Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[C:8]([O:22][CH3:23])[CH:7]=2.[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1>C(#N)C>[CH2:20]([S:17]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:22][CH3:23])[N:5]=[C:4]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:3]([CH2:2][N:34]1[CH2:39][CH2:38][CH:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH2:36][CH2:35]1)=[C:12]2[C:13]([O:15][CH3:16])=[O:14])(=[O:18])=[O:19])[CH3:21]
Reactant: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CBr)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: CC#N
Product: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A suspension of methyl 3-(bromomethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.983 g, 3.63 mmol) and 4-(4-piperidinyl)morpholine (0.803 g, 4.72 mmol) in acetonitrile (30 mL) was stirred for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and purified via reverse phase HPLC (Biotage RP, 0-50% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.0 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.98 (s, 1H), 7.90 (t, J=7.91 Hz, 2H), 7.75-7.84 (m, 2H), 4.10 (s, 3H), 4.01 (s, 3H), 3.61 (s, 2H), 3.50-3.58 (m, 6H), 2.63 (d, J=11.04 Hz, 2H), 2.38 (br. s., 4H), 1.93-2.08 (m, 1H), 1.81 (t, J=10.92 Hz, 2H), 1.61 (d, J=11.54 Hz, 2H), 1.22-1.30 (m, 2H), 1.15 (t, J=7.40 Hz, 3H); MS (m/z) 636.2 (M+H+).
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1B(O)O>>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1cc2ccccc2o1
Agent: OBO
Product: O=Cc1cccc(-c2cc3ccccc3o2)n1

Procedure:
6-(benzofuran-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and benzofuran-2-ylboronic acid (41 mg, 120.1 mg theoretical, 34.1%). LC-MS m/z 224.2 (M+1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1.[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(Cc1nc2cc(C(=O)N(CCC(=O)O)c3cccnc3)ccc2n1C)c1ccc(C(=N)N)cc1

Procedure:
Prepared analogously to Example 26 from 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[F:15][C:16]1[CH:22]=[C:21]([O:23][C:24]2[C:29]3=[N:30][CH:31]=[C:32]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[N:33]=[C:28]3[N:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[CH:22]=[C:21]([O:23][C:24]2[C:29]3=[N:30][CH:31]=[C:32]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[N:33]=[C:28]3[N:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:17]=1[NH:18][C:13]([NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])=[O:14]
Reactant: CN1CCN(c2cnc3c(Oc4ccc(N)c(F)c4)ccnc3n2)CC1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: CN1CCN(c2cnc3c(Oc4ccc(NC(=O)Nc5cc(C(F)(F)F)ccc5F)c(F)c4)ccnc3n2)CC1

Procedure:
Method F3 was used with 2-Fluoro-5-(trifluoromethyl)phenyl isocyanate and 2-fluoro-4-(3-(4-methylpiperazin-1-yl)pyrido[3,2-b]pyrazin-8-yloxy)aniline to give the title compound as a yellow solid. Yield: 30 mg (64%).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:26]=[CH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:16]=3[C:15]=2Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C(O)C>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:1]1[CH:6]=[CH:5][C:4]([C:20]2[CH:19]=[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][C:14]([N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)=[CH:15][C:16]=4[C:17]3([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:22][CH:21]=2)=[CH:3][CH:2]=1
Reactant: OB(O)c1nc2ccccc2s1
Reactant: CCC1(CC)c2ccccc2-c2ccc(N(c3ccccc3)c3ccccc3)c(Br)c21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC1(CC)c2cc(-c3ccc(-c4nc5ccccc5s4)cc3)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: 87.5 °C

