Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:16])[CH:5]=[C:6]([N:13]([CH3:15])[CH3:14])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[N+:17]([O-])([OH:19])=[O:18].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([CH3:16])[CH:5]=[C:6]([N:13]([CH3:14])[CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)cc(C)cc1N(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1c(N(C)C)cc(C)c([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 6-chloro-4,N,N-trimethylanthranilate (compound 1) (3 g) was added dropwise with stirring to a solution of nitric acid (SG 1.43) (3 ml) in conc sulphuric acid (10 ml) at room temperature. The mixture was stirred overnight at room temperature, then poured into water (200 ml). The yellow product was extracted into chloroform, and the extracts were dried by filtration after washing with water. The solvent was removed and the residue crystallised from ethanol to give ethyl 6-chloro-4,N,N-trimethyl-5-nitroanthranilate (2 g) as yellow needles, mp 76° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[C:36]([Cl:48])=[CH:35][C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([Cl:32])[C:34]([OH:49])=[CH:35][C:36]=2[Cl:48])=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)cc2Cl)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)cc4Cl)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2,5-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (85 mg, 0.300 mmol) to afford the crude product (57 mg) as a white solid: ESI MS m/z 570 [C30H33Cl2N3O4+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.S(Cl)(Cl)=O.[F:14][C:15]([F:32])([F:31])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([NH2:30])=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=1.N1C(C)=CC=CC=1C>C(OC(=O)C)(C)C>[NH2:30][C:24]1[N:25]=[C:26]([NH:29][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][CH:5]=2)=[O:9])[CH:27]=[CH:28][C:23]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:15]([F:32])([F:14])[F:31]
Reactant: Nc1ccc(-c2ccccc2OC(F)(F)F)c(N)n1
Reactant: Cc1nocc1C(=O)O
Solvent: Cc1cccc(C)n1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)OC(C)C
Product: Cc1nocc1C(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)c(N)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a suspension of 3-methylisoxazole-4-carboxylic acid (2.58 g, 20 mmol) in isopropylacetate (26 ml) was added thionyl chloride (2.4 g, 1.47 ml, 20 mmol) and the reaction heated to 70° C. for 5 hours before cooling to room temperature. 11/12ths of this solution was added dropwise to a solution of 3-[2-(trifluoromethoxy)phenyl]pyridine-2,6-diamine (Preparation 2, 4.56 g, 16.9 mmol) and 2,6-lutidine (3.98 g, 4.3 ml, 37.2 mmol) in isopropylacetate (23 ml). The reaction was stirred at room temperature for 30 minutes during which a slurry was formed caused by crystallisation of lutidine hydrochloride. 20% w/w citric acid (46 ml) was added, the biphasic mixture stirred for 10 minutes before separation. The organic phase was washed with saturated sodium bicarbonate solution (46 ml), water (46 ml) and then reduced in volume to 16 ml. Toluene was then added (2×46 ml) and the volume reduced again to 20 ml. The resultant white solid was collected by filtration, washed with toluene (10 ml) and dried to afford the title compound in 46% yield. The white solid (2.1 g) was slurried in toluene (10 ml, 5 ml/g) and heated to reflux to form a solution. The resultant solution was cooled to 0° C. and granulated for 1 hour. The solid was collected by filtration, washed with toluene (6 ml, 3 ml/g) and dried overnight to yield 1.8 g of crystalline material.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[O:15]1[CH2:17][CH:16]1[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:17][CH:16]([OH:15])[CH2:18][CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:11][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CO1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Product: O=C1c2ccccc2C(=O)N1CCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1

Procedure:
A sample of 2.1 g (9.0 mmol) 1-(2,3-dichlorophenyl)-piperazine in 40 mL 2-PrOH was reacted in the microwave (pressure vessel, Pmax 150 W, cooling, 90° C., 20 min) with 2.0 g (9.0 mmol) 25. The solvent was removed in vacuo and the foamy residue was washed with 10 mL 2-PrOH. Yield: 2.96 g (73%). 1H NMR (CDCl3): δ 1.79 (m, 2H), 2.42 (m, 2H), 2.56 (s, 2H), 2.79 (m, 2H), 3.02 (s, 4H), 3.60 (s, 1H), 3.74-3.83 (m, 3H), 6.90 (m, 1H), 7.06-7.11 (m, 2H), 7.67 (m, 2H), 7.81 (m, 2H). 13C NMR (CDCl3): δ 33.9, 35.3, 51.4, 53.4, 63.8, 64.5, 118.2, 122.7, 124.1, 127.0, 131.6, 133.4, 133.4, 150.4, 167.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].C(OC([N:17]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=[CH:18]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[N:20]1[CH:21]=[CH:22][CH:23]=[N:17][CH:18]=[CH:19]1
Reactant: Clc1cccc(Br)c1Cl
Reactant: CC(C)(C)OC(=O)N1C=CC=NC=C1
Agent: [Pd]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cccc(N2C=CC=NC=C2)c1Cl

