml of water was added 3.0 g (0.047 mole) of ethyl 5-amino-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylate (Example 1). The resulting slurry was stirred at about 90° C. for three hours, then cooled to room temperature and neutralized with 9.3 ml of acetic acid. The solid product was collected by filtration and recrystallized from dimethylformamide to give 10.3 g of 5-amino-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid, colorless crystals, m.p. 309°-313° C. (decompn.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[NH:4][CH2:3]1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH2:3][C@@H:2]([NH:1][C:21]([NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22])[CH2:11]2)#[N:13]
Reactant: N#Cc1ccc2c(c1)C[C@H](N)CN2
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)Nc1ccccc1)CN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of (S)-3-amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile (52 mg, 0.3 mmol), prepared as described in Example 1F, in CH2Cl2 (2 mL) at RT was added phenyl isocyanate (33 μl, 0.3 mmol) dropwise. After addition, the reaction was stirred at RT for 1 h. The product was collected by filtration and washed with CH2Cl2-hexanes (1:1) to give the title compound (85 mg, 97%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]C=C>CN(C)C=O>[C:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)(=[O:13])[CH:17]=[CH2:18]
Reactant: O=C([O-])[O-]
Reactant: C=CCCBr
Reactant: OCc1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)Oc1ccc(CO)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
4-(Hydroxymethyl)phenol (620 mg, 5.0 mmol) was dissolved in N,N-dimethylformamide (25 ml) and potassium carbonate (1.38 g, 10.0 mmol) and 4-bromo-1-butene (1.08 g, 8.0 mmol) were added thereto. After stirring at 70° C. for 4 hours, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain [4-(2-propenoyloxy)phenyl]methanol (267 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@@H:6]1[F:18].[NH4+].[Cl-]>CCO.O.CCOC(C)=O.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([O:4][C@H:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:7][C@@H:6]2[F:18])=[C:2]([Cl:1])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cc2Cl)[C@@H](F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2Cl)[C@@H](F)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of tert-butyl (3S,4S)-4-(2-chloro-4-nitrophenoxy)-3-fluoropiperidine-1-carboxylate (0.8 g, 1.0 eq, 2.2 mmol), Fe (0.6 g, 5.0 eq, 10.8 mmol) and NH4Cl (0.6 g, 5.0 eq, 10.8 mmol) in EtOH/H2O (1:1, 50 mL) was stirred at 90° C. for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure to leave a crude solid. The crude mixture was dissolved in EtOAc (50 mL) and partitioned with H2O (50 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the desired product in 45% yield. This product was taken to next step with out further purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([OH:22])=O)[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]1[O:62][NH2:63]>CN(C=O)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([NH:63][O:62][CH:57]4[CH2:58][CH2:59][CH2:60][CH2:61][O:56]4)=[O:22])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Reactant: NOC1CCCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (358 mg, 1.1 mmol) in DMF (8 mL) was added triethylamine (333 mg, 3.3 mmol), HATU (627 mg, 1.65 mmol) and O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine. The resulting mixture was stirred for 2.5 h at room temperature. The mixture was concentrated. Purification by flash chromatography (Biotage) over silica gel (100% ethyl acetate) afforded the title product as brown oil (149 mg, 32% yield). LC-MS (APCl, M+H+): 428.2. HPLC: 96% purity.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+:28]>CO>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O-:22])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1.[Na+:28]
Reactant: CCOC(=O)c1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 2 h

Procedure:
A stirred suspension of the product of Example 77 (353 mg) in methanol (5 ml) was treated with a 1 molar sodium hydroxide solution (3 ml). After 2 hours, the cream coloured solid was collected, washed with a little methanol and dried to give the title compound, 240 mg, m.p. >300° C.; NMR (d6DMSO) δ 8.15 (2H, d), 8.05 (4H, t, AB pattern), 6.85 (2H, d), 3.97 (2H, s), 3.38 (4H, t), 2.65 (4H, t), m/e 348 (M+H)+ ; calculated for C18H18N3NaO3. 0.25H2O: C, 61.4; H, 5.3; N, 11.9. found: C, 61.3; H, 5.2; N, 11.7%.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:3]1>CO>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:3]1
Reactant: CN1CCC(N2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Solvent: CO
Product: CN1CCC(N2CC(C)(C)c3ccc(N)cc32)CC1
Reaction time: 8 h

Procedure:
3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indole (600 mg, Step E) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (100 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford the title compound as an oil. MS:260 (M+1). Calc'd. for C16H25N3—259.39.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=2)=[O:24])=[CH:18][CH:17]=1>CN(C)C=O.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[NH2:32][C:28]1[CH:27]=[C:26]([NH:25][C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc([N+](=O)[O-])c4)cc3)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(N)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N'-(3-nitrophenyl)urea (28 mg) was dissolved in N,N-dimethylformamide/ethyl acetate (5 ml/2.5 ml), 20% palladium hydroxide-carbon (97 mg) was added, and the admixture was stirred at room temperature under hydrogen for 3 hours. The reaction mixture was filtered using Celite, the filtrate was washed with brine and then dried with anhydrous sodium sulfate. The solvent was then removed by reduced-pressure distillation to obtain 13 mg of the title compound (yield: 51%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:12]([OH:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1([C:27](=O)[C:26]2N(C)C=N[C:21]=2N(C)C1=O)C.C1(C)CCC(C(C)C)C(O)C1>O.C(O)C>[CH:26]([O:13][C:12](=[O:14])[C@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[NH2:2])([CH3:27])[CH3:21]
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC1CCC(C(C)C)C(O)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (70 g) and tyrosine (7 g) were dissolved in water (1 L). Caffeine (50 g), ethanol (100 ml) and menthol (20 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][CH2:13][CH2:14][C:15]2([OH:28])[CH2:27][CH2:26][C:18]3([O:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][O:19]3)[CH2:17][CH2:16]2)[CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH:9]2[CH2:10][CH2:11]2)[N:12]2[CH2:13][CH2:14][C:15]3([CH2:16][CH2:17][C:18](=[O:19])[CH2:26][CH2:27]3)[O:28][C:30]2=[O:32])=[CH:4][CH:3]=1.[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH:9]2[CH2:10][CH2:11]2)[N:12]2[CH2:13][CH2:14][C:15]3([CH2:27][CH2:26][C:18]4([O:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][O:23]4)[CH2:17][CH2:16]3)[O:28][C:30]2=[O:32])=[CH:6][CH:7]=1
Reactant: CC1(C)COC2(CCC(O)(CCN[C@H](c3ccc(Br)cc3)C3CC3)CC2)OC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC1(C)COC2(CCC3(CCN([C@H](c4ccc(Br)cc4)C4CC4)C(=O)O3)CC2)OC1
Product: O=C1CCC2(CC1)CCN([C@H](c1ccc(Br)cc1)C1CC1)C(=O)O2
Yield: 37 %

Procedure:
The title compound is prepared from 9-(2-{[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-amino}-ethyl)-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; besides the title compound the intermediate 3-[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one (37% of theory) is also isolated. Yield: 25% of theory; LC (method 4): tR=1.59 min; Mass spectrum (ESI+): m/z=392/394 (Br) [M+H]+.