Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([N:11]=[C:12]=[O:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH:17][CH2:18][CH:19]=[O:20])[C:15]#[CH:16]>C1C=CC=CC=1>[CH2:14]([N:17]([CH2:18][CH:19]=[O:20])[C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1)=[O:13])[C:15]#[CH:16]
Reactant: C#CCNCC=O
Reactant: O=C=Nc1nc2cccc(Br)c2s1
Solvent: c1ccccc1
Product: C#CCN(CC=O)C(=O)Nc1nc2cccc(Br)c2s1
Reaction time: 1 h

Procedure:
7-Bromobenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-propargylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(7-bromobenzothiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[C:16]([NH-:18])#[N:17]>C(O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[NH2:17][C:16]([NH2:4])=[NH:18]
Reactant: N#C[NH-]
Agent: Cc1ccc([N+](=O)[O-])cc1N
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)N

Procedure:
Referencing scheme 1 below, the synthesis begins with treatment of 2-methyl-5-nitroaniline (1) with 65% nitric acid in ethanol followed by the addition of cyanoamide to give the corresponding 2-methyl-5-nitroaniline-guanidine nitrate (2). Once completed, 3-acetylpyridine (3) is first reacted with phenyl chloroformate at nitrogen position and then regioselectively alkylated using Grignard reagents and catalytic amounts of copper (I) iodide to obtain intermediate dihydropyridine. The dihydropyridine was further deprotected to obtain 3-acetyl-4-methyl-pyridine(4) (Tanis et al., 1996). Product (4) was treated with methyl dimethoxyforamide to give 3-dimethylamino-1-(3-(4-methyl-pyridyl)-2-propene-1-one (5). Nitrate salt (2) is treated with (5) and sodium hydroxide in refluxing isopropanol to give N-(2-Methyl-5-nitrophenyl)-4-(3-(4-methyl-pyridyl))-2-pyrimidine-amine (6) which is subsequently hydrogenated with 10% palladium on carbon to give N-(2-Methyl-5-aminophenyl)-4-(3-4-methyl-pyridyl)-2-pyrimidine-amine (7). The first WBZ1 synthesis consists of the reaction of α-chloro-p-toluylic acid (8) with 4-methyl-piperazine in ethanol followed by treatment with concentrated HCl to give the corresponding dihydrochloride 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (9) which is subsequently treated with thionyl chloride to give the corresponding acid chloride dihydrochloride (10). Subsequent condensation with N-(2-Methyl-5-aminophenyl)-4-(3-(4-methyl)-pyridyl)-2-pyrimidine-amine (7) in pyridine affords the Gleevec analog WBZ1 (PCT publication WO2004108699).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[CH3:27])=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:21]1[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[O:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:28])[NH2:5])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 110 %

Procedure:
1,1-dimethylethyl[(1R)-2-({6-[(2,5-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 35, 60 mg) was dissolved in 4 mL of dry dichloromethane. To this solution, at 0° C., were added dropwise 40 equivalents of TFA (0.480 mL). The reaction was stirred for 3 hours 30 at 0° C. The reaction mixture was evaporated and then purified by SCX on a 5 g cartridge. 3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with CV of methanolic ammonia (1N). Evaporation of the volatiles, afforded the title compound (49 mg)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1.FC(F)(F)S(O[CH2:32][CH:33]([CH3:35])[CH3:34])(=O)=O>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)COS(=O)(=O)C(F)(F)F
Product: CC(C)CC(C(=O)OC(C)(C)C)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
416 mg (1.00 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 0.95 ml (0.95 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 326 mg (1.58 mmol, 2.0 eq.) of isobutyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 139 mg (purity 85%, 34% of theory)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]([O:21]CC)=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:24]>>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]([NH2:24])=[O:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: CCOC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: NC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 130 °C
Yield: 34 %

