Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[F:32][C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][C:40]([NH:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=3)=[O:41])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: O=C=Nc1cccc(F)c1
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NCCNC(=O)Nc2cccc(F)c2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 67.6 %

Procedure:
The title compound from Example 157 (42.3 mg, 0.0001 mol) was treated with 3-fluorophenylisocyanate (12 mg, 0.0001 mol) in the same manner as described in Example 158. Purification afforded 38 mg (67.6%) of the title compound as a light yellow solid (m.p. 131°-144°) LC MS (m/e)=563 (MH+). Rt=2.22 min.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:22])([CH3:23])[O:21]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])(=[O:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Reaction time: 5 h
Yield: 92.7 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-(piperidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (480 mg, 1.10 mmol) and benzaldehyde (138 mg, 131 jut, 1.30 mmol) in 1,2-dichloroethane (1 mL) was stirred for 20 minutes then treated with sodium triacetoxyborohydride (420 mg, 2.20 mmol). After 5 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), diluted with saturated aqueous sodium chloride (50 mL) and extracted with dichloromethane (3×40 mL). Organic layers were collected, dried over MgSO4, filtered and concentrated. MPLC purification (25 g column, 1-10% methanol in dichloromethane) gave 2-acetamido-2-(1-benzylpiperidin-4-yl)-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as a colorless oil (538 mg, 93%), which was used immediately in the subsequent step (approximately 10% of the product had the boronic acid deprotected).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M111) (0.25 g, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (167 mg, 85%).
Reaction SMILES: N([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[CH3:8])=O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].C(O)(=O)C>O1CCCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]([CH:7]2[CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]2)[OH:15])[CH:16]=[CH:17][CH:18]=1
Reactant: CC1(C)CCCN1N=O
Reactant: O=Cc1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)CCC(C(O)c2cccc(Cl)c2)N1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
35.4 ml (0.24 mols) of diisopropylamine are dissolved in 350 ml of tetrahydrofuran and cooled to −75° C. under nitrogen with a bath of dry ice and acetone. At this temperature, 180 ml (0.29 mols) of an approximately 1.6 molar solution of butyl lithium in hexane are added dropwise. By removing the cooling bath, the temperature is allowed to rise to −10° C. The solution of lithium-diisopropylamine thus obtained is again cooled to −78° C. This solution is mixed over the course of 20 minutes with 32 g (0.25 mols) of 1-nitroso-2,2-dimethylpyrrolidine and stirred for a further 10 minutes. Then, 35.2 g (0.25 mols) of 3-chlorobenzaldehyde are added dropwise over the course of 15 minutes, and the mixture is stirred for a further 3 hours at −75° C. To the resulting orange-coloured solution is then added dropwise, over the course of 20 minutes, a solution of 40 ml (0.7 mols) of glacial acetic acid in 80 ml of tetrahydrofuran. The reaction mixture which is now light yellow is warmed to room temperature by removing the cooling bath, and is then poured onto a mixture of 1 liter each of saturated sodium chloride solution and methyl chloride. After shaking out, the aqueous phase is separated and washed twice, each time with 200 ml of methylene chloride. The combined organic phases are washed with 200 ml of water, dried over sodium sulphate and the solvent residues are removed in a vacuum. The crystalline residue is dissolved whilst hot in a mixture of 180 ml of toluene and 270 ml of hexane. Upon cooling, the title substance is obtained in the form of white crystals having a m.p. of 143-144° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[Cl:44][C:45]1[CH:46]=[C:47]([C@H:53]([NH2:56])[CH2:54][CH3:55])[CH:48]=[N:49][C:50]=1[O:51][CH3:52].C(N(CC)CC)C>CN(C)C=O>[Cl:44][C:45]1[CH:46]=[C:47]([C@H:53]([NH:56][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:54][CH3:55])[CH:48]=[N:49][C:50]=1[O:51][CH3:52]