Procedure:
2.25 g (10 mmol) 1-bromo-2,3-dichloro-benzene was dissolved in dry toluene (50 ml), 2.3 (11 mmol) of [1,4]diazepine-1-carboxylic acid tert-butylester was added followed by 0.2 g BINAP (2,2-bis(diphenylphosphino)-1,1′-binaphtyl), 85 mg tris(dibenzylideneacetone)dipalladium(0) and 1.2 g (12 mmol) sodium-tert-butoxyde. The reaction mixture was refluxed for eight hours and filtered. The organic layer was washed with water, dried and evaporated in vacuo. The residue was purified by chromatography and deprotected at 10° C. using 20 ml ethylacetate saturated with gaseous hydrochloric acid, the precipitate was filtered giving 2.1 g (yield: 75%) hydrochloride salt of the title compound, melting at 182-3° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37](O)=[O:38])=[C:9]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:40]([CH3:43])(=[O:42])=[O:41])[CH3:2].[F:44][C:45]([F:55])([F:54])[C@@H:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH2:47].C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37]([NH:47][C@H:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45]([F:54])([F:55])[F:44])=[O:38])=[C:9]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:40]([CH3:43])(=[O:42])=[O:41])[CH3:2]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(C)(=O)=O
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 36.4 %

Procedure:
7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.303 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.069 g, 0.393 mmol), N,N-diisopropylethylamine (10.57 μL, 0.061 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.252 mL of a 50% solution in ethyl acetate, 0.424 mmol) in dichloromethane (2 mL) was stirred at 0° C. for 2 h. The solution was warmed to room temperature overnight. The solution was diluted with saturated aqueous NaHCO3 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire, 30×75 mm column, 50 mL/min, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2SO4, filtered, and concentrated in vacuo to afford 7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.086 g, 35% yield). 1H NMR (400 MHz, CDCl3) δ9.88 (br. s., 1H), 8.79 (s, 1H), 7.81 (s, 1H), 7.78 (d, J=6.02 Hz, 1H), 7.64-7.69 (m, 2H), 7.53-7.60 (m, 3H), 7.43-7.48 (m, 3H), 6.25 (quin, J=7.65 Hz, 1H), 4.36 (q, J=6.94 Hz, 2H), 3.66-3.71 (m, 4H), 3.53-3.65 (m, 2H), 3.33 (s, 3H), 2.64 (br. s., 1H), 2.38-2.46 (m, 4H), 2.20 (br. s., 1H), 2.04 (t, J=10.92 Hz, 1H), 1.56-1.66 (m, 9H); MS (m/z) 779.3 (M+H+).
Reaction SMILES: [C:1]1(C2C=[N+](CCC)C=CC=2C2C=C[NH+]=CC=2)[CH:6]=CC=C[CH:2]=1.[C:22]1(=[O:28])[O:27][CH:25](C)[CH2:24][O:23]1>CC1C=CC(O)=C(N2N=C3C(C=CC=C3)=N2)C=1.CN1C2C(=CC=CC=2)N(C)C2C=CC=CC1=2>[CH3:6][C:1]([C:22]([O:23][CH2:24][CH2:25][OH:27])=[O:28])=[CH2:2]
Reactant: CCC[n+]1ccc(-c2cc[nH+]cc2)c(-c2ccccc2)c1
Reactant: CC1COC(=O)O1
Agent: CN1c2ccccc2N(C)c2ccccc21
Agent: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Product: C=C(C)C(=O)OCCO

