Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[CH:21][C:20]=1[C:28](=[O:30])[CH3:29].C([O-])(O)=O.[Na+]>C(Cl)Cl.O1CCOCC1.CN(C=O)C>[C:28]([C:20]1[C:19]([NH:18][C:9]([C:6]2[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[O:8][N:7]=2)=[O:11])=[C:24]([Cl:25])[C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:30])[CH3:29]
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Reactant: CC(C)c1cc(C(=O)O)no1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(NC(=O)c2cc(C(C)C)on2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirred solution of 5-isopropylisoxazole-3-carboxylic acid (3.5 g, 22.6 mmol) in DCM (35 mL) was added anhydrous DMF (few drops) and oxalyl chloride (3.82 mL, 43.2 mmol) at 0° C. under nitrogen. At the end of the gas escape, the reaction mixture was allowed to warm up to room temperature. The mixture was stirred at room temperature for 2 hrs and was evaporated. Dioxane (70 mL) was added under nitrogen, followed by a solution of 1-(2-amino-3-chloro-4-methoxy-phenyl)-ethanone 201d (4.10 g, 20.6 mmol) in dioxane (15 mL). The reaction mixture was stirred at room temperature for 16 hrs. NaHCO3 was then added. The mixture was extracted with EtOAc. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was triturated in Et2O to yield compound 241d as a brown solid in 60% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.47 (s, 3H), 1.48 (s, 3H), 1.76 (brs, 1H), 2.57 (s, 3H), 3.34-3.40 (m, 1H), 3.98 (s, 3H), 6.86 (d, J=8.53 Hz, 1H), 7.64 (d, J=8.53 Hz, 1H), 8.07 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[S:3].OC1OC(C2[CH:19]=[C:20]([NH:24][C:25]([NH2:27])=[S:26])[CH:21]=[CH:22][CH:23]=2)=NN=1.[CH3:28][CH2:29][OH:30].CC(C)=O>>[C:29]([NH:27][C:25]1[S:26][C:21]([C:22]2[N:1]=[C:2]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[S:3][CH:23]=2)=[C:20]([CH3:19])[N:24]=1)(=[O:30])[CH3:28]
Reactant: CCO
Reactant: COC(=O)CCCNC(N)=S
Reactant: NC(=S)Nc1cccc(-c2nnc(O)o2)c1
Solvent: CC(C)=O
Product: COC(=O)CCCNc1nc(-c2sc(NC(C)=O)nc2C)cs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
According to the general procedure 1, methyl 4-[(aminocarbothioyl)amino]butanoate (prepared from methyl 3-aminobutanoate, hydrochloride salt (Fluka), following procedure D) is added to a solution of N-[5-(bromoacetyl)-4-methyl-1,3-thiazol-2-yl]acetamide, hydrobromide salt (Intermediate 1) and TEA (3 eq) in EtOH/Acetone 2:1 mixture. The mixture is stirred for 5 hours at RT. The solvents are evaporated and the desired product is suspended in water, filtrated and dried under vacuo. Methyl 4-{[2′-(acetylamino)-4′-methyl-4,5′-bi-1,3-thiazol-2-yl]amino}butanoate is isolated as a yellow solid (166.00 mg; 83.63%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8](O)=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].CS([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=O)=O.O>CN(C=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: CS(=O)(=O)CCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1CCc1ccccn1
Temperature: 75 °C

Procedure:
Vanillin (2.5 mmol) is added to mixture of K2CO3 (12.5 mmol) and 2-(2-Methanesulfonyl-ethyl)-pyridine (1) (2.5 mmol) in DMF (0.2 M), and the resulting reaction mixture is heated to 75° C. for 16 h. After cooling to approximately room temperature, water is added and the aqueous mixture is extracted 5 times with methylene chloride. The methylene chloride layers are combined and concentrated to afford a residue, which is recrystallized in diethyl ether.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:9]([CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH2:10][C:11]([NH:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])(=[O:28])[CH3:27]
Reactant: O=C(CNCc1cccc(Br)n1)NC1CCCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Temperature: 0 °C