Reactant: CC[C@@H](N)c1cnc(OC)c(Cl)c1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1cnc(OC)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then (R)-1-(5-chloro-6-methoxy-pyridin-3-yl)-propylamine hydrochloride (70 mg, 0.3 mmol) and triethylamine (82 mg, 0.81 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 103 mg (83%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(5-chloro-6-methoxy-pyridin-3-yl)-propyl]-amide as white solid. LC/MS (method 2): Rt=1.24 min; m/z=461.12 (M+H+). 1H-NMR: δ (ppm)=8.08 (2H, m), 7.86 (1H, s), 7.19 (1H, s), 4.97 (1H, d), 4.83-4.89 (2H, m), 3.80-4.30 (8H, m), 3.68 (2H, bs), 2.03-2.10 (1H, m), 1.99-1.92 (1H, m), 1.72-1.84 (3H, m), 1.52-1.59 (1H, m), 1.18-1.19 (3H, d), 0.87 (3H, t).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:26])[N:3]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Br[C:34]1[C:35]([NH2:41])=[N:36][CH:37]=[C:38]([Br:40])[N:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[NH2:41][C:35]1[C:34]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:26])[N:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:16][CH:15]=2)=[N:39][C:38]([Br:40])=[CH:37][N:36]=1
Reactant: Cc1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ncc(Br)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(-c3nc(Br)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A suspension of the compound prepared in Example 2 (15 g), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (2.0 g), 3,5-dibromopyrazin-2-amine (9.5 g), and sodium carbonate (Na2CO3) (7.3 g) in 3:1 mixture of dioxane/water (350 mL) was degassed with a stream of nitrogen for 10 minutes. The reaction was heated at 90° C. for 5 hours, at which time LC/MS indicated the reaction was complete. The mixture was concentrated under reduced pressure, diluted with water (200 mL) and extracted with EtOAc (3×300 mL). The organic layers were combined, dried over Na2SO4, and evaporated under reduced pressure. The product was absorbed onto silica gel (40 g) and purified by flash chromatography (silica gel, 400 g) using a gradient of 1 to 3% MeOH in DCM as the eluent. After purification, 1H NMR showed that pinicol was present as an impurity. The product was suspended in 10% aqueous potassium carbonate (300 mL), stirred for 30 minutes, filtered and washed with water (3×100 mL). The resulting solid was then evaporated from absolute ethanol (6×50 mL) to give the title compound (6.6 g) having the following physical data as a yellow solid.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[CH:5]([CH3:7])[CH3:6]>CCOCC.O1CCCC1>[CH2:4]([C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH3:1])[CH:13]=[CH:14][CH:15]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: C[Mg]Br
Reactant: CC(C)Cc1cccc(C=O)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)Cc1cccc(C(C)O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesium bromide in ether (4 ml) was added to a solution of 3-isobutylbenzaldehyde (1.0 g) in tetrahydrofuran (10 ml) at 0° C. After stirred at 0° C. for 30 minutes, the mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (30 g) eluting with a mixture of ethyl acetate and hexane (1:10) to give 1-(3-isobutylphenyl)ethanol (1.12 g) as an oil.
