Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([OH:28])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:28][CH:25]([C:5]1[C:6]2[N:7]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:26][CH3:27])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)cc1Cl
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)cc1Cl
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a stirred solution of 1-[10-chloro-1-(2-chloro-4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-yl]propan-1-ol (136 mg, 0.325 mmol) in pyridine (1.0 mL) was added acetic anhydride (92.2 μL, 0.975 mmol) at room temperature. After 24 h, the reaction mixture was quenched with aqueous sodium hydrogen carbonate, diluted with ethyl acetate, washed with water, hydrochloric acid (1 M) and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (125 mg, 0.270 mmol, 83%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:28]2[CH:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[O:30][N:29]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)no1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)C)on4)c3)c2cc1OC
Yield: 69 %

Procedure:
The title compound was prepared using the procedure described in Example 113C with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline described in Example 115B (94 mg, 0.3 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamate described in Example 133A (110 mg, 0.45 mmol). Precipitation of the desired product detected completion of reaction. The solid was filtered off and washed with diethyl ether to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (96.26 mg, 69%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.53-7.42 (m, 2H), 7.36-7.27 (m, 3H), 6.51 (s, 1H), 3.99 (s, 6H), 3.04-3.00 (m, 1H), 1.23 (d, 6H); LC-MS (ESI) m/z 466 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.Cl.[NH2:10][OH:11].[OH-].[Na+].Cl>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:10]\[OH:11]
Reactant: NO
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C\c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a suspension of 2-pyridinecarboxaldehyde (53.6 g, 500 mmol) and hydroxylamine hydrochloride (38.2 g, 544 mmol) in ethanol (36 mL) and water (69 mL) was added ice (205 g). Then an aqueous solution of sodium hydroxide (32%, 115 mL, 1.24 mol) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 1 h stirring at room temperature the resulting mixture was then acidified with HCl (5 N). The mixture was then extracted with dichloromethane to afford the title compound (47.7 g, 78%) which was obtained as an off white solid. MS: m/e=123.3 [M+H]+.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:5]=[C:6]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=[C:7]2[N:8]=1.[CH3:15]OS(=O)(=O)OC>CO>[CH3:14][C:11]1[CH:12]=[CH:13][C:6]2[C:7](=[CH:9][CH:10]=1)[N:8]=[C:4]([S:3][CH3:15])[N:5]=2
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc2nc(S)nc-2cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2ccc(C)ccc-2n1
Temperature: 45 °C

Procedure:
38 g of potassium hydroxide was dissolved in 800 ml of methanol, and 108.5 g of 2-mercapto-6-methylcycloheptimidazole was added thereto and everything was stirred under heating at an internal temperature of about 45° C. Next, 131.2 g of dimethylsulfuric acid was dropwise added and everything was further stirred under heating at an internal temperature of about 45° C. for 1 hour. After the solvent was evaporated off to some extent under reduced pressure, 1 liter of water was added and the resulting solution was extracted with chloroform (0.5 liter×2). The chloroform layer was dried with anhydrous sodium sulfate, and then the solvent was evaporated off under reduced pressure until the chloroform solution became 200 ml. To this was added one liter of hexane, whereby crystals precipitated out. The thus formed crystals were separated by filtration and dried.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH2:6][CH:5]([S:8][C:9]2[CH:15]([CH3:16])[CH:14]3[N:11]([C:12](=[O:20])[CH:13]3[CH:17]([OH:19])[CH3:18])[C:10]=2[C:21]([OH:23])=[O:22])[CH2:4]1.[Cl:24][CH2:25][CH:26]1[C:30](=O)[O:29]C(=O)[NH:27]1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[NH2:27][CH:26]([CH2:25][Cl:24])[C:30]([NH:1][CH2:2][CH:3]1[O:7][CH2:6][CH:5]([S:8][C:9]2[CH:15]([CH3:16])[CH:14]3[N:11]([C:12](=[O:20])[CH:13]3[CH:17]([OH:19])[CH3:18])[C:10]=2[C:21]([OH:23])=[O:22])[CH2:4]1)=[O:29]