Procedure:
A mixture of ethyl 4,5-diphenyl-2-oxazoleacetate (10.24 g, 33 mmol) and ammonia (35 mL) was heated in a bomb at about 130° C. for about 24 hours. After evaporation of the NH3, the residue was chromatographed on a column of silica gel using EtOAc/hexanes (4:1) as eluent to give the title compound (3.21 g, 34%), mp 129°-133° C. IR (KBr) 3340, 3200, 1665 cm-1 ; 1H NMR (CDCl3) δ3.83 (2H, s, CH2CONH2), 7.27 to 7.40 (6H, m, aromatic H), 6.50 to 6.68 (4H, m, aromatic H); MS m/z 279 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([F:23])[C:18]=1[CH2:24][OH:25])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].Cl[O-].[Na+]>C(Cl)Cl>[F:23][C:19]1[C:18]2[C:24](=[O:25])[NH:1][C@@H:2]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])[C:11]3[O:15][N:14]=[C:13]([CH3:16])[C:12]=3[C:17]=2[CH:22]=[CH:21][N:20]=1
Reactant: Cc1noc([C@@H](N)CC(=O)OC(C)(C)C)c1-c1ccnc(F)c1CO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1noc2c1-c1ccnc(F)c1C(=O)N[C@H]2CC(=O)OC(C)(C)C
Yield: 22.8 %

Procedure:
To a solution of (3S)-tert-butyl 3-amino-3-(4-(2-fluoro-3-(hydroxymethyl)pyridin-4-yl)-3-methylisoxazol-5-yl)propanoate (200 mg, 0.569 mmol) and TEMPO (4.45 mg, 0.028 mmol) in CH2Cl2 (5 mL) at 0° C. was sequentially added potassium bromide (33.9 mg, 0.285 mmol) and an aqueous solution of sodium hypochlorite (˜0.35M buffered to pH ˜8.6 with sodium bicarbonate) (4.879 mL, 1.708 mmol). The reaction was vigorously stirred (to produce an emulsion) at 0° C. for 45 min before diluting with CH2Cl2. The product was extracted with CH2Cl2 (repeated once), with CH2Cl2/MeOH (95:5) (repeated once) and CH2Cl2/TFE (95:5) (repeated once). The organic layers were combined, dried over a cotton plug and concentrated to dryness under vacuum. The residue was purified by flash chromatography (Hexane/EtOAc 8:2 to 5:5) to give tert-butyl 2-((4S)-7-fluoro-1-methyl-6-oxo-5,6-dihydro-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-4-yl)acetate as a solid (45 mg). LC/MS m/z 348 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]2[NH:10][N:11]=[CH:12][C:4]=12.C([O-])(=O)C.[Na+].[I:18]Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O>[I:18][C:12]1[C:4]2[C:5](=[N:6][C:7]([NH2:9])=[N:8][C:3]=2[O:2][CH3:1])[NH:10][N:11]=1
Reactant: COc1nc(N)nc2[nH]ncc12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(N)nc2[nH]nc(I)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
A mixture of compound 4 (105 g, 0.636 mol), sodium acetate (263 g) and iodine monochloride (140 g) was mechanically stirred in 1.3 L of water at a temperature between 92-98° C. for 5 h. The mixture was cooled to room temperature and a solution of sodium metabisulfite (139 g in 500 ml of water) was added. The mixture was stirred for 10 minutes and then filtered. The solid was rinsed with water and dried. The resulting dried solid was dissolved in 840 ml of hot DMF and precipitate by addition of 800 ml of water. The mixture was cooled in an ice-bath and the solid was filtered and dried to provide 144 g (78% yield) of 3-iodo-4-methoxy-6-aminopyrazolo[3,4-d]pyrimidine (5).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([N:7]1[CH2:12][C:11](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2=[N:20][N:21]([CH3:29])[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:9]2[CH2:8]1)=[O:6])[CH3:3].[OH:30]O>C(O)(=O)C>[CH3:3][N:2]([CH2:4][C:5]([N:7]1[CH2:12][C:11](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2=[N+:20]([O-:30])[N:21]([CH3:29])[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:9]2[CH2:8]1)=[O:6])[CH3:1]
Reactant: CN(C)CC(=O)N1CC(=Cc2ccccc2)C2=NN(C)C(c3ccccc3)C2C1
Reactant: OO
Solvent: CC(=O)O
Product: CN(C)CC(=O)N1CC(=Cc2ccccc2)C2=[N+]([O-])N(C)C(c3ccccc3)C2C1

