Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=CC=2)=[CH:4][C:3]=1OC1C=CC(S(O)(=O)=O)=C(N)C=1.N1C(Cl)=NC(Cl)=NC=1Cl.[Cl-].[Na+]>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Oc2cc(Sc3ccc(S(=O)(=O)O)cc3)c3c(c2N)C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-(3'-amino-4'-sulfophenoxy)-4-(4'-sulfophenylthio)anthraquinone (6 parts) and cyanuric chloride (1.8 parts) were subjected to condensation reaction in an aqueous medium in a conventional manner, followed by condensation reaction with 1-aminobenzene-3-β-sulfatoethylsulfone (2.8 parts) at 20° to 40° C. under weak acid conditions. Thereafter, salting out of the reaction mixture with sodium chloride gave an anthraquinone compound of the following formula (free acid form). ##STR27##
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:39][C:40]2[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)=[C:11]([C:13]2[N:18]=[C:17]([N:19]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:16]=[C:15]([CH3:38])[N:14]=2)[CH:12]=1)(=O)=O.[OH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)CC)C.CO>ClCCl.O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:17]2[N:16]=[C:15]([CH3:38])[N:14]=[C:13]([C:11]3[CH:12]=[C:7]([CH2:6][N:52]4[CH2:53][CH2:54][CH:49]([OH:48])[CH2:50][CH2:51]4)[CH:8]=[N:9][C:10]=3[NH:39][C:40]3[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[N:18]=2)=[CH:22][CH:23]=1
Reactant: OC1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(COS(C)(=O)=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCC(O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A suspension of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl methanesulfonate (0.510 g, 0.775 mmol), 4-hydroxypiperidine (0.254 g, 2.51 mmol) and triethylamine (0.491 mL, 3.53 mmol) in dichloromethane (25 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 5% to 20% 2 M NH3.MeOH in CH2Cl2 to give 1-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperidin-4-ol (0.385 g, 0.581 mmol, 74.9% yield). m/z (ESI, +ve ion) 663.3 (M+H)+.
Reaction SMILES: [C:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@:12]4([CH3:21])[C:17](=[CH:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH2:16][C@@H:15]([OH:20])[CH2:14][CH2:13]4)#[CH:2].[Al].C1(=O)CCCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@:12]4([CH3:21])[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)#[CH:2]
Reactant: C#C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: [Al]
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C#C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reaction time: 1 h

Procedure:
A solution of 900 mg of the crude 13-ethinyl-10-methyl-gon-5-ene-3β,17β-diol, obtained according to Example 2E, and 540 mg of aluminium isopropylate in 135 ml of toluene and 5.4 ml of cyclohexanone is boiled under reflux, under a water separator, for 60 minutes. After cooling, the reaction mixture is diluted with ethyl acetate, washed with potassium sodium tartrate solution, water and saturated sodium chloride solution, dried and evaporated. The oily residue is chromatographed on 80 g of silica gel. Using a mixture of hexane/ethyl acetate (3:1), 13-ethinyl-10-methyl-gon-4-ene-3,17-dione is eluted, melting point 148°-150° C; [α]D25 = +63°, after which 13-ethinyl-17β-hydroxy-10-methyl-gon-4-en-3-one, melting point 147°-149° C, [α]D25 =+154°, is obtained by elution with a mixture of the same solvents in a ratio of 2:1.
Reaction SMILES: [N:1]([CH2:10][C:11]([O-:13])=[O:12])([CH2:6][C:7]([O-:9])=[O:8])[CH2:2][C:3]([O-:5])=[O:4].[Na+:14].[Na+].[Na+].S(=O)(=O)(O)O>>[N:1]([CH2:2][C:3]([O-:5])=[O:4])([CH2:6][C:7]([O-:9])=[O:8])[CH2:10][C:11]([OH:13])=[O:12].[Na+:14].[Na+:14]
Reactant: O=C([O-])CN(CC(=O)[O-])CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C([O-])CN(CC(=O)[O-])CC(=O)O

Procedure:
The process of claim 1 wherein the NTA powder is trisodiumnitrilotriacetate powder and the total amount of sulfuric acid added is sufficient to provide disodiumnitrilotriacetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:34][C:35]1[C:44]2[C:39](=[CH:40][C:41](O)=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[C:35]([NH2:34])=[N:36][CH:37]=[CH:38]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1nccc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3c(N)nccc3c2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.2 %

