Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[C:12]([O:16][C:17](=[O:37])[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:35][Cl:36])([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+:39].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[C:12]([O:16][C:17](=[O:37])[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:39])[C:25]=2[N:24]=[C:23]1[CH2:35][Cl:36])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperoxybenzoic acid (13.3 g of 77% max, 59.4 eq.) was added in portions over a period of 5 minutes to a solution of tert-butyl[3-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate (8.9 g, 23.7 mmol) in chloroform (200 mL). The reaction mixture was allowed to stir at ambient temperature overnight. Ammonium hydroxide (50 mL) was added and the reaction mixture was stirred vigorously. Para-toluensulfonyl chloride (5.43 g, 28.5 mmol) was added over a period of 5 minutes. The reaction mixture was stirred at ambient temperature for 2 hours; an additional 1 g of para-toluensulfonyl chloride was added and the reaction mixture was stirred for another hour. The reaction mixture was filtered to remove solids. The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer was washed with 1:1 water:saturated aqueous sodium bicarbonate (2×150 mL). The combined aqueous was extracted with dichloromethane (2×150 mL) and ethyl acetate (1×100 mL). The combined organic extracts were concentrated under reduced pressure to provide 13.6 g of crude product as a brown foam. The foam was dissolved in dichloromethane (20 mL). The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g). The first cartridge was eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 5% methanol in 1:1 ethyl acetate:hexanes, and 10% methanol in 1:1 ethyl acetate:hexanes. The second cartridge was eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 7% methanol in 1:1 ethyl acetate:hexanes, and 7% methanol in 1:1 ethyl acetate:hexanes. The fractions containing product were combined and then concentrated under reduced pressure to provide 4.3 g of tert-butyl[3-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate as a light yellow foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][CH2:35][O:36][C:37]1[CH:43]=[C:42]([CH:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([CH:44]4[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH3:52])[CH2:48][CH2:49]4)=[CH:43][C:37]=3[O:36][CH2:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 130 °C
Yield: 58.9 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(2-ethyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 154, step E) (51 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.51 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (32 mg, 0.112 mmol, 24%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.36 (d, J=6.78 Hz, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 8.27 (d, J=5.31 Hz, 1H), 8.04 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.87 Hz, 1H), 7.73 (d, J=8.97 Hz, 1H), 7.65 (d, J=8.06 Hz, 1H), 7.59 (t, J=7.78 Hz, 1H), 7.42-7.49 (m, 1H), 7.34-7.42 (m, 1H), 7.19 (t, J=8.06 Hz, 2H), 6.98 (t, J=6.78 Hz, 1H), 6.93 (s, 1H), 6.76 (d, J=8.42 Hz, 1H), 6.55 (d, J=5.13 Hz, 1H), 4.08 (q, J=6.90 Hz, 2H), 2.88-3.00 (m, 2H), 2.38-2.45 (m, 1H), 2.19-2.30 (m, 2H), 1.87-1.99 (m, 2H), 1.63-1.75 (m, 4H), 1.39-1.49 (m, 2H), 1.26 (t, J=6.96 Hz, 3H), 0.84 (t, J=7.23 Hz, 3H). MS (ESI): 688 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[CH:27][C:28]=1[F:29].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[F:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[F:29])[O:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1ccc(Oc2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cc1F
Yield: 34.5 %

Procedure:
A solution of 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (60 mg, 0.203 mmol, 1.0 equiv.), 3,4-difluorophenol (0.223 mmol, 1.1 equiv.), Cs2CO3 (86 mg, 0.264 mmol, 1.3 equiv) and dimethylsulfoxide (1 mL) were mixed in a microwave tube and capped. The microwave tube was reacted in a microwave reactor (Personel Chemistry, Emrys Optimizer) at 70° C. for 10 minutes. The solvent was removed by rotary evaporation and the crude product purified via flash column chromatography (SiO2, CH2Cl2:CH3OH 100:0-80:20) to return the title compound as a white solid (27.2 mg, 0.07 mmol, 34% yield). Analytical data presented in Table 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([O:33][CH3:34])[CH:25]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=1[O:33][CH3:34]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-fluoro-2-methoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2,4′-difluoro-2′-methoxy-biphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 413 [MH+].
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:17][S:18][C:19]2[NH:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:17][S:18]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[O:36])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:12])([F:14])[F:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC(F)(F)C(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Solvent: ClC(Cl)Cl
Product: Cc1c(OCC(F)(F)C(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 77.8 %