Procedure:
The pre-polymer solution of Example 13 A was diluted to 7% by weight polymer with propylene carbonate. The pre-polymer solution was made 30 millimolar in Tinuvin p, 17 millimolar in 1,1′-d-(3-phenyl(n-propyl)-4,4′ bipyridinium and 14 millimolar in 5,10-dihydro-5,10-dimethlphenazine simply by dissolving appropriate amounts of these materials in the pre-polymer solution. This solution was degassed by vacuum and flushed with nitrogen. Sufficient tolylene 2,4-diisocyanate (available from Aldrich Chemical Company, Inc. Milwaukee, Wis.) crosslinker was added to crosslink approximately 50 percent of the theoretical hydroxyl position. This solution was thoroughly mixed to ensure that the crosslinker was evenly distributed throughout the fluid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:25])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(C(=O)O)cc(C#N)c1OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Cl)cc(C#N)c1OC
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To 3-cyano-5-ethyl-4-methoxybenzoic acid (347 mg), toluene (3.5 mL), N,N-dimethylformamide (0.01 mL) and thionyl chloride (0.15 mL) were added, and then the mixture was stirred at 60° C. for 14 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (387 mg) as a brown oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[O:5])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])(=[O:30])[CH3:29]
Reactant: CCOC(=O)C1(C(=O)OCC)c2cc(OC)ccc2NC1C=CC(=O)OC
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)c2cc(OC)ccc2N(C(C)=O)C1C=CC(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude indoline 9 was dissolved in acetic anhydride (35 ml). This solution was stirred for 1 h at room temperature. Thereupon the acetic anhydride was removed in vacuo. The residue (~27 g) was sufficiently pure for further conversions. A sample of this residue was purified by flash column chromatography (SiO2, CH2Cl2 /acetone 95/5). A pale yellow oily product was obtained.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1C=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][N:33]=1.BrC1[N:48](C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:35]4[C:36]([O:38][CH3:39])=[N:48][C:32]([O:31][CH3:30])=[N:33][CH:34]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: COc1cc(OC)c(B(O)O)cn1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)cn(C)c1=O)C2=O
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(Cl)cn(C)c2=O)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate L) and 2,4-dimethoxypyridine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a white solid. ESI-MS: tR=1.12 min, [M+H]+ 554/556/558 (LC-MS 1); 1H-NMR (d6-DMSO, 400 MHz): 8.29 (s, 1H), 7.87 (m, 1H), 7.36-7.43 (m, 3H), 7.22 (m, 2H), 6.65 (s, 1H), 6.34 (s, 1H), 3.94 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.42 (s, 3H), 1.29 (m, 3H), 0.46 (m, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)=[CH:3][C:4]=1[O:11][CH3:12]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCC(O)CC2)ccc1N
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (3.0 g, 17.5 mmol), 4-hydroxypiperidine (1.77 g, 17.5 mmol) and potassium carbonate (2.9 g, 21 mmol) in DMSO was stirred for 24 h. The reaction was diluted with water and extracted three times with Ethyl acetate. The combined organic solutions were dried over MgSO4 and concentrated. The resulting residue was stirred in ethanol and acetic acid with 10% Pd/C under 30 psi of hydrogen for 16 hr. The reaction was filtered through a pad of celite, rinsed with Ethyl acetate. The filtrate was concentrated and dissolved in methylene chloride. The organic solution was washed with saturated sodium bicarbonate, dried over MgSO4, and concentrated to give 1-[4-amino-3-(methyloxy)phenyl]-4-piperidinol (2.44 g, 63% yield over 2 steps). 1H NMR (400 MHz, d6-DMSO) δ 6.49-6.45 (m, 2H), 6.27 (dd, J=8.4 and 2.4 Hz, 1H), 4.60 (d, J=4.0 Hz, 1 H), 4.18 (s, 2H), 3.71 (s, 3H), 3.54-3.48 (m, 1H), 3.25-3.22 (m, 2H), 2.63-2.56 (M, 2H), 1.80-1.76 (m, 2H), 1.51-1.42 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](=[O:20])[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: C1CNCCN1
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCNCC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with piperazine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:29]>C(O)C.[Pd]>[ClH:29].[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:17]1[C:18]2[C:19]3[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=3[NH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccccc1-c1cccc2[nH]c3c(c12)CCN(Cc1ccccc1)CC3
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Fc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Yield: 17.9 %

Procedure:
A mixture of 3-benzyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.11 g, 0.30 mmol), 1 N hydrochloric acid (0.3 mL, 0.3 mmol) and Pd/C (10%, 0.2 g) in ethanol (50.0 mL) was reacted in a manner similar to Example 8 to give 0.017 g of the title compound as a pale green solid: mp >259° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 11.29, 9.29, 7.51-7.41, 7.39-7.25, 7.08, 6.77, 3.33-3.20, 3.20-3.09, 3.09-2.99, 2.63-2.50; MS (EI) m/z 294 (M+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[C:6](F)[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:10]2[CH2:9]1.FC1C=CC(C(C2C=CC=CC=2)=O)=CC=1>>[CH2:9]1[N:8]([C:7]2[CH:2]=[CH:3][C:4]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:5][CH:6]=2)[CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:10]12
Reactant: O=C(c1ccccc1)c1cc(F)c(N2CCN3CCCC[C@@H]3C2)c(F)c1
Agent: O=C(c1ccccc1)c1ccc(F)cc1
Product: O=C(c1ccccc1)c1ccc(N2CCN3CCCC[C@@H]3C2)cc1