Procedure:
To a solution of (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (209 mg, 1.04 mmol), triphenylphosphine (327 mg, 1.249 mmol), 1-amino-isoquinolin-6-ol (200 mg, 1.249 mmol) in THF (4 ml) and DMF (394 μL) at 0° C., under argon, was added dropwise diethylazodicarboxylate (197 mL) over 5 min. The mixture was then warmed to ambient temperature and stirred for 48 h. Water was then added and the mixture basified with dilute NaOH. The mixture was extracted with ethyl acetate (X3), dried (sodium sulphate) filtered and evaporated under reduced pressure to give a residue. Flash chromatography of the residue on silica (eluent: 2-10% methanol in dichloromethane with 1% aqueous ammonia) gave (S) 3-(1-amino-isoquinolin-6-yloxy)piperidin-1--carboxylic acid tert-butyl ester (72 mg), El-MS: m/z=344.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].O.O.[NH2:12][NH2:13]>O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[N:12][NH2:13])[CH3:2])[CH:5]=1
Reactant: NN
Reactant: CC(=O)c1cccnc1
Solvent: O
Product: CC(=NN)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To 3-acetylpyridine (6.1 g, 52 mmol) in industrial methylated spirits (50 ml) was added dropwise hydrazine hydrate monohydrate (3.11 ml, 0.1 mol). The reaction mixture was refluxed for 4 h, before cooling to room temperature and stirring for 16 h. Water (25 ml) was added and the volatile organics were removed in vacuo. The predominantly aqueous residual liquor was extracted with ethyl acetate, and the combined organic extracts were dried (Na2SO4) and concentrated to give a yellow oil (5.4 g, 80%) which was taken forward without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C@@H:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:9]2[O:8][N:7]=1)=O)C.[BH4-].[Na+].O>C(O)C>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]2[C@H:10]([C:6]([CH2:4][OH:3])=[N:7][O:8]2)[CH2:11]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C1=NO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(CO)[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To ester 6 (1.50 g; 5.29 mmol) in ethanol (50 mL) at 0° C., was added sodium borohydride (1.57 g; 41.5 mmol) in several portions. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 3 hours. The reaction mixture was carefully added to water (150 mL) and extracted with methylene chloride (3×100 mL). The combined organic layers were washed with several portions of water, brine, dried (MgSO4), filtered and evaporated to yield alcohol 7 as a white solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH3:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:23][CH2:24][C:25]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH3:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CCl)cc2)C1
Reaction time: 3 h

Procedure:
Triethylamine (2.03 g) was added to a solution of (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine (3.15 g) in dichloromethane (120 ml), and then chloroacetyl chloride (2.26 g) was added dropwise. After 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 281.79 (C14H20CIN3O); MS (ESI): 282 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:46])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41])[CH2:36][CH2:35]4)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:43]([S:40]([N:37]1[CH2:38][CH2:39][N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:10]4[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=4[O:14][C:15]([F:17])([F:18])[F:16])=[CH:20][CH:21]=3)=[O:46])=[CH:28][CH:29]=2)[CH2:35][CH2:36]1)(=[O:41])=[O:42])[CH2:44][CH3:45]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)OC(C)(C)C)ccc4OC(F)(F)F)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(N)ccc4OC(F)(F)F)cc3)cc2)CC1
Yield: 95.6 %

Procedure:
(4′-{4-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]-phenylcarbamoyl}-6-trifluoromethoxy-biphenyl-3-yl)-carbamic acid tert-butyl ester (459 mg) in DCM (4 ml) and Trifluoroacetic Acid (4 ml) was stirred for 2 hrs. The mixture was evaporated and the residue partitioned between EtOAc and saturated potassium carbonate. The dried extracts were then evaporated giving the title compound as a tan foam (374 mg).
Reaction SMILES: [CH:1](=[N:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.CCOCC>[CH2:1]([NH:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCOC1CCCCO1)N=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(CO)(CCOC1CCCCO1)NCc1ccccc1
Yield: 92.1 %