Procedure:
To a solution of 2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methylthio]benzimidazole (2.2 g) in chloroform (20 ml), a solution of m-chloroperbenzoic acid (*1.3 g) in chloroform (15 ml) was added dropwise while ice-cooling over a period of 30 minutes and the resulting reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate. After drying over magnesium sulfate, the solvent was concentrated. The residue was applied on a silica gel (50 g) column, eluted with ethyl acetate and then recrystallized from acetone-isopropyl ether to give 1.78 g of 2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methylsulfinyl]benzimidazole as pale yellow prisms. Melting point: 161°~163° C. (decomposition).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(Br)=CC=2)C)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:27].O=O>CN(C=O)C.Cl[Cu].Cl[Pd]Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:4]2([CH2:1][C:2](=[O:27])[CH3:3])[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)=[CH:21][CH:22]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: CN(C)C=O
Product: CC(=O)CC1(c2ccc(F)cc2)CCNC(=O)O1
Yield: 92 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl) -1,3-oxazinan-2-one (5 g, 12 mmol) and CuCl (2.75 g, 27.8 mmol) in dry DMF (50 mL) was added H2O (20 mL) and PdCl2 (950 mg, 3.2 mmol) at room temperature. The mixture was vigorously stirred under a balloon of oxygen for 24 h. After TLC showed the starting material had disappeared, the solid was filtered off. Water (200 mL) and EtOAc (50 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (S)-3-(S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (5.25 g, 92%), which was purified by column chromatography. 1H NMR (CDCl3): 1.47 (s, 3H), 2.06 (s, 3H), 2.10-2.36 (m, 3H), 2.58 (m, 1H), 2.90 (m, 2H), 5.58 (m, 1H), 6.69 (m, 1H), 6.79 (m, 1H), 7.02 (m, 2H), 7.19-7.33 (m, 4H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][C:18]1[C:19]([OH:31])=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[OH:31][C:19]1[C:18]([NH:17]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)=[CH:23][CH:22]=[C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[N:20]=1
Reactant: CN1CCN(c2ccc(N)c(O)n2)CC1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)c(O)n2)CC1
Temperature: 100 °C

Procedure:
(4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.12 g, 0.35 mmol), 3-amino-6-(4-methyl-piperazin-1-yl)-pyridin-2-ol (0.15 g, contaminated with triethylammonium trifluoroacetate) were coupled in N,N-dimethylformamide (3 mL) with triethylamine (0.27 mL). The mixture is heated in a 100° C. oil bath for three hours. The reaction mixture is purified by reverse phase HPLC to give (4Z)-4-({[2-hydroxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}methylene)-6-iodoisoquinoline-1,3(2H,4H)-dione.2 trifluoroacetic acid salt (18 mg, 7.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu]Cl>[Br:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cccc(I)c1
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Clc1ccc(Oc2cccc(Br)c2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A solution of 4-chloro-2-phenoxy-phenol (1.65 g, 7.5 mmol), 1-bromo-3-iodobenzene (6.35 g, 22.4 mmol), copper(I) chloride (0.37 g, 3.74 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.345 g, 1.87 mmol), and cesium carbonate (2.93 g, 9 mmol) in NMP (20 mL) is heated to 120° C. The reaction is stirred overnight and cooled to rt. The reaction is quenched with 1N aqueous HCL and extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude is purified by silica gel column chromatography using 5/1 hexanes/ethyl acetate to elute the pure product. The solvent is removed to afford 1.13 g (40%) of the desired product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C18H12BrClO2 374, found 375 and 377 (M+1 and M+3, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:23][CH2:24][C:25]([NH:28][S:29]([C:32]1[S:33][C:34]([Cl:38])=[C:35]([NH2:37])[CH:36]=1)(=[O:31])=[O:30])([CH3:27])[CH3:26]>>[Cl:38][C:34]1[S:33][C:32]([S:29](=[O:31])(=[O:30])[NH:28][C:25]([CH3:26])([CH3:27])[CH2:24][OH:23])=[CH:36][C:35]=1[NH:37][C:20]([C:19]1[CH:18]=[N:17][N:11]2[C:12]([CH:14]3[CH2:16][CH2:15]3)=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][C:10]=12)=[O:21]
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.19) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Pale-yellow solid. (ISN) 580.0 [(M−H)−]; mp 238-241° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3-Hydroxy-2-nitrobenzoic acid (10.5 g) was dissolved in 60 ml of N,N-dimethylformamide, then 15 ml of benzyl bromide and 19.0 g of potassium carbonate were added at 0° C. and the mixture was stirred at room temperature for one night. The reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. Water was added to the resulting residue, the mixture was extracted with ether and the extract was washed with a saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give 20.7 g of benzyl 3-benzyloxy-2-nitrobenzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@H:13]3[CH2:15][C@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.[F:19][C:20]([F:26])([F:25])[C:21]([CH3:24])([NH2:23])[CH3:22]>>[F:19][C:20]([F:26])([F:25])[C:21]([NH:23][C:16]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:15][C@@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])([CH3:24])[CH3:22]
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Reactant: CC(C)(N)C(F)(F)F
Product: CC(C)(NC(=O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21)C(F)(F)F