Procedure:
A mixture of diphenylamino-9,9-diethyl-bromofluorene (7.02g, 0.015 mol), benzothiazole boronic acid (7.5 g 0.029 mol.), ethanol (50 ml), in NMP (50 ml) was degassed by bubbling nitrogen through the solution for 20 min. Sodium carbonate (13.0 g, 0.12 mol.) and 5% palladium on charcoal (1.5 g ) were then added, the mixture heated at 85-90° C. for 42 hrs. The resulting solids (18.0 g) that separated upon cooling were collected, washed with ethanol and dried. The solids were then transferred to a chromatograph column containing 300 g of alumina. Elution with 1:1 toluene-heptane gave the product, 4.98 g. (55.5% yield), m.p. 243.6-246.1° C. Recrystallization from toluene did not raise the melting point. Mass Spec: m/z 598, (M+). Analysis calculated for C42H34N2S: C, 84.25; H, 5.72; N, 4.68; S, 5.34. Found: C, 83.87; H, 6.02; N, 5.04; S, 5.29.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:14][C:15]1[CH:27]=[CH:26][C:18]([O:19][CH:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])=[CH:17][C:16]=1[CH3:28]>C1C=CC=CC=1>[CH2:1]([NH:7][C:21](=[O:22])[CH:20]([O:19][C:18]1[CH:26]=[CH:27][C:15]([Cl:14])=[C:16]([CH3:28])[CH:17]=1)[CH2:24][CH3:25])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Oc1ccc(Cl)c(C)c1)C(=O)Cl
Reactant: NCc1ccco1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCC(Oc1ccc(Cl)c(C)c1)C(=O)NCc1ccco1
Yield: 27.1 %

Procedure:
In 50 ml of benzene were dissolved 1.5 g (0.015 mole) of furfurylamine and 4.0 g (0.051 mole) of pyridine, and thereto was added dropwise a solution of 3.0 g (0.012 mole) of 2-(4-chloro-3-methylphenoxy)-butyroyl chloride in 20 ml of benzene at room temperature with stirring, followed by stirring for further 5 hours. Subsequently, after the same procedure as in Synthesis Example 4 and 5 was followed, the resultant crude crystals were recrystallized from ethanol to give 1.0 g of N-furfuryl-2-(4-chloro-3-methylphenoxy)-butyramide melting at 100°~102° C. as pale brown needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:33]=[CH:32]2>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][N:15]2[CH2:20][CH2:19][N:18]([S:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([Cl:28])[CH:30]=4)[CH:35]=3)(=[O:40])=[O:41])[CH2:17][C:16]2=[O:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCNCC2=O)CC1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the resultant 1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone in ethyl acetate (30 ml) and a 10% aqueous solution of sodium carbonate (30 ml) was combined at 0° C. with 6-chloronaphthalene-2-sulfonyl chloride (2.24 g) and stirred at room temperature for 30 minutes, and then the organic phase was separated, washed with brine, dried and concentrated. The residue thus obtained was purified by a column chromatography on a silica gel (hexane:ethyl acetate=1:2) to obtain 1-[1-(tert-Butoxycarbonyl)-4-piperidinylamino]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (3.55 g) as a colorless amorphous material.
Reaction SMILES: [P:1]([O:19][CH2:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][OH:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:28].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:4]([O:3][P:1]([O:19][CH2:20][C:21]([CH3:26])([CH3:25])[CH2:22][C:23]([OH:28])=[O:24])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(CCO)COP(=O)(OCc1ccccc1)OCc1ccccc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(COP(=O)(OCc1ccccc1)OCc1ccccc1)CC(=O)O
Reaction time: 48 h
Yield: 85.1 %

Procedure:
To a solution of the product from Example 9B (0.396 g, 1.0 mmol) in DMF (10 mL) at room temperature was added pyridinium dichromate (2.3 g), and the mixture was stirred for 48 hours. 10% citric acid was added and the reaction was extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient of 0-5% methanol in chloroform, to give the title compound (0.334 g, 81%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][S:16]([OH:19])(=O)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][S:16]([Cl:23])(=[O:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cc1ccccc1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)Cc1ccccc1OCc1ccccc1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
Tetrahydrofuran (10 ml), (2-Benzyloxy-phenyl)-methanesulfonic acid (138 mg), and N,N-dimethylformamide (2 drops) was cooled to −78° C. and oxalyl chloride (315 mg) was added slowly. The reaction mixture was stirred for 3 h from −78° C. to 0° C. The reaction mixture was clarified by filtration. The filtrate was washed with iced-water and heptane, and dried to give (2-benzyloxy-phenyl)-methanesulfonyl chloride (114 mg, 77%). 1H NMR (400 MHz, CDCl3): δ 5.06 (s, 2 H) 5.15 (s, 2 H) 7.04 (m, 2 H) 7.42 (m, 7 H).
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[C:19]([C:21]1([OH:28])[CH2:25][CH:24]([CH3:26])[NH:23][C:22]1=[O:27])#[CH:20]>>[OH:28][C:21]1([C:19]#[C:20][C:2]2[CH:18]=[CH:17][C:5]3[O:6][CH2:7][CH2:8][C:9]4[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=4)[C:4]=3[CH:3]=2)[CH2:25][CH:24]([CH3:26])[NH:23][C:22]1=[O:27]
Reactant: C#CC1(O)CC(C)NC1=O
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Product: CC1CC(O)(C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2CCO3)C(=O)N1

