Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)=O.S(=O)(=O)(O)O>O>[CH2:11]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a 500 ml round bottomed flask was placed 75 g of crude 3,4-dichlorophenyl benzyl carbinol and 300 ml of acetone. The reaction mixture was cooled to 0° C. and a solution of 20 g of chromic anhydride and 17.25 ml of concentrated sulfuric acid in 60 ml of water was added at a rate to keep the internal temperature below 5° C. After stirring an additional 15 minutes, the reaction was quenched with 10 ml of isopropanol and partitioned between ethyl ether and water. The organic layer was washed with brine, dried, and concentrated. The resulting crude ketone was crystallized from hexane yielding 51 g of 3,4-dichlorophenyl benzyl ketone. NMR data was consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(Cl)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cn3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyridin-2-yl)-phenol (Preparation 17) and 3-iodomethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (133 mg, 65.2%)
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1.O.NN.O.O.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>CO>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH2:3][CH2:12][C:13]1([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1(CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CN)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl {1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]cyclopropyl}carbamate (80.0 g, 253 mmol) in methanol (1600 mL) was added hydrazine hydrate (80% solution in water, 15.9 g, 320 mmol). The reaction mixture was heated to reflux. After 4 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was washed with DCM (3×500 mL) and then the combined organic layers were concentrated under reduced pressure. This residue was dissolved in diethyl ether (1000 mL) and diluted with oxalic acid dihydrate (solution in ethanol, 35.2 g, 279 mmol), which was added dropwise. After 1 hour, the precipitated solids were collected by filtration, washed with diethyl ether (4×200 mL), and dried to give tert-butyl [1-(aminomethyl)cyclopropyl]carbamate oxalate salt. MS ESI calc'd. for C9H19N2O2 [M+H]+ 187. found 187. 1H NMR (400 MHz, D2O) δ 2.98 (s, 2H), 1.36-1.30 (m, 9H), 0.81 (s, 4H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([N:17]3[CH2:26][C@H:25]4[N:21]([CH2:22][CH2:23][CH2:24]4)[C:20]4[N:27]=[C:28]([NH:31][CH2:32][CH3:33])[N:29]=[CH:30][C:19]=4[C:18]3=[O:34])[CH:14]=[CH:15][CH:16]=2)=[N:8][N:7]=1)(=O)C.[OH-].[Na+].C(OCC)(=O)C>CO>[CH2:32]([NH:31][C:28]1[N:29]=[CH:30][C:19]2[C:18](=[O:34])[N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:9]4[O:10][C:6]([CH2:5][OH:4])=[N:7][N:8]=4)[CH:12]=3)[CH2:26][C@H:25]3[N:21]([CH2:22][CH2:23][CH2:24]3)[C:20]=2[N:27]=1)[CH3:33]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(COC(C)=O)o3)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(CO)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
(S)-5-[3-(5-Acetoxymethyl-1,3,4-oxadiazol-2-yl)phenyl]-9-ethylamino-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (20.0 mg, 0.0432 mmol) obtained in Step 1 was dissolved in methanol (2 mL), and the mixture was stirred at room temperature for 30 minutes after adding a 1 mol/L aqueous sodium hydroxide solution (2 mL). The mixture was diluted by addition of ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from diisopropylether to give the title compound (Compound 48) (6.0 mg, 33%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1.[F:16][C:17]([F:48])([F:47])[O:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][NH:24][C:25]([C@H:27]2[CH2:32][NH:31][CH2:30][CH2:29][N:28]2[S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]3[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[O:26])=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:48][C:17]([F:16])([F:47])[O:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][NH:24][C:25]([C@H:27]2[CH2:32][N:31]([C:2]3[S:3][C:4]4[C:9]([Cl:10])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=4[N:15]=3)[CH2:30][CH2:29][N:28]2[S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]3[CH2:43][CH2:44]3)=[CH:38][CH:37]=2)(=[O:34])=[O:35])=[O:26])=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1nc(Cl)c2sc(Cl)nc2n1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a mixed solution of the compound (27 mg) obtained in Example 1001, Step 8, the compound (43 mg) obtained in Step 4 and chloroform (0.50 ml) was added N,N-diisopropylethylamine (19 μl) under ice-cooling. After stirring overnight at room temperature, the reaction mixture was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (66 mg).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH:19]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1.[H][H]>CO.O1CCOCC1.[Pd]>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)OC