Procedure:
N2-[(6-Bromopyridin-2-yl)methyl]-N-cyclopentylglycinamide (Example 187, Step 1) (0.25 g, 0.80 mmol) was dissolved in dichloromethane (3.2 mL) and triethylamine (0.34 mL, 2.4 mmol) was added and the reaction was cooled to 0° C. Acetyl chloride (0.06 mL, 0.88 mmol) was added and the reaction was allowed to warm to room temperature and stir to completion. The solution was diluted with dichloromethane, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC to yield the title compound.
Reaction SMILES: [C:1]1([CH:7](Br)[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.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[N+:33]([O-:35])=[O:34])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCCN1CCC(O)CC1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccc(F)cc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-(5-fluoro-2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy1-[3-(5-fluoro-2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1[C:27]([CH2:28]Cl)=[C:26]([NH:30][C:31]([NH2:33])=[O:32])[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([O:1][CH2:28][C:27]3[C:22]([CH3:21])=[CH:23][CH:24]=[CH:25][C:26]=3[NH:30][C:31]([NH2:33])=[O:32])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH2:12][C:13]#[CH:14]
Reactant: C#CCc1c(C)nc2c(O)cccn12
Reactant: Cc1cccc(NC(N)=O)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(N)=O)cccn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
A mixture of 8-hydroxy-2-methyl-3-(2-propynyl) imidazo-[1,2-a]pyridine (0.571 g) and potassium carbonate (0.424 g) in N,N-dimethylformamide (11.5 ml) was stirred at room temperature for 20 minutes under a nitrogen atmosphere and then 6-methyl-2-ureidobenzyl chloride (0.6 g) was added. After being stirred for 2.5 hours. The mixture was poured into water and the resulting precipitates were collected by filtration. The crude product was purified by column chromatography on silica gel (25 g) with a mixture of chloroform and methanol (100:1 to 100:4) as eluents to give 2-methyl-8-(6-methyl-2-ureidobenzyloxy)-3-(2-propynyl)imidazo[1,2-a]pyridine (0.13 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:15]([N:18]([CH3:20])[CH3:19])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[N:10]=[CH:15][N:18]([CH3:20])[CH3:19])=[O:4]
Reactant: COC(=O)c1sc(C=O)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(C=O)cc1N=CN(C)C

Procedure:
3-Amino-5-formylthiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 240.28 (C10H12N2O3S) was obtained in this way; MS (ESI): 241 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(=O)[nH]1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from 6-methyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (20 g, 79 mmol) and phosphoryl chloride (36.0 mL, 395 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (17.35 g, 81%). NMR (DMSO-d6) δ 7.71 (s, 1H), 7.73 (s, 1H), 7.88 (d, 2 H, J, J=8.1 Hz), 8.05 (d, 2 H, J, J=8.1 Hz) ppm.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[H-].[H][H].Br[CH2:15][CH2:16][Cl:17]>CN(C)C=O>[O:10]=[C:2]1[N:3]([CH2:15][CH2:16][Cl:17])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: ClCCBr
Reactant: [H][H]
Agent: [H-]
Solvent: CN(C)C=O
Product: O=c1oc2ccccc2n1CCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Sodium hydride (3.9 g, mmol, 50% mineral oil dispersion) was washed with hexane to remove mineral oil (3×10 ml) under a stream of nitrogen. A solution of 1,3-benzoxazolin-2-one (Aldrich, 10 g, 74 mmol) in dimethylformamide (DMF) (70 ml) was then added dropwise with stirring to the hydride until hydrogen evolution ceased. The reaction flask was immersed in an ice bath and 2-bromochloroethane (12.3 ml, 148 mmol) in dimethylformamide (30 ml) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then heated to reflux for 3 days. At the end of this time thin layer chromatography analysis showed consumption of starting material. The reaction mixture was then cooled and the solvent evaporated under vacuum. The residue was worked-up as described above and purified by column chromatography (400 g fine silica, chloroform-methanol-ammonium hydroxide, 80:1:0.1) to yield 11.7 g (80%) of pure 2-(2-oxo-1,3-benzoxazolin-3-yl)ethyl chloride (mp. 77°-79° C. as a pale orange solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:15]=[CH:14][C:13]2[C:12]([S:16][CH3:17])=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1.CCN(CC)CC.O>C1COCC1>[C:1]([NH:5][C:6]1[N:15]=[CH:14][C:13]2[C:12]([S:16][CH3:17])=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ncnc2cc(NC(C)=O)ncc12
Temperature: 20 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Acetyl chloride (0.70 mL, 9.84 mmol) is added to a solution of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (0.20 g, 1.04 mmol) (described in a previous experimental) and Et3N (1.51 mL, 10.8 mmol) in THF at 0° C., and then the mixture is stirred at 20° C. for 4 h. Water (50 mL) was added, then the solution was extracted with EtOAc (3×50 mL). Evaporation and chromatography on alumina (1% EtOH/CHCl3) yields 7-acetylamino-4-methylthiopyrido[4,3-d]pyrimidine (0.12 g, 49%) as a yellow solid,. 1H NMR (DMSO) δ 11.05 (1H, s), 9.30 (1H, s), 9.02 (1H, s), 8.38 (1H, s), 2.71 (3H, s), 2.18 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:7][C@@H:6]([CH2:8][C:9]#[N:10])[CH2:5][C@@H:4]([CH2:11][CH:12]=C)[O:3]1.[O:15]=[O+][O-]>ClCCl>[O:15]=[CH:12][CH2:11][C@H:4]1[O:3][C:2]([CH3:14])([CH3:1])[O:7][C@@H:6]([CH2:8][C:9]#[N:10])[CH2:5]1
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC(C)(C)O1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC1(C)O[C@H](CC=O)C[C@H](CC#N)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-2,2-dimethyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 3 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90 V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution allowed to warm to room temperature. Flash chromatography provides, after concentration in vacuo, 2.5 g of pure (±)-cis-6-(2-oxoethyl)-2,2-dimethyl-1,3-dioxane-4-acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.[CH3:21]S(O)(=O)=O.[N:26]1C=CC(CN)=[CH:28][CH:27]=1>>[NH2:20][C:8]([NH:4][CH2:5][C:6]1[CH:2]=[CH:1][N:26]=[CH:27][CH:28]=1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: CS(=O)(=O)O
Reactant: NCc1ccncc1
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2ccc(Cl)cc2)n1
Product: Cc1ccc(S(=O)(=O)N=C(N)NCc2ccncc2)cc1