Procedure:
The title compound was prepared in a manner similar to that described in Method UU using Intermediate 4 and 1,1,1-trifluoro-2-methylpropan-2-amine. LCMS m/z=352.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.6 and 3.2 Hz, 1H), 1.23-1.29 (m, 1H), 1.71 (s, 6H), 2.27-2.33 (m, 1H), 2.74-2.80 (m, 1H), 2.93 (d, J=17.1 Hz, 1H), 3.00 (dd, J=16.6 and 6.2 Hz, 1H), 6.94 (s, 1H), 8.42 (dd, J=2.5 and 1.5 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H).
Reaction SMILES: C1COCC1.[O:6]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:19](=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(O)C.CCCCCC>[O:28]=[C:19]1[O:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1
Reactant: O=CC=Cc1ccccc1
Reactant: CCOC(=O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(c2ccccc2)OC(=O)CC1c1ccccc1
Temperature: 23 °C
Reaction time: 36 h

Procedure:
A flame dried 2 dram vial equipped with a stirbar is brought into the glovebox and charged with (+)-4 (0.016 mmol, 0.10 equiv), TBD (6.6 mg, 0.048 mmol, 0.30 equiv), and 4 Å molecular sieves (100 mg). The vial is then sealed with a screw cap equipped with a teflon septa. The vial is then taken out of the glovebox and THF (0.80 mL), ethyl 2-oxo-2-phenylacetate (57 mg, 0.32 mmol, 2.0 equiv) and cinnamaldehyde (21 mg, 0.16 mmol) are added. The reaction mixture is then stirred at 23° C. for 36 hours (monitored by GC/MS). The crude reaction mixture is filtered through celite and an aliquot is taken to determine dr. After filtration the crude mixture is concentrated and the crude residue is purified by column chromatography on silca gel (2% EtOAc/Hex) to provide the pure products. Analytical data matches that reported in the literature (Li, Y. et al., Adv. Synth. Catal. 2008, 350, 1885, incorporated herein by reference). Major diastereomer (Cis) 1H NMR (500 MHz, CDCl3): δ 7.72-7.67 (m, 2H), 7.45-7.27 (m, 8H), 4.08 (dd, J=8.4, 4.1 Hz, 1H), 3.87-3.80 (m, 2H), 2.88 (dd, J=17.6, 8.4 Hz, 1H), 2.79 (dd, J=17.7, 4.1 Hz, 1H), 0.89 (d, J=7.7 Hz, 3H). Enantiomeric ratio is determined by chiral phase HPLC (chiralcel AD-H; i-PrOH-hexane, 2:98, 1.0 mL/min, 210 nm); tr (major)=39.4 min, tr (major)=60.0 min. and tr (minor)=17.1 min, tr (minor)=18.7 min. Absolute stereochemistry is assigned by analogy.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH2:24][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Fc1ccc(F)c(CBr)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)ccc2F)c1
Yield: 49.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (205 mg, yield: 49.2%).
Reaction SMILES: CC([CH:5]([N:15]([C@H:19]1[CH2:22][C@H:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH2:20]1)C(=O)[O-])[C:6]1[C:7]2[N:8]([CH:12]=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1)(C)C.O1CCOCC1>Cl.CS(C)=O.CO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C@H:21]2[CH2:22][C@H:19]([NH:15][CH2:5][C:6]3[C:7]4[N:8]([CH:12]=[CH:13][N:14]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:20]2)=[CH:25][C:26]=1[C:31]([F:33])([F:32])[F:34]
Reactant: CC(C)(C)C(c1cccn2ccnc12)N(C(=O)[O-])[C@H]1C[C@H](Oc2ccc(F)c(C(F)(F)F)c2)C1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: Fc1ccc(O[C@H]2C[C@H](NCc3cccn4ccnc34)C2)cc1C(F)(F)F