Yield: 95.7 %

Procedure:
To a solution of dimethyl 4-[2-(5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylidenemalonate (2.24 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.16 g, 96%). HRMS calcd for C24H28O6: 412.4827. Found: 412.4825. MA calcd for C24H28O6: C, 69.99%; H, 6.84%. Found: C, 69.82%; H, 6.88%.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[C:14](Cl)=[O:15])[CH3:9]>>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:14](=[O:15])[C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:9]
Reactant: COC(=O)C(C)C
Reactant: CCOc1ccc(C(=O)Cl)cc1OCC
Product: CCOc1ccc(C(=O)C(C)(C)C(=O)OC)cc1OCC

Procedure:
Prepared analogously as described for the example D1 using methyl 2-methylproponate and 3,4-diethoxybenzoyl chloride as starting compounds.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[C:12]([N:18]4[CH:22]=[CH:21][N:20]=[N:19]4)=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:24]1[N:29]=[C:28]([CH3:30])[C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:17][C:14]1[N:13]=[C:12]([N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)[C:11]([C:9]([N:8]2[C@H:1]3[C@H:6]([CH2:5][CH2:4][N:3]([C:24]4[N:29]=[C:28]([CH3:30])[C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=4)[CH2:2]3)[CH2:7]2)=[O:10])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)N2C[C@H]3CCNC[C@H]32)c(-n2ccnn2)n1
Reactant: Cc1nc(Cl)nc(C)c1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2C[C@H]3CCN(c4nc(C)c(C)c(C)n4)C[C@H]32)c(-n2ccnn2)n1
Temperature: 180 °C
Yield: 53.4 %

Procedure:
To a microwave safe vial was added (1S,6R)-3,8-diazabicyclo[4.2.0]octan-8-yl(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methanone (80 mg, 0.27 mmol), 2-chloro-4,5,6-trimethylpyrimidine (84 mg, 0.54 mmol), ACN (3 mL) and DIPEA (0.093 mL, 0.54 mmol). The resulting mixture was heated to 180° C. in a microwave reactor. After 2 hours the mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC (acidic) to yield the title compound (60.3 mg, 42%) as the TFA salt. MS (ESI) mass calcd. for C22H26N8O, 418.2; m/z found, 419.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.44-8.32 (m, 1H), 7.82-7.72 (m, 2H), 7.22-7.16 (m, 1H), 4.52-4.46 (m, 1H), 4.30 (dd, J=10.0, 9.0 Hz, 1H), 4.04 (tt, J=9.6, 4.8 Hz, 1H), 3.99-3.92 (m, 1H), 3.89-3.57 (m, 2H), 3.13-2.83 (m, 2H), 2.65-2.57 (m, 3H), 2.39-2.31 (m, 6H), 2.15-2.02 (m, 4H), 1.99-1.81 (m, 1H).
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.[Cl:13][C:14]1[CH:22]=C2[C:17]([CH2:18][NH:19]C2=O)=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:11]([O:8][C:9]1[C:10]2[C:17](=[CH:16][CH:15]=[C:14]([Cl:13])[CH:22]=2)[CH2:18][N:19]=1)[CH3:12]
Reactant: CC[O+](CC)CC
Reactant: O=C1NCc2ccc(Cl)cc21
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC1=NCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of 151 g of triethyloxonium tetrafluoroborate in 3200 ml of methylene chloride was stirred under argon at room temperature for 3.5 hours after the addition of 106.6 g of 6-chloro-2,3-dihydro-1H-isoindole-1-one. The mixture was then treated within 40 minutes with 1.28 1 of saturated sodium hydrogen carbonate solution, the organic phase was separated and washed with 1.28 1 of water. After drying over sodium sulphate the organic phase was filtered and evaporated. The residue was taken up in 1.3 1 of diethyl ether, whereupon it was stirred at room temperature for about 30 minutes. After removing insoluble material by filtration the filtrate was evaporated. There was obtained 110.5 g of 1-ethoxy-6-chloro-3H-isoindole with a m.p. of 64°-66°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][NH2:13].Cl>C(O)C.O>[OH2:5].[ClH:1].[CH3:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:13][CH3:12])[N:10]=1.[CH3:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:13][CH3:12])[N:10]=1.[OH2:5]
Reactant: CN
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNc1nc(C)ccc1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-6-methylnicotinic acid (25.00 g) and 33% methylamine in ethanol (100 ml) was heated in a pressure vessel at 100° C. for 18 hours. The mixture was cooled, diluted with water (200 ml) and acidified to pH 2-3 with concentrated hydrochloric acid. The mixture was cooled in an ice bath and filtered to give 6-methyl-2-methylaminonicotinic acid hemihydrochloride hydrate, m.p. 195°-197° C.