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with a ˜1:1 diastereomeric mixture of 3-ethynyl-3-hydroxy-5-methylpyrrolidin-2-one to give a mixture of titled compounds after purification by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]2[N:16]=[C:17]([NH:19][CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[N:18]=[C:10]12.Cl.[Cl:34][C:35]1[CH:40]=[C:39](F)[CH:38]=[CH:37][N:36]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]2[N:16]=[C:17]([NH:19][CH:20]3[CH2:21][CH2:22][N:23]([C:39]4[CH:38]=[CH:37][N:36]=[C:35]([Cl:34])[CH:40]=4)[CH2:24][CH2:25]3)[N:18]=[C:10]12
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3n(n2)CC(O)CC3c2ccc(F)cc2Cl)CC1
Reactant: Fc1ccnc(Cl)c1
Agent: Cl
Product: OC1CC(c2ccc(F)cc2Cl)c2nc(NC3CCN(c4ccnc(Cl)c4)CC3)nn2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 4-(8-(2-chloro-4-fluorophenyl)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)piperidine-1-carboxylate (0.05 g, 0.1 mmol) was added HCl (3 mL, 4 N in dioxane) and the reaction stirred for 0.5 hour. The reaction was then concentrated to dryness, the residue redissolved in dimethylacetamide (0.5 mL), triethylamine added until the mixture was basic, followed by the addition of 2-chloro-4-fluoropyridine (0.04 g, 0.3 mmol) and the mixture heated to 80° C. for 1 hour. The reaction was evaporated to dryness, redissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate, water, brine, dried with sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate/MeOH (v/v 1:0 to 95:5) as eluent. The title compound was obtained as a light yellow gum (0.04 g, 76%), an inseparable 1:1 mixture of diasteriomers. MS ISP (m/e): 477.1 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH2:8])[CH2:3]1.C[Al](C)C.C([O:15][C:16]([C:18]1[C:22]([NH:23][C:24]([NH2:26])=[O:25])=[CH:21][N:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:19]=1)=O)C>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:16]([C:18]2[C:22]([NH:23][C:24]([NH2:26])=[O:25])=[CH:21][N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH:19]=2)=[O:15])[CH2:3]1
Reactant: CN1CCC[C@H](N)C1
Reactant: CCOC(=O)c1cn(-c2cccc(F)c2)cc1NC(N)=O
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CN1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
To a solution of (S)-1-methyl-piperidin-3-yl amine (120 mg, 1.05 mmol) in THF (8.0 mL), under nitrogen, was added 2N trimethylaluminium in hexanes (1.0 mL, 2.0 mmol), and the reaction mixture was allowed to stir at room temperature for 1.5 hours. After this time, a THF (5.0 mL) solution of 1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carboxylic acid ethyl ester (291 mg, 1.0 mmol), was added and the reaction mixture was heated at 65-70° C. for a period of 18 hours. After this time, the reaction mixture was allowed to cool to room temperature and was then quenched by addition of a saturated solution of Rochelle's salt. After 0.5 hours, the mixture was extracted with DCM (3×10 mL) and EtOAc (1×10 mL). The combined organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was then purified by flash chromatography (silica, 5 g column, Isolute, 0-20% MeOH in DCM) to afford the title compound (60 mg, 0.17 mmol, 17%). LCMS (method A), RT=5.13 min, M+H+=360; 1H NMR (DMSO-D6, 400 MHz): 8.97 (s, 1H), 8.05 (d, J=2.6 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.55-7.48 (m, 1H), 7.39 (dt, J=10.6, 2.3 Hz, 1H), 7.36-7.33 (m, 1H), 7.12 (td, J=8.5, 2.4 Hz, 1H), 6.29 (s, 2H), 3.95-3.88 (m, 1H), 2.85-2.77 (m, 1H), 2.65-2.57 (m, 1H), 2.18 (s, 3H), 1.92-1.73 (m, 3H), 1.74-1.67 (m, 1H), 1.58-1.46 (m, 1H), 1.33-1.19 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[F:13][C:14]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:15]=1[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:13][C:14]1[CH:27]=[C:26]([O:28][C:7]2[CH:6]=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=2)[CH:25]=[CH:24][C:15]=1[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1F
Reactant: Clc1cnc2cc(Br)ccc2n1
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Br)ccc3n2)cc1F

