Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[S:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[S:31]>C(O)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[C:35]2[S:29][C:30](=[S:31])[NH:32][C:33]2=[O:34])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCc2ccccc2Cc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccccc2Cc2ccccc2)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(2-benzylphenyl)methoxy]benzaldehyde (4.5 g, 14.9 mmol), sodium acetate (4.27 g, 52 mmol), and rhodanine (1.98 g, 14.9 mmol) were dissolved in 75 ml of acetic acid. The reaction solution was then heated to reflux and maintained at this temperature for about three days.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:13][C:14]([F:30])([F:29])[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[N:16]=1>>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:17]3[N:16]=[C:15]([C:14]([F:29])([F:13])[F:30])[O:19][N:18]=3)[CH:21]=2)=[O:24])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1cnc(N2CCNCC2)nc1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2ncccn2)CC1
Yield: 33 %

Procedure:
This compound was synthesized from 2-piperazin-1-yl-pyrimidine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (52 mg, yield 33%). 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=4.7 Hz, 2H), 8.23-8.21 (m, 2H), 7.68-7.61 (m, 2H), 6.58-6.56 (t, J=4.7 Hz, 1H), 3.97-3.85 (m, 6H), 3.53 (m, 2H). MS (ESI) m/z: Calculated for C18H16F3N6O2: 404.12. found: 405.1 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:32])[C:6]([NH:19][CH:20]([C:26]2([CH3:31])[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:21][C:22]([O:24]C)=[O:23])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)#[N:2].C(C1C=C(F)C(N[C@@H](C2(C)CCCC2)CC(OC)=O)=NC=1C1C2C(=NC=C(F)C=2)NC=1)#N.[OH-].[Li+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([F:32])[C:6]([NH:19][C@@H:20]([C:26]2([CH3:31])[CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:21][C:22]([OH:24])=[O:23])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)#[N:2]
Reactant: COC(=O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F)C1(C)CCCC1
Agent: COC(=O)C[C@@H](Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F)C1(C)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1([C@@H](CC(=O)O)Nc2nc(-c3c[nH]c4ncc(F)cc34)c(C#N)cc2F)CCCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of racemic methyl 3-(5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoate, 145a, (0.090 g, 0.204 mmol) in THF (30 mL) was added a solution of lithium hydroxide (0.035 g, 0.819 mmol) in H2O (10 mL). The reaction mixture was stirred at 70° C. overnight. The organic phase was removed under reduced pressure and the resulting residue was purified by preparatory HPLC. The appropriate HPLC fractions were extracted with EtOAc, and the solvent was removed under reduced pressure: 1H NMR (400 MHz, MeOD) δ 8.64 (dd, J=8.4, 2.4 Hz, 1H), 8.57 (s, 1H), 8.24 (d, J=4.4 Hz, 1H), 5.19 (d, J=8.7 Hz, 1H), 2.78 (qd, J=15.9, 6.6 Hz, 2H), 1.85-1.57 (m, 6H), 1.48 (dd, J=11.8, 6.0 Hz, 1H), 1.36 (dt, J=12.0, 6.0 Hz, 1H), 1.11 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.21 minutes (M+H) 426.25.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9](=[O:20])[N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:11]=[C:5]2[C:4]=1[O:21][CH3:22]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:22][O:21][C:4]1[C:5]2[N:6]([C:9](=[O:20])[N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:11]=2)[CH:7]=[CH:8][C:3]=1[CH:2]=[O:1]
Reactant: COc1c(CO)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1c(C=O)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Reaction time: 16 h
Yield: 94.1 %

Procedure:
To a stirred solution of 7-hydroxymethyl-8-methoxy-2-(2-trimethylsilanyl-ethoxymethyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (1.23 g, 3.78 mmol) in DCM (100 mL) was added manganese dioxide (3.30 g, 37.8 mmol). After 16 hours, the reaction mixture was filtered through Celite®. The filtrate was evaporated to dryness to afford the title compound (1.15 g, 94%) as a pale yellow solid. LCMS (Method A): RT=4.52 min, [M+Na]+=346.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[CH:23]=[CH:22][N:14]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=4[CH:21]=[C:13]3[C:12]2=[O:24])[C:3]=1[CH:4]=[O:5].[CH2:25]([C@H:27]1[CH2:32][N:31]([CH:33]2[CH2:36][O:35][CH2:34]2)[CH2:30][CH2:29][N:28]1[C:37]1[CH:38]=[CH:39][C:40]([NH:43][C:44]2[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:49]=2)=[N:41][CH:42]=1)[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH2:25]([C@H:27]1[CH2:32][N:31]([CH:33]2[CH2:34][O:35][CH2:36]2)[CH2:30][CH2:29][N:28]1[C:37]1[CH:38]=[CH:39][C:40]([NH:43][C:44]2[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=[C:48]([C:2]3[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]4[CH:23]=[CH:22][N:14]5[C:15]6[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=6[CH:21]=[C:13]5[C:12]4=[O:24])[C:3]=3[CH:4]=[O:5])[CH:49]=2)=[N:41][CH:42]=1)[CH3:26]
Reactant: O=Cc1c(Br)cc(F)cc1-n1ccn2c3c(cc2c1=O)CCCC3
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Temperature: 80 °C
Yield: 43.2 %