Reaction SMILES: [Na].C[Si](C)(C)[C:4]#[C:5][CH:6]([N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[Cl-].[NH4+]>CO>[CH:14](=[N:13][CH:6]([C:5]#[CH:4])[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CCC(C#C[Si](C)(C)C)N=Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: C#CC(CCC(=O)OC)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.0764 g of sodium was dissolved in 5 ml of methanol. The solution was added at room temperature to a solution of 1.0 g of 3A in 2 ml of dry methanol. The mixture was stirred at room temperature for 4 hours, then 0.1765 g of ammonium chloride was added and the mixture was stirred for 15 minutes. Then the methanol was evaporated, the residue was triturated with ether and the solid phase was filtered off. The solvent was evaporated from the filtrate and the residue was distilled to give 4, b.p.: 170° C. (0.07 Torr).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:8].[H][H]>CO.[Pd].S([O-])([O-])(=O)=O.[Ba+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:8]
Reactant: [H][H]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CCC(=O)O)cc1

Procedure:
7.19 g. 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-cinnamic acid are hydrogenated in methanol, with the use of 1 g. palladium/barium sulphate, at ambient temperature. After taking up 1 mol hydrogen/mol of starting material, the hydrogenation is discontinued and the solution is filtered, evaporated and the residue recrystallised from isopropanol/water. There are obtained 6.14 g. (about 85% of theory) β-{4-[2-(5-chloro-2-methoxybanzamido)-ethyl]-phenyl}-propionic acid; m.p. 118°- 120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:31]5[CH:32]=[CH:33][N:34]=[C:29]([Cl:28])[N:30]=5)[CH2:24][CH2:25]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCN(c2ccnc(Cl)n2)CC1
Temperature: 110 °C

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one (40 mg, 0.094 mmole) in n-butanol (1.0 mL) is added 2,4-dichloropyrimidine (14, 0.094 mmole) and diisopropylethylamine (0.016 mL, 0.094 mmole) and this mixture is heated at 110° C. for 4 hours. The reaction is concentrated and purified by column chromatography (silica, 25% ethyl acetate/dichloromethane) to yield 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-piperazin-2-one. 1H NMR (300 MHz, CDCl3) d 8.01 (d, 1H), 7.89-7.87 (m, 3H), 7.48 (dd, 1H), 6.35 (d, 1H), 4.41-4.20 (m, 2H), 3.87 (s, 2H), 3.48 (s, 4H), 3.28 (dd, 2H), 2.05-1.95 (m, 1H), 1.67 (d, 2H), 1.31-1.20 (m, 2H); MS (Ion spray) 542 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].C(=O)([O-])[O-:22].[K+].[K+].CC(C)=O.NC(N)=O.OO>O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)O)c1
Agent: NC(N)=O
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1

Procedure:
A mixture of 3-cyano-5-[(dipropylamino)carbonyl]benzoic acid (IX/XXXII, PREPARATION 7, 0.602 g, 2.19 mmol), potassium carbonate (0.212 g, 1.53 mmol), and acetone (2.5 mL) is stirred at 20–25 degrees C. Water (2.5 mL) and urea-hydrogen peroxide adduct (0.825 g, 8.78 mmol) are added and the mixture is stirred for 15 hours at 20–25 degrees C., at which time additional urea-hydrogen peroxide adduct (0.204 g) is added; after stirring for another 3 hours, an additional 0.205 g of urea-hydrogen peroxide is added. After a total of 39 hours has elapsed, the acetone is removed under reduced pressure and the residue is acidified with hydrochloric acid (3N) to pH=2–4. The mixture is extracted with dichloromethane, the organic layer is separated and washed with hydrochloric acid (0.5 N), and the organic phase is dried with anhydrous magnesium sulfate to a solid. The solid is crystallized from dichloromethane/hexane/methanol to give the title compound, MS (ESI+) for C15H20N2O4 m/z (M+H)+=293.2.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[N:11][CH:10]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)=[N:11][CH:10]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1ccncn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccncn2)n1
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
Into 4 g of N,N-dimethylformamide were dissolved 304 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 200 mg of 4-pyrimidylmethyl alcohol, 87 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 15 minutes. After stirring for 2 hours at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 210 mg of 5-(4-pyrimidylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (39)).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.[Cl:12][CH2:13][CH2:14][CH2:15]I>>[Cl:12][CH2:13][CH2:14][CH2:15][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2]1