Procedure:
A solution of the free base of the product of Example 3 in acetic acid is treated with an equivalent quantity of 30% hydrogen peroxide and the solution then heated at 80°-90° for 1 hour and cooled. The solvent is then removed on a rotary evaporator at reduced pressure to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7]2.[H-].[Na+].Br[CH2:31][C:32]#[N:33].Cl>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]3[O:14][C:15]4[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=4[C:17]=3[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:31][C:32]#[N:33]
Reactant: N#CCBr
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
To an ice-cooled solution of 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.2 g, 2.8 mmol) in dry DMF (12 mL) was added sodium hydride (0.315 g, 7.88 mmol of a 60% dispersion on mineral oil) in three portions. Bromoacetonitrile (0.49 mL, 7.0 mmol) was added and the mixture was stirred at room temperature for 1.5 hours, then poured into excess water and acidified with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage apparatus) using 15% tert-butyl methyl ether in hexane as an eluant to afford 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile as a yellow solid (0.776 g, 60%), mp 98-100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[F:8][C:5]1[CH:6]=[CH:7][C:2](=[NH:1])[N:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1cc(F)ccc1=N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-amino-5-fluoro pyridine (2.0 g, 17.84 mmol) was added ethyl bromoacetate (6.92 mL, 62.4 mmol). The resulting mixture was stirred at room temperature for 18 hours, then filtered. The solids were collected, washed with dichloromethane, and dried under reduced pressure to afford the title compound: LCMS m/z 199.00 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.05 (s, 1H), 7.93-7.90 (m, 1H), 7.14-7.12 (m, 1H), 5.02 (s, 2H), 4.25 (t, J=7.1 Hz, 2H), 1.27 (q, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][N:4]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][O:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccnc(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccnc(COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
The 2-hydroxymethyl-4-methoxypyridine, (3.48 g, 0.024 mol) was dissolved in 50 ml CH2Cl2 and cooled to 0° C. The p-toluenesulfonyl chloride (5.7 g, 0.03 mol) was added followed by triethylamine (5 g), in 10 ml of CH2Cl2. After 15 minutes, the reaction was stirred at room temperature for one hour. The reaction was diluted with CH2Cl2 (200 ml) and washed with water. The organic layer was separated and dried with MgSO4, filtered and concentrated to afford 7.3 g of crude subtitle compound suitable for further use.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])[NH2:32]>>[CH3:37][O:36][CH2:35][CH2:34][O:33][C:31]1[N:32]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COCCOC(N)=NO
Product: COCCOc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 1, 300 mg (0.717 mmol) of the compound from Example 9A and 480 mg (2.15 mmol, purity 60%) of 2-methoxyethyl N′-hydroxyimidocarbamate from Example 44A were reacted. Yield: 65 mg (17% of theory).
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH2:22][N:21]([CH3:23])[CH2:20][CH2:19][CH:18]=4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28]>C(O)C>[CH2:27]([O:29][N:30]=[C:1]([C:4]1[CH:25]=[CH:24][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH2:22][N:21]([CH3:23])[CH2:20][CH2:19][CH:18]=4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)[CH3:2])[CH3:28]
Reactant: CCON
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(C2=CCCN(C)C2)c1
Agent: Cl
Solvent: CCO
Product: CCON=C(C)c1ccc2c(c1)ncn2-c1cccc(C2=CCCN(C)C2)c1