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Reactant: O=C1NC(CCl)C(=O)O1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CNC(=O)C(N)CCl)C3)C(C)C12
Yield: 38.7 %

Procedure:
The title compound is prepared by the procedure of Example 47 using 0.0685 g of product from Example 46 in 1.5 ml of sodium phosphate buffer (pH 8.5) and 0.0299 g of product from Example 53 to give 0.0347 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:13][CH3:14])=[N:10][S:11][N:12]=2)=[CH:4][CH:3]=1.[Cu](C#N)[C:16]#[N:17].CN(C)C=O.[C-]#N.[Na+]>O>[C:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:13][CH3:14])=[N:10][S:11][N:12]=2)=[CH:4][CH:3]=1)#[N:17]
Reactant: N#C[Cu]C#N
Reactant: COc1nsnc1-c1ccc(Br)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nsnc1-c1ccc(C#N)cc1
Yield: 62.1 %

Procedure:
In a manner similar to L. Friedman and H. Shechter, J. O. C., 26, 2522 (1961), incorporated herein by reference, 1.15 g (0.0043 mole) of 4-(4-bromophenyl)-3-methoxy-1,2,5-thiadiazole, 0.46 g (0.0051 mole) of copper cyanide, 15 ml of N,N-dimethylformamide, and a solution of 66.5 g of sodium cyanide in 200 ml of water were reacted to produce 0.58 g of 4-(4-cyanophenyl)-3-methoxy-1,2,5-thiadiazole, Compound 30 of Table I. Compounds 8 and 44 were also prepared by this method.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1>N1C=CC=CC=1.C1COCC1>[CH2:1]([NH:4][C:11]([C:9]1[S:10][C:6]([Cl:5])=[CH:7][CH:8]=1)=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C(Cl)c1ccc(Cl)s1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in 14.2 ml of absolute pyridine and 14.2 ml of absolute THF is admixed dropwise with 5-chloro-thiophene-2-carbonyl chloride (7.61 g, 42 mmol). Ice-cooling is removed and the mixture is stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue is admixed with water and the solid is filtered off. The crude product is purified by flash chromatography over silica gel (dichloromethane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[C:10]#[N:11]>CN(C=O)C>[F:16][C:13]1[CH:14]=[CH:15][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: N#Cc1cc(F)ccc1F
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1N1CCNCC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
A mixture of piperazine (Aldrich; 1.28 g), 2,5-difluorobenzonitrile (Lancaster; 0.422 g), and DMF (4 mL) is stirred at 80° C. for 1.5 h, after which the mixture is cooled and partitioned between dichloromethane, water, and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue is crystallized from dichloromethane/ethyl ether/hexane to give 0.282 g of 5-fluoro-2-(piperazin-1-yl)benzonitrile; mp 83-83.5° C.; 1H NMR (CDCl3) δ3.10, 7.00, 7.21, 7.27.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[OH-].[K+].[CH3:15]I.O>CC(C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CN1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 5-nitro-2,3-dihydro-1H-indole (1 g, 6.09 mmol) in acetone (12 ml) was added powdered potassium hydroxide (1.7 g, 30.45 mmol), followed by methyl iodide (1.2 g, 9.14 mmol) and stirred overnight at ambient temperature. The solvent was evaporated under vacuum to give a residue, to which water was added and the product extracted with ethyl acetate. Drying and concentration of the organic layer yielded 1-methyl-5-nitro-2,3-dihydro-1H-indole (1 g, 92%) as solid.