Procedure:
A round-bottomed flask was charged with 2-bromo-4-fluoro-6-(1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)benzaldehyde 121f (159 mg, 0.41 mmol), 122a (213 mg, 0.43 mmol), PdCl2(dppf) (29 mg, 0.04 mmol), K3PO4 (182 mg, 0.86 mmol), sodium acetate (71 mg, 0.86 mmol), acetonitrile (15 mL), and water (1.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 122b as a red solid (120 mg, 43%). MS: [M+H]+ 678.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[H-].[Na+].[Cl:31]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Cl:31][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16][N:17]=[C:18]12
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)c3)nnc21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)c3)nnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
Under an argon atmosphere, to a mixture of ethyl 3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.32 g) in DMF (11 mL) was added sodium hydride (60%, 0.14 g) at 0° C., and the mixture was stirred at room temperature for 30 min. N-Chlorosuccinimide (0.46 g) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (0.15 g).
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH2:18]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C(C2C=CC=CC=2)N2CCN(C([C@@H](NC(=O)OC(C)(C)C)CC(C)C)=O)CC2)C=CC=CC=1>>[CH2:18]([N:27]1[CH2:32][CH2:31][N:30]([C:15]([C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:29][CH2:28]1)[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C(=Cc1ccccc1)CN1CCNCC1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(CC=Cc2ccccc2)CC1
Yield: 86 %

Procedure:
Tert-butoxycarbonyl-L-leucine monohydrate (7.47 g) and 1-cinnamylpiperazine (6.06 g) were condensed in the same manner as employed in the preparation of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate to yield 10.7 g of tert-butyl (s)-1-(4-cinnamylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate as a colorless amorphous substance (yield: 86%).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([CH3:20])[C:14]2([CH3:22])[CH3:21])C(=O)COCC(O)=O.CN(C1C=CC2N=C(C)SC=2C=1)C(=O)COCC(O)=O.CN.C1(=O)OC(=O)COC1>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([CH3:20])[C:14]2([CH3:22])[CH3:21]
Reactant: CC1=Nc2ccc(N(C)C(=O)COCC(=O)O)cc2C1(C)C
Agent: CN
Agent: Cc1nc2ccc(N(C)C(=O)COCC(=O)O)cc2s1
Agent: O=C1COCC(=O)O1
Solvent: ClC(Cl)Cl
Product: CNc1ccc2c(c1)C(C)(C)C(C)=N2
Yield: 86 %

Procedure:
The yield was 86%, yellow solid. 1H NMR (500 MHz, CDCl3): δ 1.34 (s, 6H, 2×CH3), 2.29 (s, 3H, CH3), 2.94 (s, 3H, NCH3), 3.52 (s, 1H, NH), 6.5-7.5 (m, 3H, aromatic ring). ESI-MS: 189 (MH+). {2-[Methyl(2,3,3-trimethyl-3H-indol-5-yl)amino]-2-oxoethoxy}-acetic Acid (20) and {2-[Methyl(2-methyl-1,3-benzothiazol-6-yl)-amino]-2-oxoethoxy}acetic Acid (21). N-Methylamine from the previous synthesis (1.0 mmol) was dissolved in 20 mL of chloroform. A 1.1 mmol sample of diglycolic anhydride was added, and the mixture was stirred under reflux for 2 h. After cooling, the solvent was evaporated. The solid was recrystallized from acetone to give pure acids.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].[OH-].[Na+]>CC(C)=O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCOc1ccc(F)cc1

Procedure:
This compound was prepared from 4-fluorophenol and allyl bromide according to the process described in Example 5, stage A. The solvent used is acetone and the reaction was carried out in the presence of sodium hydroxide.
Reaction SMILES: [H-].[Na+].N#N.[Br:5][C:6]1[CH:7]=[C:8]([SH:12])[CH:9]=[CH:10][CH:11]=1.Cl[CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]([S:12][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: Sc1cccc(Br)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cccc(SCc2csc(-c3ccccc3)n2)c1
Reaction time: 8 h