Reaction SMILES: CN.[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][CH2:13][C:14](=O)[CH3:15].[C:17]([BH3-])#[N:18].[Na+].[ClH:21].CN.Cl>CO.CCOCC>[ClH:21].[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][CH2:13][CH:14]([CH3:15])[NH:18][CH3:17]
Reactant: [BH3-]C#N
Reactant: COc1ccc(I)c(CCC(C)=O)c1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CNC(C)CCc1cc(OC)ccc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A solution of 19.41 g (0.625 mole) of methylamine in 400 ml of anhydrous methanol was treated with 37.92 g (0.125 mole) of 4-(2-iodo-5-methoxyphenyl)-2-butanone, 6.28 g (0.1 mole) of sodium cyanoborohydride and 21.07 g (0.312 mole) of methylamine hydrochloride and allowed to stir at room temperature under an atmosphere of nitrogen for 21/2 hours. The resulting mixture was cooled in an ice bath and treated with concentrated hydrochloric acid to pH 1. The solvent was evaporated in vacuo and the residue partitioned between 1.5 l of water and 600 ml of ether. The water layer was separated and treated with 50% sodium hydroxide solution until basic. The resulting crude product was extracted into 500 ml of ether, washed with brine, and the brine layer extracted with an additional 400 ml portion of ether. The combined ether layers were dried over anhydrous potassium carbonate and evaporated in vacuo to yield 31.09 g (78%) of crude oil. The oil was dissolved in methanol and treated with ethereal hydrogen chloride until neutral. Ether was added to the mixture and the resulting hydrochloride salt separated by filtration to give 19.75 g (44%) of crude product. One recrystallization from 2-propanol yielded pure 2-iodo-5-methy-N-alphadimethylbenzenepropanamine hydrochloride a white solid, mp 189°-190° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.O.Cl.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH2:28].C(=O)([O-])[O-].[Ca+2]>C(O)(C)C>[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]=12
Reactant: COc1ccccc1OCCN
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Solvent: O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 43.2 g 4-(oxirane-2-ylmethoxy)-9H-carbazole (II), 80.0 g of 2-(2-methoxyphenoxy)ethylamine hydrogenchloride monohydrate (IV) and 52.4 g of anhydrous calcium carbonate in 330 ml isopropanol is, with intensive stirring, heated at 80° C. for 4 hours. When the epoxide has reacted, the mixed salts are filtered off from the reaction mixture and isopropanol is distilled off from the filtrate. The obtained honey-like concentrate is dissolved, when hot, in 210 ml of ethylacetate, the solution is cooled to the temperature of 40° C., inoculated and stirred at the temperature of 40° C. for 30 minutes. After the crystal precipitates, the mixture is cooled to 0° C., and is kept like that with stirring for a minimum of four hours. After filtration and washing with cooled ethylacetate, 65 to 70 g of wet crude Carvedilol is obtained (HPLC contents>98 area %, HPLC contents of the bis-derivative 1.2-1.5 area %).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCn1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCn1ccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.17 g (0.34 mmol) t-butyl 8-(p-chlorophenylsulfonamido)-4-[3-(1-imidazolyl)propyl]octanoate in 5 mL methylene chloride is added 1 mL trifluoroacetic acid and the solution is stirred at room temperature for 1.5 hours. The solvent is evaporated and the residue taken up in 5 mL water. The pH of the solution is adjusted to 6.5 using 1N aqueous sodium hydroxide. Then the aqueous solution is extracted twice with ethyl acetate. The combined organic layer is washed with water and brine, dried, filtered and concentrated to give a pale yellow oil. The product is triturated five times with 2 mL ether and finally dried to yield 8-(p-chlorophenylsulfonamido)-4-[3-(1-imidazolyl)propyl]octanoic acid, m.p. 136-138° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N+:21]=1[O-:29].C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N+:21]=2[O-:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cc[n+]([O-])c(NCCCOc2cccc(CN3CCCCC3)c2)c1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (6.21 g), 2-chloro-4-nitropyridine-N-oxide (4.36 g) and triethylamine (6.32 g) were stirred, in ethanol (30 ml), under reflux for 31/2 hours. The reaction mixture was cooled gradually to 0° C. to yield 