Procedure:
To a solution of 5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]-benzimidazole (7) (free base from above) in ethanol was added O-ethyl hydroxylamine hydrochloride. The mixture was heated to reflux for 1.5 hours whereafter the solvent was removed under reduced pressure. The residue was triturated with a mixture of diethyl ether and ethanol leaving 5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazole O-ethyl oxime (3f8) as hygroscopic crystals. Mp 138-143° C., m/e 374.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[C:39]3[C:34](=[C:35]([Cl:44])[CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=3)[NH:33][N:32]=2)[CH:9]([C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:45]([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.[Na+].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[N:32]([CH3:45])[N:33]=[C:34]3[C:39]=2[CH:38]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:36]=[C:35]3[Cl:44])[CH:9]([C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1n[nH]c2c(Cl)cc(C(F)(F)F)cc12
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1c2cc(C(F)(F)F)cc(Cl)c2nn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step A (59 mg, 0.091 mmol) in NMP (3 mL) was added Cs2CO3 (38.5 mg, 0.118 mmol) then Mel (0.007 mL, 0.1 mmol). After being stirred at RT for one hour, the mixture was diluted with saturated NaCl (act) then extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-20% MeOH/DCM, then further purified by PTLC eluting with 50% EtOAc/hexanes to afford the 1-methyl regioisomer (EXAMPLE 2, Step B) as well as the title compound. The title compound was resolved to provide enantiopure material by HPLC on a ChiralPak IA (2 cm×25 cm) column eluting with 9 mL/min of 3% EtOH/n-heptane. LC1 2.83 min. (M-tBu+H)+ 606.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=O)[CH2:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([C:43]2[NH:47][C:46]3[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=3[N:44]=2)[O:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[CH:29]=1.C(O)(=O)C(O)=O>C(Cl)Cl>[NH:24]1[CH2:23][CH2:22][N:21]=[C:25]1[CH2:26][S:27][C:28]1[CH:29]=[C:30]([CH:34]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:43]2[NH:47][C:46]3[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=3[N:44]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: CN1CCC(OC(c2cccc(SCC(=O)NCCN)c2)c2nc3ccccc3[nH]2)CC1
Agent: O=C(O)C(=O)O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(OC(c2cccc(SCC3=NCCN3)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine oxide (2.2 mmoles) in 4 mL CH2Cl2 cooled at 0° C. is added dropwise trifluoromethanesulfonyl anhydride (310 mg, 1.1 mmoles). The reaction mixture is stirred at 0° C. for 30 minutes, then a solution of N-(2-aminoethyl)-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide (Example 436) (250 mg, 0.55 mmole) in 2 mL CH2Cl2 is added dropwise. The reaction mixture is allowed to reach room temperature and stirred for 1.5 h. The organic phase is washed with 1N sodium hydroxide solution, then dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0 to 80/20/2). The residue is then dissolved in acetone and one equivalent of oxalic acid is added. Acetone is removed under reduced pressure to afford 2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole melting at 62° C. (déc.); MS, [M+H]+=436.1.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][N:21]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CN(C)C(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CCNC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CCN(C(=O)N(C)C)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 163) (99 mg, 0.23 mmol) and NEt3 (35 μL, 0.25 mmol) in DMF (2 ml) was added dimethylcarbamoyl chloride (29 μL, 0.25 mmol). Reaction mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (42 mg, 37%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].CC(C[AlH]CC(C)C)C>ClCCl>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a suspension of N-{3-[5-(2-cyano-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (2.12 g, 3.80 mmol) in dichloromethane (DCM) (38.0 ml) at −78° C. was added DIBAL-H (18.98 ml, 18.98 mmol). The yellow suspension was slowly warmed to RT and stirred 1 hr. The reaction was quenched with Rochelle's salts and stirred about 1 hr. 4N HCl was added to clear the emulsion. The HCl solution was extracted with DCM (3×). The aqueous was passed through celite and neutralize with 6N NaOH. Solid formed during neutralizing and was filtered to obtain N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (1.57 g, 73%). MS (ESI): 563 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][C@H:12]([OH:16])[C@H:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br.C([O-])(O)=O.[Na+]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][C@H:12]([O:16][CH2:28][C:27]2[CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=[C:25]([C:24]([F:23])([F:37])[F:38])[CH:26]=2)[C@H:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O[C@H]1OCCN(Cc2ccccc2)[C@@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(CO[C@H]2OCCN(Cc3ccccc3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a suspension of 0.592 g (14.8 mmol) of NaH in 30 mL of dry THF at 0° C. was added 3.32 g (12.3 mmol) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenyl-morpholine prepared in step A. After 15 min 0.915 g of tetrabutylammonium iodide (2.47 mmol) and 2.4 mL (13 mmol) of 3,5-bis(trifluoromethyl)benzyl bromide were added. The resulting mixture was stirred at ice-bath temperature for 1 h, then poured into saturated NaHCO3 solution and extracted with ethyl acetate (EtOAc). The organic layers were combined, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the resiue was chromatographed on a Waters Prep500 HPLC system using 50% EtOAc/Hexane to isolate 3.6 g (59%) of 4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.