Procedure:
1,1-Dimethylethyl(trans-3-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}cyclobutyl)(imidazo[1,2-a]pyridin-8-ylmethyl)carbamate (62 mg, 0.129 mmol) was stirred in 4M HCl in dioxane (5 mL, 20 mmol) for 3 hours when LCMS indicated the reaction to be complete. The mixture was loaded onto a SCX cartridge (2 g) and eluted with MeOH (3 column volumes) and flushed with ammonia in MeOH. The eluant was concentrated in vacuo to give slightly impure product which was dissolved in 50:50 DMSO/MeOH (1 mL) and purified by MDAP to give the title compound (16.8 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:29]([N:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][NH2:35])[CH3:30].Cl.C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C.C(Cl)Cl>[CH2:29]([N:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][NH:35][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:30]
Reactant: CCN(CC)CCCN
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2F)ccc(-c2ccoc2)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Temperature: 130 °C
Yield: 93.2 %

Procedure:
A solution of methyl 6-(2-fluorobenzenesulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 96, 0.07 g) in acetonitrile (2.2 ml) was added to a solution of N,N-diethyl-1,3-propanediamine (0.225 g) in triethylamine (0.07 g) in a microwave vial. The mixture was heated in the microwave at 130° C. for 2 hours. After cooling, DCM and hydrochloric acid (1M) were added and the pH was adjusted to 8 by addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with DCM, washed with brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM, methanol, acetic acid and water (350:20:3:2) to give methyl 6-[2-(3-diethylaminopropylamino)benzenesulphonylmethyl]-3-(furan-3-yl)-2-methoxybenzoate (0.083 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:18]>O1CCOCC1>[ClH:1].[Cl:12][C:10]1[N:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:15]([CH3:14])[CH:16]=3)[C:3]=2[CH:11]=1
Reactant: Cc1cc(N)ccc1Oc1ccccc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncnc3cnc(Cl)cc23)ccc1Oc1ccccc1
Temperature: 75 °C
Yield: 100 %

Procedure:
The 4,6-dichloro-pyrido[3,4-d]pyrimidine obtained from the previous reaction was taken up in dioxane (50 ml), the 3-methyl 4-phenoxy aniline hydrochloride (2.8 g, 12 mmol) was added and the contents heated to an external bath temperature of -80 oC for 3 hours, whereupon yellow precipitation occurred. Further dioxane (20 ml) was added and the contents heated at ˜75° C. for 12 hours. The solution was then filtered and the yellow solid placed under vacuum to provide the desired (6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine hydrochloride (3.6 g, ˜100%). 1H NMR (CD3OD; 400 MHz) δ 9.05 (s, 1H), 8.87 (s, 1H), 8.64 (s, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.58 (dd, J=8.7, 2.5 Hz, 1H),7.35 (dd, J=8.7, 7.5 Hz, 2H), 7.10 (t, J=7.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 3H), 2.29 (s, 3H). MS m/z (MH+): 363.2