Procedure:
A solution of ethyl 2-benzylideneamino-2-methyl-4-((tetrahydro-2Hpyran-2-yl)oxy)butyrate (10C, 100.0 g, 0.3 mol) in THF (100 mL) was added slowly to a suspension of lithium aluminum hydride (Alfa, 22.77 g, 0.6 mol) rapidly stirred in dry THF (1L) at such a rate to maintain a gentle reflux. After the addition was complete the mixture was refluxed for 4 h. The reaction mixture was cooled and treated successively with H2O (23 mL), 15N NaOH (23 mL) and H2O (45 mL). The solid was removed by filtration and washed with THF (200 mL). The organic layers were combined and concentrated by rotary evaporation to give 2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (81.1 g, 92.0%) as a thick oil which was used without further purification.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[CH:29]1[C:34](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:33][CH:32]=[C:31]([OH:40])[CH:30]=1>C(O)(C)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:37]([O-:39])(=[O:38])/[CH:36]=[CH:35]/[C:34]1[CH:33]=[CH:32][C:31]([OH:40])=[CH:30][CH:29]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Product: O=C([O-])/C=C/c1ccc(O)cc1

Procedure:
Sitagliptin free base (0.25 gms) and coumaric acid (0.10 gms) were dissolved in Isopropanol (4 ml) at 60° C. to 65° C. and the resultant solution left for slow solvent evaporation at room temperature for 48 hours. Precipitated solids were filtered and dried at 50° C. to 55° C. for 4 hours to obtain the title compound. Yield: 0.14 gms.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13]S(C)(=O)=O)[CH2:9]1)=O)(C)(C)C.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25](O)=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O.CO.C(O)(=O)C>[NH:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[C:19]([NH2:18])=[N:20][CH:21]=[CH:22]3)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: Nc1nccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1nccc2cc(O[C@H]3CCNC3)ccc12
Reaction time: 1 h

Procedure:
A solution of (R)-3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (2.95 g) in N, N-dimethylformamide (2 ml) was added dropwise to a stirred solution of 1-amino-6-hydroxyisoquinoline (1.2 g, 7.4 mmol) and K2CO3 (1.02 g, 7.4 mmol) in N, N-dimethylformamide (10 ml) at 100° C. The mixture was stirred for 1 h then cooled and water added. The mixture was acidified with glacial acetic acid then diluted with methanol. The mixture was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford crude (S)-6-(pyrrolidin-3-yloxy)isoquinolin-1-ylamine, which was purified by flash chromatography on silica (eluent: 10% methanol in DCM with 1% ammonium hydroxide), El-MS: m/z=230.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([OH:13])[C:10]2[C:5](=[C:6]([C:14]([OH:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.[CH3:26]COCC>CO>[F:24][C:2]([F:1])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[C:6]([C:14]([O:16][CH3:26])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOCC
Reactant: O=C(O)c1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Yield: 51 %

Procedure:
2-(2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamido)-3-carbamoylbenzoic acid (28.5 g, 81 mmol) in MeOH (1000 mL) was treated with 2M HCl/ether (4 mL) and then heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (17.5 g, 62%). Separately, 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-hydroxyquinazoline-8-carboxylic acid (10.5 g, 31 mmol) in MeOH (200 mL) was treated with 2M HCl/ether (1 mL) and was heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (5.5 g, 51%). The filtrates from the two procedures above were concentrated at 65° C. and allowed to cool. The solid was collected by filtration to afford additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (3 g). Purification of the filtrate by silica gel chromatography eluting with EtOAc/hexanes afforded additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (4 g). The isolated solids were combined to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate as a solid (30 g). LC-MS (ESI) m/z 350 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](Cl)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][NH:35][C:36](=[O:38])[CH3:37].O1CCCC1>O>[C:36]([N:35]([CH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=1)[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=1)(=[O:38])[CH3:37]
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1OCCCCCCC
Reactant: CC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1OCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 5.0 g of product from Example 111, 0.683 g of washed 50% sodium hydride, 2.14 g of product from Example 12 and 100 ml of dry tetrahydrofuran. The reaction is stirred at room temperature for 1 hour, heated at reflux temperature for 18 hours and cooled to room temperature. The mixture is poured into water, extracted with chloroform and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 15-30% ethyl acetate/hexane) to give 2.93 g of the desired product.
Reaction SMILES: [C:1]1([PH:7](=[S:14])[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.[CH2:15]([N:17]([CH2:22][CH3:23])[C:18](=[O:21])[CH2:19]Cl)[CH3:16].[OH-].[K+].O>C(Cl)Cl>[CH2:15]([N:17]([CH2:22][CH3:23])[C:18]([CH2:19][P:7](=[S:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:21])[CH3:16]
Reactant: CCN(CC)C(=O)CCl
Reactant: S=[PH](c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)CP(=S)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A stirred mixture of diphenylphosphine sulfide (4.365 g, 0.02 mol) and N,N-diethylchloroacetamide (4.189 g, 0.028 mol) in methylene chloride (80 ml) was cooled to 8–10° C. in an ice-water bath. Small pieces of solid potassium hydroxide (3.927 g, 0.07 mol) were added while stirring under nitrogen atmosphere. After 30 minutes, water (25 ml) was added and the organic layer was separated, washed with more water (25 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure using a rotary evaporator and the oily residue was crystallized from ethyl acetate-hexane mixture to give 3.5 g (53%) of large cubes. mp: 108–110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[N:3]=1.F[C:14]1[C:19]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:27]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:20]([C:19]3[C:14]([NH:12][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)=[N:15][CH:16]=[CH:17][CH:18]=3)[N:21]=2)=[CH:43][CH:42]=1
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc4nc(C)ccc4c3)n2)cc1
Yield: 49.1 %