Reactant: O=c1[nH]nnc2ccccc12
Reactant: ClCCCI
Product: O=c1c2ccccc2nnn1CCCCl

Procedure:
3-(3-chloropropyl)-1,2,3-benzotriazin-4(3H)one was prepared according to the general procedure outlined in example 6, step 1. Starting from 1,2,3-benzotriazin-4(3H)one (2 g, 13.6 mmol) and 1-chloro-3-iodopropane (1.6 mL, 14.95 mmol), 1.57 g (52%); yellow solid; m.p. 69° C., MS: 223.9 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[NH2:14][S:11]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[C:3]([N:2]([CH3:10])[CH3:1])=[O:9])(=[O:13])=[O:12]
Reactant: CN(C)C(=O)[C@H]1CCCN1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@H]1CCCN1S(N)(=O)=O

Procedure:
To a solution of the subtitle compound of step ii) (2.20 g) in dioxane (25 ml) was added sulfamide (7.20 g) and the mixture heated at reflux for 45 h. The reaction mixture was cooled and adsorbed on to silica gel and then purified by column chromatography (5% methanol/EtOAc) to afford the subtitle compound as an oil. Yield: 1.6 g.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[H-].[Na+].[CH3:11][C:12]1[O:16][C:15]([C:17]([C:19](=[C:22](SC)[S:23][CH3:24])[C:20]#[N:21])=O)=[CH:14][CH:13]=1>CN(C=O)C>[NH2:7][C:6]1[N:8]=[C:17]([C:15]2[O:16][C:12]([CH3:11])=[CH:13][CH:14]=2)[C:19]([C:20]#[N:21])=[C:22]([S:23][CH3:24])[N:5]=1
Reactant: N=C(N)N
Reactant: CSC(SC)=C(C#N)C(=O)c1ccc(C)o1
Agent: O=C(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
2.22 g (12.3 mmol) guanidine carbonate was added portionwise to a stirred suspension of 0.41 g (10.3 mmol, 60% dispersion in mineral oil) sodium hydride in 20 ml DMF under argon at room temperature and stirring continued at 40° C. for 1 hour. A solution of 2.60 g (10.3 mmol) 2-(5-methyl-furan-2-carbonyl)-3,3-bis-methylsulfanyl-acrylonitrile in 10 ml DMF was then added dropwise and the reaction mixture heated at 100° C. for 1 hour. The reaction mixture was then poured onto 700 ml ice-water, and the precipitate collected by filtration, washed with water then hexane, and dried in vacuo to afford 2.38 g (94%) 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow solid. EI-MS m/e (%): 246 (M+, 64), 245 ([M—H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[CH2:29][CH2:30][CH2:31][OH:32])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:38][CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[CH2:29][CH2:30][CH2:31][O:32][CH2:38][CH3:39])=[CH:33][CH:34]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(CCCO)n2Cc1ccc(Cl)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCCc1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-(3-hydroxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.204 mmol) in DMF (3 mL) was added sodium hydride (24.5 mg, 0.612 mmol, 60% dispersion in mineral oil) at 0° C. The mixture was stirred at room temperature for 30 min. Iodoethane (63.6 mg, 0.408 mmol) was added to the reaction and it was stirred at room temperature for 16 h. The reaction was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (2:1 to 1:1) to give 7-(4-chlorobenzyl)-8-(3-ethoxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (96 mg, 90.6% yield) as a yellow solid. LCMS retention time 1.870 min; LCMS MH+ 519.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:23]([O:25][C:26](=[O:37])[C@@H:27](OS(C(F)(F)F)(=O)=O)[CH3:28])[CH3:24]>C1COCC1>[CH2:23]([O:25][C:26](=[O:37])[C@H:27]([N:7]1[C:6]2[CH:12]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH3:28])[CH3:24]
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)N1C(=O)COc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a mixture of 6-bromo-4H-benzo[1,4]oxazin-3-one (59 g, 259 mmol) in anhydrous THF (800 mL) was added KHMDS solution (1M in THF, 259 mL, 259 mmol) drop-wise at 0° C. and the reaction mixture was stirred for 30 min. (S)-2-trifluoromethanesulfonyloxy-propionic acid ethyl ester (Preparation #10, Step B, 117 g, 466 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched by the addition of water (1000 mL). The organic phase was separated and the aqueous solution was extracted with EtOAc (4×500 mL). The combined organic phase was washed with brine (1 L), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (82.4 g, 97%) as a brown liquid. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8.8 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.23 (q, J=6.8 Hz, 2H), 4.67-4.58 (d, J=14.8 Hz, 2H), 4.26-4.20 (m, 2H), 1.60 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H). SFC (Table 1, Method 29) Rt=4.146 min.; [α]D20=31.45 (C=0.002 g/mL in methanol).