Procedure:
NaH (53 mg, 2.2 mmol) was suspended in dry THF (1.5 ml) under a stream of N2 and 3-bromo-benzenethiol (378 mg, 2 mmol) was added dropwise to the suspension over 5 min. 4-Chloromethyl-2-phenyl-thiazole (419 mg, 2 mmol) was added and the solution left stirring overnight. The reaction mixture was quenched with a saturated K2CO3 solution (8 ml) and extracted with EtOAc (3×4 ml). The combined organic layers were washed with saturated K2CO3 solution (4 ml), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C@H:16]([OH:18])[CH3:17])=[CH:9][CH:10]=2)[N:5]=1.[CH3:19]I>CN(C=O)C>[CH3:19][O:18][C@H:16]([CH3:17])[CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[CH:13][C:4]([CH3:3])=[N:5]2)=[CH:10][CH:9]=1
Reactant: CI
Reactant: Cc1ccc2ccc(OC[C@@H](C)O)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H](C)COc1ccc2ccc(C)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
To a stirred suspension of NaH (60% dispersion in oil, 95 mg, 2.4 mmol) in DMF (8 mL) was added dropwise a solution of (R)-1-(2-methylquinolin-7-yloxy)propan-2-ol (344 mg, 1.58 mmol) in DMF (4 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes. MeI (0.198 mL, 3.17 mmol) was added dropwise. The reaction was stirred at ambient temperature overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexanes/EtOAc) to give (R)-7-(2-methoxypropoxy)-2-methylquinoline (185 mg, 51%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[OH:1][C@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCCCC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Yield: 88 %

Procedure:
The compound 11 obtained above (220 mg, 0.518 mmole) was dissolved in 4 ml of a mixture of acetic acid-water-tetrahydrofuran (65:35:10) and the solution was heated with stirring at 40°-45° C. for one and half hours. Then, the reaction mixture was treated following the procedure similar to that of Example 4, to yield the title compound 12 (156 mg, 88%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.F[C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[C:33]([O:34][CH3:35])=[CH:32][C:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30][C:24]=3[CH:23]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>CS(C)=O>[ClH:3].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[C:33]([O:34][CH3:35])=[CH:32][C:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30][C:24]=4[CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: COc1cc2c(cc1S(=O)(=O)c1ccc(F)cc1)CCN(C)CC2
Reactant: OCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1S(=O)(=O)c1ccc(OCc3ccc(Cl)cc3)cc1)CCN(C)CC2
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in oil) (2.52 g, 63 mmol) was suspended in dry dimethylsulfoxide (30 mL) and 4-chlorobenzyl alcohol (12 g, 84 mmol) in dry dimethylsulfoxide (30 mL) was added over 15 min by syringe keeping the temperature below 30° C. (internal). This solution was stirred for 15 minutes to give a grey clear solution. The fluorosulfone D5 (15 g) was then added as a solid portionwise over 10 minutes keeping the temperature below 35° C. and the solution was stirred until the temperature began to fall, (approximately 10 minutes). The solution was then heated to 40° C. and stirred at this temperature for 1.5 hours with monitoring by LC and MS. The reaction mixture was then poured into 2M HCl (600 mL) and extracted with ethyl acetate (400 mL×1 and 250 mL×2) [this extraction was done by decantation into a separating funnel as leaving the oil which had precipitated in the conical flask along with some aqueous]. The ethyl acetate extracts were washed with a mixture of water 200 mL, brine 20 mL and 2M HCl 10 mL. The combined aqueous layers were cooled and basified with 12.5M sodium hydroxide and extracted with ethyl acetate (400 mL×1 and 250 mL×2), washed with brine and dried over sodium sulfate. The solvent was removed to give the title compound E31 (free base) as a cream coloured solid (18.24 g). A combined batch of 35.6 g of the free base was recrystallised from ethanol (following the addition of ethereal hydrogen chloride) which afforded the title compound E31 as the hydrochloride salt 30.6 g. MH+ 471. 1H NMR δ(DMSO) 2.78 (3H, s), 2.9-3.2 (4H, m), 3.2-3.6 (4H, m), 3.73 (3H, s), 5.19 (2H, s), 7.08 (1H, s), 7.18 (2H, d), 7.47 (4H, s), 7.79-7.83 (3H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N+:16]([O-])=O)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]2)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:16])[CH2:9][O:10][C:11]([CH3:14])([CH3:15])[O:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(c2ccc(F)cc2)([N+](=O)[O-])CO1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1(C)OCC(N)(c2ccc(F)cc2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 490 mg of 5-(4-fluorophenyl)-2,2-dimethyl-5-nitro-1,3-dioxane in 7.4 ml of acetic acid was added 628 mg of zinc powder, followed by stirring at room temperature for 2 hours. The insoluble materials were separated by filtration and washed with chloroform, and the filtrate was then concentrated under reduced pressure. To the obtained residue was added a 1 M aqueous sodium hydroxide solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 325 mg of 5-(4-fluorophenyl)-2,2-dimethyl-1,3-dioxan-5-amine.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Br[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[N:43][CH:44]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[CH3:22][N:6]1[C:5]2[N:23]=[CH:24][C:2]([O:1][C:39]3[CH:44]=[N:43][C:42]([CH3:45])=[CH:41][CH:40]=3)=[CH:3][C:4]=2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:7]1=[O:21]
Reactant: Cc1ccc(Br)cn1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(O)cnc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Oc2cnc3c(c2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)cn1
Temperature: 135 °C
Yield: 77.1 %

