Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].O.[CH2:28]=[C:29]1[O:33][C:31](=[O:32])[CH2:30]1>CC(C)=O>[C:31]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)(=[O:32])[CH2:30][C:29]([CH3:28])=[O:33]
Reactant: C=C1CC(=O)O1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
While a mixture of 0.344 g. of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, 0.42 g. of sodium hydrogen carbonate, 5 ml. of water and 5 ml. of acetone is stirred under cooling at 5° C, 0.2 g. of diketene is added and the mixture is further stirred at room temperature for 30 minutes. The acetone is removed from the reaction mixture by distillation under reduced pressure and the residual is washed with ethyl acetate. The water layer is separated, adjusted to pH 2 with 50 % phosphoric acid and extracted three times with ethyl acetate. The extracts are pooled, washed with a saturated aqueous solution of sodium chloride, dehydrated over magnesium sulfate, concentrated and allowed to stand under cooling with ice. With the addition of ether the resultant crystals are loosened and recovered by suction-filtration. The procedure gives 7-acetoacetamido-3(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid as crystals melting at 177°-180° C (decomp.). Yield 0.129 g. (30 %).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]([CH:11]1C(=O)OC(C)(C)[O:13][C:12]1=O)(=[O:10])[CH3:9]>C1C=CC=CC=1>[O:10]=[C:8]([CH3:9])[CH2:11][C:12]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:13]
Reactant: CC(=O)C1C(=O)OC(C)(C)OC1=O
Reactant: OC1CCOCC1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OC1CCOCC1

Procedure:
A solution of tetrahydro-4H-pyran-4-ol (1.6 ml, 16.8 mmoles) and 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (3.0 g, 16.1 mmoles) in dry benzene (50 ml) was heated under reflux for 4 hours. The solvent was removed in vacuo and the residue distilled at 146°-151°/14 mm Hg to afford the title product as a colourless oil, 2.84 g. Nmr (CDCl3)δ5.1 (m,H), 3.5 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([N:20]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl>C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:3]([CH:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: FC(F)(F)c1cnc(C(Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Product: NC(Cc1ccccc1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from stage b) (1.29 g) in diethyl ether (5 ml) was added 1M hydrochloric acid (10 ml) at room temperature and the solution was stirred at room temperature for 2 hours. The mixture was filtered to give a solid, which was washed with water (15 ml) then ether (15 ml). Drying in vacuo gave the title product. Water was removed from the aqueous phase by azeotropic distillation with toluene (×3), to give further quantities of the title product.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C:15]1([CH3:41])[NH:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=2[F:40])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:40][C:29]1[CH:30]=[C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:33][C:28]=1[CH:26]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][C:15]([CH3:41])([CH3:14])[N:27]1[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)/C=C/c1ccc(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (1.259 g, 5.62 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-fluorophenyl)acrylate (racemate) (850 mg, 2.25 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.467 ml, 8.42 mmol) in 1,4-dioxane (5 ml). The mixture was heated at 60° C. for 4 hours, then stirred at ambient temperature for 12 hours. The mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was extracted with ethyl acetate (2×25 ml) and the extracts combined with the organic layer. The combined extracts were evaporated under vacuum. The residue was purified by flash silica chromatography, elution solvent 10% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (mixture of diastereoisomers) (600 mg, 59.0%). m/z: ES+ [M+H]+ 453.
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([S:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: O=C(O)CCC(F)(F)Cl
Reactant: SCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCC(F)(F)Cl)SCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4.0 g of 4-chloro-4,4-difluorobutyric acid are added dropwise over the course of 45 minutes to a solution of 4.5 g of N,N'-carbonyldiimidazole in 30 ml of dimethylformamide at 0° C. After the solution has been stirred at 0° C. for 2 hours, 2.82 g of benzyl mercaptan are added and the mixture is allowed to warm to room temperature over the course of 17 hours. Then 100 ml of ethyl acetate are added and the organic solution is washed with saturated sodium chloride solution. The organic phase is dried over MgSO4 and evaporated. The resulting crude product is purified by chromatography on silica gel (mobile phase: hexane/ethyl acetate 9:1). This results in 4.0 g of S-benzyl 4-chloro-4,4-difluorothiobutyrate as an oil, nD20 : 1.5220.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: C1COCCN1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCOCC5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and morpholine. LCMS (M+H)+=517.0/519.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH2:14](N(CC)CC)C.CI.[Cl-].[NH4+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][CH2:10][CH2:11][N:12]([CH3:14])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: Brc1ccc(C2CNCCN2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1CCNC(c2ccc(Br)cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
To a cooled (0° C.) solution of 2-(4-bromophenyl)piperazine (4.07 g, 16.0 mmol) and triethylamine (17 mL, 122 mmol) in acetone (50 mL) was added a solution of methyl iodide (1.4 mL, 22 mmol) in acetone (20 mL) over 50 min and the reaction mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for 16 h. The reaction mixture was slowly treated with saturated ammonium chloride (150 mL) and extracted with ethyl acetate (200 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash silica gel column chromatography (heptane/ethyl acetate) gave 3-(4-bromo-phenyl)-1-methyl-piperazine (1.89 g, 46% yield). LCMS (m/z): 257.00 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH2:16][CH2:17][CH3:18])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH2:19]([N:21]([CH3:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)[CH3:20]>>[CH2:19]([N:21]([CH3:29])[C:22]1[N:23]=[CH:24][C:25]([NH:28][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:9][C:10]=2[CH2:16][CH2:17][CH3:18])=[O:15])=[CH:26][CH:27]=1)[CH3:20]
Reactant: CCCc1oc(-c2ccccc2Cl)nc1C(=O)O
Reactant: CCN(C)c1ccc(N)cn1
Product: CCCc1oc(-c2ccccc2Cl)nc1C(=O)Nc1ccc(N(C)CC)nc1