Reaction SMILES: BrC1C=CC(O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1(CCC(=O)C)[CH:41]=[CH:40][CH:39]=[N:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:12]=[C:11]3[C:10](=[CH:15][CH:14]=2)[N:9]=[C:8]([CH2:17][CH2:16][N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:6]=[CH:7]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)CCn1cccn1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(CCn4cccn4)ccc3c1)n2C1CCCCC1
Yield: 50 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 4-pyrazol-1-yl-butan-2-one (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in Ethanol (506 μL, 0.64 mmol) to produce the title compound (14 mg, 50% yield). MS: 466.27 (M+H+); HPLC Procedure A, retention time=8.41 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([CH3:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>O1CCOCC1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:7]2[C:3]([C:2]([F:1])([F:10])[F:11])([CH3:9])[CH2:4][CH2:5][C:6]2=[O:8])=[O:28])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1(C(F)(F)F)CCC(=O)N1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C(=O)N2C(=O)CCC2(C)C(F)(F)F)cc1

Procedure:
5.0 g (0.03 mol) of 5-(trifluoromethyl)-5-methylpyrrolidin-2-one in 10 ml of dioxane are stirred with 3.3 g of triethylamine and 6.8 g (0.04 mol) of anisoyl chloride for 16 h at 110°-120° C. The solid which precipitates is filtered off with suction and the salt is washed with a little dioxane. The dioxane solution is stirred into 50 ml of water and the organic phase is separated off with the addition of a little methylene chloride. After stripping off the solvent, the residue is a brownish solid which is recrystallized from ligroin.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[F:31][C:32]([F:51])([F:50])[CH2:33][N:34]=[C:35]([NH2:49])[NH:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[N:38]=1>C1COCC1>[F:51][C:32]([F:31])([F:50])[CH2:33][N:34]=[C:35]([NH2:49])[NH:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[N:38]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NCCCCCc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: NC(=NCC(F)(F)F)Nc1ccnc(CCCCCNC(=O)CNC(=O)OCc2ccccc2)n1
Yield: 34.2 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (0.21 g.) in freshly distilled THF (5 ml.) was added N-methylmorpholine (0.1 g.). The resulting solution was stirred with cooling in an ice-salt bath, and a solution of i-butyl chloroformate (0.136 g.) in a small volume of THF was added in one portion. A precipitate formed immediately, and the mixture was stirred for cooling for 5 minutes. A solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(5-aminopentyl)pyrimidine (0.35 g.) in THF (10 ml.) was gradually added. The mixture was stirred at room temperature for 2 hours, then evaporated in vacuo. Sodium bicarbonate solution was added to the residue and the mixture extracted with EtOAc. The extract was dried (MgSO4) and evaporated to give a pale yellow oil which was purified by medium pressure chromatography, eluting with 5% v/v MeOH in methylene chloride to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[5-(2-benzyloxycarbonylaminoacetylamino)pentyl]pyrimidine (0.17 g.) which was used without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)=[C:21]2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([O:50][CH3:51])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]4[N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[CH:19]=[CH:20][C:21]=34)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([O:50][CH3:51])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
N,N-Diisopropylethylamine (1.0 mL, 6.0 mmol) was added to a mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (0.96 g, 2.0 mmol) and methyl 5-chloropyrazine-2-carboxylate (0.34 g, 2.0 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 120° C. overnight. The mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-60%) to afford the desired product (0.13 g, 12%). LCMS (M+H)+: m/z=545.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:11][C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1.[CH3:27][NH:28][CH3:29]>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[CH2:17][O:16][C:12]1[CH:13]=[C:14]([CH3:15])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:28]([CH3:29])[CH3:27])[CH:4]=2)[C:10](=[O:26])[CH:11]=1
Reactant: CNC
Reactant: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(CCl)c1
Solvent: CO
Product: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(CN(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
1-[3-(chloromethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (from step 1 of the synthesis of EXAMPLE 293) (0.500 g, 1.330 mmol) was suspended in a stock solution of N,N-dimethylamine in methanol (2.0 mL, 2.0 M) and stirred overnight at room temperature. Reaction was concentrated and the residue partitioned between H2O (25 mL) and ethyl acetate (25 mL). The aqueous layer was further extracted with ethyl acetate (2×30 ml), and the combined organics were washed with brine (30 mL), dried over MgSO4, and concentrated to afford an off-white solid (0.508 g, 99%).