Procedure:
The compound of Example 22 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 4-picolylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 304.37; found mol. wt. (M+H) 305.2; 609.1 (Dimer)
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:26][C:27](Cl)=[O:28]>>[I:1][C:2]1[C:7]([C:27](=[O:28])[CH3:26])=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1
Reactant: O=C(O)c1ccc(-c2c(I)cc(I)cc2I)cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I

Procedure:
Freidel-Crafts acylation is performed on 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) in the presence of AlCl3 and CH3COCl to yield 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.[OH:21]C(C(C)=C)C(OCC)=O.Cl.[C:32]1([CH3:38])C=CC=C[CH:33]=1>[Cl-].C[N+](C)(C)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:21])[C:17](=[C:32]([CH3:38])[CH3:33])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: Cc1ccccc1
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (3.01 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (2.16 g, 15 mmol) and tetramethylammonium chloride (278 mg, 1.0 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 2 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, methanol (3.5 mL) acidified with hydrochloric acid was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with a 10:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (0.323 g, yield 9.1%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[N:18]=[CH:17][N:16]([C:19]5[CH:20]=[C:21]([NH2:33])[CH:22]=[C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH:24]=5)[C:13]4=[N:14][CH:15]=3)[N:7]=[N:6]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[N:18]=[CH:17][N:16]([C:19]5[CH:20]=[C:21]([NH:33][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])[CH:22]=[C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH:24]=5)[C:13]4=[N:14][CH:15]=3)[N:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC5CC5)nn4)cnc32)c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC5CC5)nn4)cnc32)c1
Yield: 33 %

Procedure:
To a solution of 5-(6-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo-[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (50 mg, 0.112 mmol) in DCM was added pyridine (26 mg, 0.33 mmol, 3.0 eq.) and ethanesulfonyl chloride (17 mg, 0.135 mmol, 1.2 eq.). After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 33% yield (20 mg). 1H NMR (300 MHz, DMSO): δ 10.3 (s, 1H) 9.02-8.99 (m, 2H), 8.81 (d, 1H), 8.63-8.61 (d, 1H) 7.95 (d, 1H), 7.77-7.69 (m, 2H), 7.49-7.42 (m, 2H), 7.31-7.25 (d, 1H), 4.33 (d, 2H), 3.42-3.26 (m, 2H), 1.34-1.24 (t, 3H), 0.63-0.60 (t, 2H), 0.49-0.48 (t, 2H); LC-MS (ESI): Calculated mass: 535.5; Observed mass: 535.8 [M+H]+ (rt: 0.1.33 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:29](O)=[O:30])=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([C:25]([F:27])([F:26])[F:28])=[CH:22][N:21]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)N=C(N)OC[C@H]1F

Procedure:
The condensation of (4R,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.1) and 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=449.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].[CH3:13]I>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:13])[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4]
Reactant: CI
Reactant: CCCC1CCC(C(=O)OC)C1
Solvent: C1CCOC1
Product: CCCC1CCC(C)(C(=O)OC)C1