Procedure:
Ethyl 2-[2-fluoro-4-(6-bromoquinoxalin-2-yloxy)phenoxy]propionate (10) was prepared from 6-bromo-2-chloro quinoxaline and ethyl 2-(2-fluoro-4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1 part (b). The title compound was obtained as colourless crystals mp 107°-108.6° C. and the assigned structure was characterised by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][C:2]([CH3:12])([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1)([O-:15])=[O:14]
Reactant: CC1(C)CNc2ccccc2C1
Reactant: O=[N+]([O-])O
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1,2,3,4-Tetrahydro-3,3-dimethylquinoline (51 mg, 0.32 mmol) was dissolved in sulfuric (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (14 mL, 0.32 mmol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 39 mg (58%) of 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.40 (dd, J=8.3, 2.1, 1H), 7.29 (d, J=1.8, 1H), 7.01 (d, J=8.3H, 1H), 4.25 (s, 1H), 2.98 (s, 2H), 2.54 (s, 2H), 1.01 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]([N:10]1[C:15](=[O:16])[C:14]2[N:17]=[CH:18][CH:19]=[CH:20][C:13]=2[NH:12][C:11]1=[O:21])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]1[C:29]2[C:30]([CH3:35])=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=2[S:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6](=[O:22])[C@@H:7]([N:10]1[C:15](=[O:16])[C:14]2[N:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]([CH2:24][C:25]2[C:29]3[C:30]([CH3:35])=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=3[S:27][N:26]=2)[C:11]1=[O:21])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2cccnc2c1=O
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC[C@@H](C(=O)OC(C)(C)C)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
A mixture of 46 mg of (S)-2-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-butyric acid tert-butyl ester, 41 mg of 3-bromomethyl-4,6-dimethyl-1,2-benzoisothiazole and 111 mg of potassium carbonate is stirred at room temperature for 4 h. The reaction mixture is diluted with water and the product is filtered and washed with water. The isolated solid is purified by flash chromatography on silica gel to give 72 mg (99%) of (S)-2-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-butyric acid tert-butyl ester.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:31]([CH3:33])[CH3:32])[C:5]([C:7]1[NH:8][C:9]([CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[N:10][C:11](=[O:21])[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.ClCCl.CO>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])[N:8]2[CH2:2][CH2:3][N:4]([CH:31]([CH3:33])[CH3:32])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCn2c(Cc3c(Cl)cccc3Cl)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
5-Benzyloxy-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (64) (0.11 g, 224 μmol, Eq: 1.00) was dissolved in dichloromethane (1.5 ml) and Ph3P (88.3 mg, 336 μmol, Eq: 1.5) was added. The clear colorless solution was stirred at room temperature for approx. 10 min and then diisopropyl azodicarboxylate (diisopropylazodicarboxylate) (71.6 mg, 68.9 μl, 336 μmol, Eq: 1.5) was added. Stirring was continued at room temperature for 1 h. The solvent was removed and the remaining oil was purified by SiO2 flash chromatography (12 g SiO2, dichloromethane/methanol 0-3% methanol). SiO2 flash chromatography was repeated (12 g SiO2, hexanes/ethyl acetate 7-50% ethyl acetate, then dichloromethane/methanol 0-3% methanol) to afford 9-benzyloxy-6-(2,6-dichlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (65) (0.045 g, 95.3 μmol, 42.5% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1
Yield: 94.2 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl pyrrolidin-3-ylcarbamate (931 mg, 5 mmol) followed by reduction to afford the desired product (813 mg, 94%) as a purple solid: ESI MS m/z 279 [C14H22N4O2+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32].[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>CN(C)C=O.C(#N)C>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[C:29]([O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Reactant: CCCC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCC(=O)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-3-hydroxy-1-isoindolinone (8 g) in anhydrous dimethylformamide (75 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (1.2 g) in anhydrous dimethylformamide (15 cc) at a temperature close to 20° C. in the course of 15 minutes and agitation is continued for 3 hours. Then, 2.6 g of butyryl chloride is added in the course of 10 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (400 cc) and extracted with methylene chloride (4×200 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in acetonitrile (120 cc). A solution of oxalic acid (2.3 g) in acetonitrile (60 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 8.1 g of 3-butyryloxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 160° C.