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 2-methylquinolin-6-amine (Acros Organics) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine. Purification using an ISCO Combiflash Companion (12 g column, 20-60% EtOAc in hexanes over 30 min, product eluted with 35-45% EtOAc) gave the title compound as a yellow amorphous solid (49.1%). 1H NMR (400 MHz, d6-DMSO) δ 12.19 (s, 1H); 8.84 (dd, J=7.8, 2.0 Hz, 1H); 8.45 (dd, J=4.7, 2.0 Hz, 1H); 8.39 (d, J=2.2 Hz, 1H); 8.08 (d, J=8.2 Hz, 1H); 7.78-7.83 (m, 1H); 7.71-7.77 (m, 1H); 7.34 (d, J=8.4 Hz, 1H); 7.26 (dd, J=8.6, 6.3 Hz, 4H); 6.98 (dd, J=7.8, 4.7 Hz, 1H); 6.90 (t, J=8.3 Hz, 4H); 4.84 (d, J=17.6 Hz, 4H); 3.72 (d, J=14.5 Hz, 6H); 2.62 (d, J=2.0 Hz, 6H). m/z (ESI, +ve ion) 584.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]([C:15](=[O:26])[NH:16][CH2:17][CH2:18][CH:19](OCC)[O:20]CC)[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]([C:15](=[O:26])[NH:16][CH2:17][CH2:18][CH:19]=[O:20])[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Yield: 96.6 %

Procedure:
By using an analogous procedure to that described for Reference Example 14, [(1S,2S)-1-(3,3-diethoxy-propylcarbamoyl)-2-hydroxy-propyl]-carbamic acid benzyl ester (2 g, 5.24 mmol, obtained from Reference Example 17) in tetrahydrofuran (10 ml) was reacted with 0.5 N hydrochloric acid (10 ml) for 30 minutes at room temperature, to provide [(1S,2S)-2-hydroxy-1-(3-oxo-propylcarbamoyl)-propyl]-carbamic acid benzyl ester (1.56 g, 97%) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5].C=O.N1CCC[CH2:15]1.C(O)(=O)CC>C(O)(C)C>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11])[C:3](=[CH2:15])[CH:4]=[O:5]
Reactant: C1CCNC1
Reactant: CC(C)=CCC[C@H](C)CC=O
Agent: C=O
Solvent: CCC(=O)O
Solvent: CC(C)O
Product: C=C(C=O)[C@@H](C)CCC=C(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (S)-3,7-dimethyloct-6-enal (3.0 g, 19.45 mmol) in isopropyl alcohol (20 mL) at room temperature. was added 37% aqueous formaldehyde (14.46 mL, 194.5 mmol), pyrrolidine (1.61 mL, 19.45 mmol) and propionic acid (1.45 mL, 19.45 mmol). The mixture was warmed to 45° C. and stirred for 2 hours. The reaction was then cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with dichloromethane and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:petroleum ether/ethyl acetate=160:1->110:1) to afford the title compound as a colorless oil (3.2 g, Yield: 98%). Rf=0.7 (10:1) petroleum ether/:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 6.22 (s, 1H), 5.98 (s, 1H), 5.09-5.05 (m, 1H), 2.73-2.67 (m, 1H), 1.94-1.90 (m, 2H), 1.67 (s, 3H), 1.57 (s, 3H), 1.54-1.48 (m, 1H), 1.42-1.37 (m, 1H), 1.06 (d, J=6.8 Hz, 3H) ppm.