Procedure:
Under an atmosphere of nitrogen, 3 ml. of a 1.4M solution of n-butyllithium in n-hexane were added to a solution of 0.643 ml. of diisopropylamine in 3 ml. of dry tetrahydrofuran at -78° C., and the solution was stirred at that temperature for 15 minutes. To the lithium diisopropylamide solution thus obtained was added dropwise a solution of 300 mg. of 1-methoxycarbonyl-3-propylcyclopentane in 5 ml. of dry tetrahydrofuran and the mixture was stirred at -78° C. for 30 minutes. To the solution was added a solution of 0.216 ml. of methyl iodide in 5 ml. of dry tetrahydrofuran and the mixture was stirred at -78° C. for one hour. The reaction mixture was quenched with an aqueous solution of ammonium chloride and extracted with diethyl ether. The extract was washed with 1N hydrochloric acid, an aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 330 mg. of the title compound having the following physical characteristic:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([Cl:17])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(Cl)Cl.C(OCC)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.[ClH:17]
Reactant: CN1CCNCC1
Reactant: CCOc1ccc(Cc2nc3cc(S(=O)(=O)Cl)ccc3n2CC2CC2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOc1ccc(Cc2nc3cc(S(=O)(=O)N4CCN(C)CC4)ccc3n2CC2CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general procedure 36B: Used 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazole-5-sulfonyl chloride (from 0.2 mmol of aniline precursor), 1-methylpiperazine (0.4 mmol) pyridine (0.5 mL) in CH2Cl2 (4 mL). The resulting mixture was stirred at room temperature overnight. Isolated the desired product as the HCl salt after column chromatography and treatment with 1 M HCl solution in diethyl ether (59 mg, 75%). 1H NMR (400 MHz, CD3OD): δ 8.02 (s, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.80 (s, 3H), 4.31 (s, 2H), 4.10 (d, J=7.2 Hz, 2H), 3.95 (q, J=8.0 Hz, 2H), 3.04–2.96 (m, 4H), 2.50–2.44 (m, 4H), 1.32 (t, J=8.0 Hz, 3H), 1.08–0.98 (m, 1H), 0.47–0.43 (m, 2H), 0.31–0.26 (m, 2H). MS (ESI) (M+1)+: 469. Anal. Calcd for C25H32N4O3S.2.7HCl.0.4H2O: C, 52.29; H, 6.23; N, 9.76. Found: C, 52.54; H, 6.21; N. 8.67.
Reaction SMILES: [Cl:1][C:2]1[C:7]2N(C)CC[C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1>CO>[ClH:1].[C:19]([C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:7]3[C:7]([CH3:6])=[CH:2][NH:3][C:2]=3[N:3]=[CH:4][N:5]=2)[CH:18]=[CH:17][CH:16]=1)#[CH:20]
Reactant: C#Cc1cccc(N)c1
Reactant: CN1CCc2ncnc(Cl)c21
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3[nH]cc(C)c23)c1
Product: Cl
Temperature: 125 °C
Yield: 77.3 %

Procedure:
To 4-chloro5-methyl-7H-pyrrolopyrimidine (0.17 g, 1.0 mmol) in dry methanol (3 ml) was added m-aminophenyl acetylene (0.14 g, 1.2 mmol). The suspension was heated in a sealed pressure tube at 125° C. for 18 hours. The reaction mixture was cooled to ambient temperature, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (15 g,40 mm mesh) using 5% methanol/methylene chloride to afford the title compound as a yellow solid (0.11 g, 43%). TS-MS: 249 (MH+); anal. RP18-HPLC RT: min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][O:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[OH-:36].[Na+].OO.Cl>CCO.CS(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][O:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([NH2:20])=[O:36])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Temperature: 60 °C

Procedure:
To a solution of compound 54a (60 mg, 0.13 mmol) in EtOH (4 mL) and DMSO (1 mL) was added a 3N aqueous NaOH (0.06 mL, 0.18 mmol) and 30% hydrogen peroxide (0.3 mL). The reaction mixture was refluxed at 60° C. for 12 h. The reaction mixture was allowed to cool to rt and acidified with 2N HCl to pH˜2 and extracted with DCM (2×30 mL). The combined DCM layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (0-10% MeOH/DCM) to give the title compound 84. 1H-NMR (400 MHz, MeOH) δ (ppm): 3.83-3.87 (m, 4H), 4.27-4.32 (m, 4H), 5.62 (s, 2H), 6.90 (d, J=8.8 Hz, 1H), 7.32-7.38 (m, 2H), 7.59 (ddd, J=8.4, 7.0, 1.5 Hz, 1H), 7.65-7.72 (m, 1H), 7.74-7.81 (m, 2H), 7.97 (d, J=8.8 Hz, 1H), 8.03 (dd, J=8.1, 2.2 Hz, 1H), 8.25 (d, J=8.1 Hz, 1H), 8.73 (d, J=1.5 Hz, 1H). (LCMS, ESI pos.) Calcd. for C26H23N7O3: 482.2 [M+H]. found 482.2.