Procedure:
180 mg of the title compound were prepared as described for [3,5-difluoro-4-((R)-octahydropyrido[1,2-a]pyrazin-2-yl)phenyl]-[phenyl]methanone, using 4-fluorobenzophenone instead of 3,4,5-trifluorobenzophenone.
Reaction SMILES: [BH4-].[Na+].C(Cl)Cl.CO.[CH:8]([C:10]1[CH:14]=[C:13]2[C:15]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=3[NH:79][C:80](=[O:85])[C:81]([CH3:84])([CH3:83])[CH3:82])=[C:16]3[N:20]=[C:19]([C:21]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=4[NH:66][C:67](=[O:72])[C:68]([CH3:71])([CH3:70])[CH3:69])=[C:22]4[NH:26][C:25](=[C:27]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=5[NH:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C:28]5[CH:29]=[CH:30][C:31](=[C:33]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=6[NH:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C:11]=1[NH:12]2)[N:32]=5)[CH:24]=[CH:23]4)[CH:18]=[CH:17]3)=[O:9]>O>[OH:9][CH2:8][C:10]1[CH:14]=[C:13]2[C:15]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=3[NH:79][C:80](=[O:85])[C:81]([CH3:84])([CH3:83])[CH3:82])=[C:16]3[N:20]=[C:19]([C:21]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=4[NH:66][C:67](=[O:72])[C:68]([CH3:69])([CH3:70])[CH3:71])=[C:22]4[NH:26][C:25](=[C:27]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=5[NH:53][C:54](=[O:59])[C:55]([CH3:56])([CH3:57])[CH3:58])[C:28]5[CH:29]=[CH:30][C:31](=[C:33]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=6[NH:40][C:41](=[O:46])[C:42]([CH3:43])([CH3:44])[CH3:45])[C:11]=1[NH:12]2)[N:32]=5)[CH:24]=[CH:23]4)[CH:18]=[CH:17]3
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1c2nc(c(-c3ccccc3NC(=O)C(C)(C)C)c3cc(C=O)c([nH]3)c(-c3ccccc3NC(=O)C(C)(C)C)c3nc(c(-c4ccccc4NC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccccc1-c1c2nc(c(-c3ccccc3NC(=O)C(C)(C)C)c3cc(CO)c([nH]3)c(-c3ccccc3NC(=O)C(C)(C)C)c3nc(c(-c4ccccc4NC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 0.25 h

Procedure:
NaBH4 (41.5 mg, 1.1 mmol) was added to a solution of CH2Cl2 --MeOH (1/3 v/v) (8 ml) containing 2-formyl-5,10,15,20-tetrakis(o-pivalamidophenyl)porphyrin (0.11 g, 0.11 mmol) under argon stirred for 15 min. After adding water to the solution, the mixture was extracted by CHCl3 and washed with water. After drying (Na2SO4), the organic layer was chromatographed on a silica gel flash column using CHCl3 --MeOH (10/1 v/v) as the eluent. The residue was dried at room temperature in vacuo to give a purple product, (2-hydroxymethyl-5,10,15,20-tetrakis(o-pivalamidophenyl)porphyrin, 0.11 g, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:24])[CH3:23])=[CH:14][C:13]=2[CH3:27])=[CH:7][CH:6]=1)[CH3:2].[CH:29](=O)[CH2:30][CH3:31].C([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:25])([CH3:26])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:23])[CH3:24])=[CH:14][C:13]=2[CH3:27])[CH2:29][CH2:30][CH3:31])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1C)C(C)(C)CCN2C(C)C
Yield: 17.9 %

Procedure:
A solution of 4-(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-7-ylamino)-benzoic acid ethyl ester (Compound 46, 60.3 mg, 0.1585 mmol), propionaldehyde (36.4 mg, 0.792 mmol), sodium cyanoborohydride (49.77 mg, 0.792 mmol), acetic acid (0.125 mL), and acetonitrile (1 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.44) to give the title compound (12.0 mg, 18%) as a solid:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[N:28]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(OC(=O)NCCCC(N1CCC(N2N=C(C3C=CC(OC)=C(OC)C=3)[C@@H]3[C@@H](CC=CC3)C2=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][C:14]([N:41]1[CH2:42][CH2:43][CH:38]([N:29]2[N:28]=[C:27]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=3)[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30]2=[O:37])[CH2:39][CH2:40]1)=[O:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCSCCC(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: COc1ccc(C2=NN(C3CCN(C(=O)CCCNC(=O)OC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCN(C(=O)CCSCCNC(=O)OC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from 12 mmol of 3-(2-tert-butoxycarbonylamino-ethylsulfanyl)-propionic acid and 10 mmol of compound 5c as described for compound 5b. M. p. 132-134° C.