Procedure:
To a suspension of 6-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 2, 500 mg, 1.49 mmol), CuI (85.2 mg, 0.45 mmol), Cs2CO3 (971.6 mg, 2.98 mmol) and 2-(dimethylamino)acetic acid (76.87 mg, 0.75 mmol) in dioxane (20 mL) was added 5-bromo-2-methylpyridine (641.2 mg, 3.73 mmol). The reaction was heated at 135° C. for 5 h followed by heating at 100° C. for 18 h, cooled to RT then diluted with EA (25 mL) and water (10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 1-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (490 mg, 77.1% yield) as a yellow oil. LCMS: [MH+-THP] 343 and TR=1.215 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:22][CH2:21][S:20][C:19]([CH3:24])([CH3:23])[C@@H:18]3[C:25]([OH:27])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:35][OH:36].C(=O)(O)[O-].[Na+].Cl>ClCCl.O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[OH:36][NH:35][C:25]([C@H:18]1[C:19]([CH3:24])([CH3:23])[S:20][CH2:21][CH2:22][N:17]1[S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])=[O:27]
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(-c3ccc(Br)cc3)cc2)[C@H]1C(=O)O
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(-c3ccc(Br)cc3)cc2)[C@H]1C(=O)NO
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.3 %

Procedure:
The carboxylic acid obtained in Example 1 (12.2 g, 0.026 mol) was diluted with dichloromethane (150 mL) and oxalyl chloride (16.5 g, 0.13 mol). N,N-Dimethylformamide was added as a catalyst. The solution was stirred at room temperature for 14 hours, at which time the solvent was concentrated in vacuo. The crude acid chloride was triturated with hexane and collected by filtration. The solid was diluted with tetrahydrofuran (75 mL) and added dropwise to a mixture of hydroxylamine hydrochloride (9 g, 0.13 mol) and sodium bicarbonate (16.4 g, 0.19 mol) in tetrahydrofuran (150 mL)/water (75 mL) cooled to 0° C. The reaction mixture gradually warmed to room temperature and was stirred for 14 hours. Ethyl acetate and aq. HCl (1M) were added, the layers were separated, and the organic portion was washed with brine, dried (MgSO4), and concentrated. The resulting viscous liquid yielded a white solid (11.4 g, 90%) upon treatment with cold diethyl ether/petroleum ether (4:1), mp 190-192° C.; 1HNMR (DMSO-d6) δ 10.7 (s, 1H), 8.9 (s, 1H), 4.1 (s, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 2.9 (m, 1H), 2.5 (m, 1H), 1.4, (s, 3H), 1.1 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2OCC(=O)O)CC1
Yield: 101 %

Procedure:
4-(2-Ethoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (21.4 g, 56.5 mmol) was set stirring in MeOH (150 mL). A solution of NaOH (4.5 g, 112.5 mmol) in water (150 mL) was added. After 3 h the mixture was acidified to pH 4 with 6 N HCl. MeOH was removed under reduced pressure and the aqueous layer extracted with EtOAc (2×150 mL). The organics were combined, dried (MgSO4) and evaporated to give 20 g (100%) of a brown solid. MS (electrospray): exact mass calculated for C18H26N2O5, 350.18. m/z found, 351.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]([CH:10]1[O:12][CH2:11]1)Cl.[OH-].[Na+]>O>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[CH2:8][CH:10]([OH:12])[CH2:11][N:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCN(CC=C)CC(O)CN(CC=C)CC=C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
17.4 g (173.8 mmol) of diallylamine (from Aldrich) and 10.0 g of deionized water are stirred in a round-bottomed flask at 55° C. while 8.08 g (86.48 mmol) epichlorohydrin is added from an addition funnel. After 30 minutes the addition is complete. Then sodium hydroxide (10.0 g, 125 mmol, 50%) is added to the reaction mixture and it is stirred for an additional 3.5 hours, after which time the alkylation is complete as determined gas chromatography. The temperature is then cooled to 25° C. and the pH is made alkaline with caustic. The product is extracted from the reaction mixture with ether (three times, 25 ml). On removal of the ether a clear yellow liquid is obtained with a purity of 98.6% (GC and NMR).