Reaction SMILES: ClC(OC(Cl)C)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][N:28](CC4C=CC=CC=4)[CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>ClCCCl>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][NH:28][CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1-Chloroethyl chloroformate (732 mg, 5.12 mmol) was added dropwise to the solution of N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (1.07 g, 2.56 mmol) and diisopropylethyl amine (660 mg, 5.12 mmol) in 1,2-dichloroethane (10 mL, anhydrous) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hr. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at room temperature overnight. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and was washed by sodium bicarbonate's aqueous solution, brine and dried over sodium sulfate. Solvent was removed in vacuo and residue was triturated by diethyl ether to yield the product as a light brown solid (303 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[S:43])[NH:24][C@H:25]([CH2:33][N:34](C)[C:35](OC(C)(C)C)=O)[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[S:43])[NH:24][C@H:25]([CH2:33][NH:34][CH3:35])[CH2:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=S)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC[C@H](CC1CCCCC1)NC(=S)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(tert-butoxycarbonyl)amino)propan-2-ylcarbamothioyl)piperidin-3-yl)methoxy)ethylcarbamate (640 mg, 0.1 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 1 h, a solution of saturated sodium bicarbonate was added dropwise to adjust the pH to 7-8. The resulting mixture was extracted with CH2Cl2 (3×15 mL), washed with brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by preparative HPLC to afford methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamothioyl)piperidin-3-yl)methoxy)ethylcarbamate (10 mg, 19%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:8]([NH2:7])[CH2:9][CH3:10])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:14]=2[CH:22]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [(S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propyl]carbamic acid tert-butyl ester (557 mg, 1.5 mmol) in DCM (8 mL) was added TFA (4 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification. Yellow oil (349 mg, 86%). LCMS (Method B): RT 1.75 min [M+H]+ 270.92.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]#[N:19])=[CH:7][C:6]=1[F:20].[CH3:26][CH:27]([NH2:30])[CH2:28][OH:29]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]([NH:30][CH:27]([CH3:26])[CH2:28][OH:29])=[NH:19])=[CH:7][C:6]=1[F:20]
Reactant: N#Cc1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Reactant: CC(N)CO
Solvent: CCO
Product: CC(CO)NC(=N)c1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 5-[4-(2,5-dichloro-phenoxy)-3-fluoro-phenylamino]-3-hydroxy-isothiazole-4-carbonitrile (0.2 g) and DL-2-amino-1-propanol (0.7 g) in 20 ml of ethanol was placed in a high-pressure reaction equipment and heated to 100° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was chromatographed by silica gel column (chloroform/methanol, 25:1) to give the desired product as a light yellow solid. MS: 470; 1H NMR (DMSO-d6, 300 MHz): δ 10.60 (brs, ½H, NH, D2O exchangeable), 9.69 (brs, ½H, NH, D2O exchangeable), 9.22 (brs, ½H, NH, D2O exchangeable), 8.55 (s, 1H, OH, D2O exchangeable), 7.91 (brs, ½H, NH, D2O exchangeable), 7.70 (brs, ½H, NH, D2O exchangeable), 7.61 (d, 1H, J=8.7 Hz, ArH), 7.22 (dd, 1H, J=2.1, 8.7 Hz, ArH), 7.16 (t, 1H, J=8.7 Hz, ArH), 6.99 (dd, 1H, J=2.1, 12.6 Hz, ArH), 6.88 (d, 1H, J=2.1 Hz, ArH), 6.83 (dd, 1H, J=2.1, 8.7 Hz, ArH), 5.09 (brs, 1H, OH), 3.80 (m, 1H, CH), 3.49 (m, 1H, CH). 3.44 (m, 1H, CH), 1.15 (d, 3H, J=6.3 Hz, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21].[C:24](Cl)(=[O:26])[CH3:25].Cl>O1CCOCC1.N1C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21])(=[O:26])[CH3:25]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1N
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 315 mg(1 mmole) of 4-(2-aminophenyl)-2,6-dimethyl-3,5-bis(methoxycarbonyl)-1,4-dihydropyridine [J. Am. Chem. Soc., 71, 4003 (1949)] in 1 ml of dioxane and 1 ml of pyridine a solution of 0.18 g of acetylchloride in 1 ml of dioxane was added drop-wise during 20 minutes in a temperature range of 0° to 10° C., then the mixture was stirred for 40 minutes at this temperature and for 3 hours at room temperature, thereafter it was poured into 10 ml of aqueous 10% hydrochloric acid. The precipitate formed was filtered, washed with water and dried. Yield 350 g (97.5%), m.p. 284° to 285° C. (ethanol).