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-nitropyridine-N-oxide (4.23 g), m.p. 90°-90.5° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:25])[CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[C:37]([C:40](O)=[O:41])=[CH:36][N:35]([CH2:43][CH3:44])[C:34]2=[O:45])=[CH:29][CH:28]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:25][C:40]([C:37]3[C:38](=[O:39])[N:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)[C:34](=[O:45])[N:35]([CH2:43][CH3:44])[CH:36]=3)=[O:41])[CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C3CC3)c2cc1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C3CC3)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [3-cyclopropyl-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide was synthesized from 3-cyclopropyl-4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (0.06 g, 0.20 mmol) and 3-(4-fluoro-phenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.06 g, 0.21 mmol) in an analogous manner to Example 1. mp 183-185° C.; LCMS m/z=597 (M+1). 1H NMR (DMSO-d6) δ: 10.84 (s, 1H), 8.86 (s, 1H), 8.44 (d, 1H, J=5.2 Hz), 7.71 (d d, 1H, J=2.53 Hz, J=8.73 Hz), 7.58 (s 1H), 7.31-7.46 (m, 5H), 7.27 (d, 1H, J=2.53 Hz), 7.17 (d, 1H, J=8.73 Hz), 6.33 (d, 1H, J=5.2 Hz), 4.00 (q, 2H, J=7.04 Hz), 3.94 (s, 6H), 1.77-1.87 (m, 1H), 1.29 (t, 3H, J=7.04 Hz), 0.72-0.82 (m, 2H), 0.62-0.71 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH2:14][C@@H:15]([C@@H:22]([OH:29])[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH:11]=[C:10]([CH3:30])[CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[CH2:35]([O:29][C@H:22]([C@H:15]([CH2:14][C:12]1[CH:11]=[C:10]([CH3:30])[CH:9]=[C:8]([N:3]2[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]2[CH3:1])[N:13]=1)[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: Cc1cc(C[C@H](C(=O)OC(C)C)[C@@H](O)C(=O)OC(C)C)nc(-n2c(C)ccc2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H](C(=O)OC(C)C)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of alcohol 4b (300 mg, 0.72 mmol) in THF (10 mL) at 0° C. was added NaH (60% in mineral oil, 35 mg, 0.87 mmol). The mixture was allowed to stir at 0° C. for an additional 30 min then allyl bromide (93 μL, 1.08 mmol) was added dropwise. The reaction was allowed to warm to room temperature and maintained for an additional 6 h. The reaction was quenched with saturated NH4Cl (1 mL) and partitioned between EtOAc (100 mL) and H2O (50 mL). The organic layer was washed with brine (50 mL) and dried over Na2SO4. The solvent was removed by rotary evaporation, the resulting brown oil was purified by flash column chromatography (EtOAc/hexanes, 1:9-1:1) to give 10 (316 mg, 0.69 mmol, 97%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.07-1.09 (d, J=6.0 Hz, 3H), 1.16-1.19 (d, J=6.0 Hz, 3H), 1.25-1.35 (m, 6H), 2.13 (s, 6H), 2.39 (s, 3H), 3.01-3.05 (dd, J=5.5, 15.5 Hz, 1H), 3.20-3.25 (dd, J=9.5, 15.0 Hz, 1H), 3.67-3.68 (dd, J=3.0, 4.5 Hz, 1H), 3.89-3.94 (dd, J=7.0, 13.0 Hz, 1H), 4.02-4.03 (d, J=5.0 Hz, 1H), 4.24-4.28 (dd, J=4.5, 12.0 Hz, 1H), 4.93-4.96 (m, 1H), 4.97-5.17 (m, 1H), 5.17-5.19 (d, J=10.0 Hz, 1H), 5.25-5.29 (dd, J=1.5, 17.0 Hz, 1H), 5.80-5.95 (m, 3H), 6.86 (s, 1H), 7.02 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.6, 21.2, 21.8, 21.9, 22.0, 22.1, 35.6, 47.7, 68.5, 68.9, 72.1, 78.1, 106.9, 118.0, 120.4, 123.7, 128.7, 134.2, 149.7, 151.8, 158.8, 170.4, 171.2; LCQ-MS (M+H+) calcd for C26H37N2O5 457. found 457; LC-TOF-MS (M+H+) calcd for C26H37N2O5 457.27025. found 457.26984.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CCOCC>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1/[CH:14]=[N:1]/[C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4]
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=Cc1ccccc1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOCC
Product: OC[C@@H](/N=C/c1ccccc1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a stirred solution of (S)-(+)-2-amino-2-phenylethanol (271 mmol, 37.2 g) in methylene chloride (350 mL) was added 2-bromobenzaldehyde (271 mmol, 31.8 mL, 50.2 g) and anhydrous magnesium sulfate (50 g). The mixture stirred 3 h at room temperature then left to stand overnight. Filtered through dicalite and evaporated to dryness to give a pale yellow solid. This solid was stirred in dry ether (100 mL) for 30 min, then filtered, washed with ether, and dried in vacuo to give (S,E)-2-(2-bromobenzylideneamino)-2-phenylethanol (65.1 g) as a colourless solid.