Procedure:
With a procedure similar to example 16 above, 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid and N2-ethyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H23ClN4O2 (m/e) 398, obsd 399 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[C:9](Br)[C:8]1=[O:20].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C([O-])=O)C=CO1)#[N:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:9]1[C:8](=[O:20])[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=1)#[N:22]
Reactant: N#Cc1ccccc1B1OC=CC(C(=O)[O-])O1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccccn2)c1=O

Procedure:
A mixture of 0.05 g of 1-(2-pyridyl)-5-(2-pyridyl)-3-bromo-1,2-dihydropyridin-2-one, 0.04 g of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 0.02 g of tetrakistriphenylphosphine palladium and 0.1 g of cesium carbonate was stirred at 120° C. in a nitrogen atmosphere for 2 hours in dimethylformamide. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then saturated saline water, and dried by magnesium sulfate anhydride. The solvent was concentrated under a vacuum, and the residue was refined by silica gel chromatography (ethyl acetate/hexane=3:1), to obtain 0.04 g of the white, powdery subject compound.
Reaction SMILES: [CH:1]([C:13]([O:15]CC)=O)([C:8](OCC)=[O:9])[CH2:2][C:3]([O:5][CH2:6]C)=[O:4].C[O-].[Na+].Cl.[CH:22]([NH2:24])=[NH:23].Cl>CO>[OH:15][C:13]1[C:1]([CH2:2][C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:24]=[CH:22][N:23]=1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(O)ncnc1O
Reaction time: 8 h
Yield: 100 %

Procedure:
Add triethyl ethane-1,1,2-tricarboxylate (74.75 g; 1.00 equiv; 303.54 mmol; 69.41 mL) to a solution of sodium methoxide (139.6 mL of 25% wt in MeOH, 4.35M) (131.2 g; 2.00 equiv; 607 mmol) in methanol (224.8 mL), then add formamidine hydrochloride (25.19 g, 1.01 equiv; 306.58 mmol) at RT. Stir the mixture overnight. Acidify with 37% HCl at 0° C.; filter the solids and dry in vacuo overnight to give the title compound (55.89 g; 99.99% yield) as a white solid. 1H NMR (300 MHz, DMSO): 8.03 (s, 1H), 3.55 (s, 3H), 3.24-3.15 (m, 2H).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[C:29][CH2:30][CH2:31][CH2:32]O>C(Cl)Cl>[Br:1][CH2:32][CH2:31][CH2:30][C:29]#[C:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: BrBr
Reactant: OCCCC#Cc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCC#Cc1ccccn1
Temperature: 5 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
Br2 (1.11 mL, 21.4 mmol) was added to a solution of triphenylphosphine (8.30 g, 30.7 mmol) in DCM (40 mL) at −5° C. A solution of 5-pyridin-2-yl-pent-4-yn-1-ol (3.00, 18.6 mmol) in DCM (10 mL) was added dropwise to the reaction mixture in order to maintain a temperature lower than 5° C. The reaction mixture was stirred for 5 hours at −10° C. and was quenched with a saturated solution of NaHCO3. The aqueous phase was extracted with DCM. The resulting organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5) to yield 2-(5-bromo-pent-1-ynyl)-pyridine (1.20 g, 5.35 mmol, 29%) with a purity of 50%.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]1[C:18]([NH2:26])=[N:19][NH:20][C:21]=1[C:22]([F:25])([F:24])[F:23].O=[C:28]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[CH2:29][C:30](OCC)=[O:31]>C(O)(=O)C>[Cl:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]1[C:21]([C:22]([F:25])([F:23])[F:24])=[N:20][N:19]2[C:30]([OH:31])=[CH:29][C:28]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:26][C:18]=12
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Reactant: Nc1n[nH]c(C(F)(F)F)c1Cc1cccc(Cl)c1Cl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(C2CCOCC2)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Reaction time: 8 h

Procedure:
To a suspension of 4-[(2,3-dichlorophenyl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-amine TFA salt (201 mg, 0.48 mmol) in acetic acid (2 mL) was added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (100 mg, 0.50 mmol). The reaction vessel was sealed, stirred and irradiated (microwave) at 140° C. for 40 minutes. The reaction mixture was cooled and diluted with acetic acid (5 mL). It was stood still overnight. The precipitate was collected, washed with acetic acid (2 mL), then with cooled methanol (2 mL) and dried to give crude product. The crude material was purified by reverse-phase HPLC to provide titled compound. (16 mg, 7.5%); LC/MS: MS (ES+) m/e 446 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.77 (m, 4H) 2.82 (s, 1H) 3.38-3.41 (m, 2H) 3.96 (dd, J=10.99, 2.91 Hz, 2H) 4.21 (s, 2H) 5.84 (s, 1H) 6.77-6.83 (m, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.54 (dd, J=7.96, 1.39 Hz, 1H) 12.22 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(I)cc2c(N2CCCCC2)c1S(C)(=O)=O
Yield: 54.4 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), piperidine (74 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 4 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, and the residue directly purified by chromatography on silica gel in dichloromethane. One obtained 184 mg (54%) of white crystals. MS: m/z=431 (M+H).
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([CH:40]=[CH:41][CH:42]=1)[CH2:17][C:18]1[C:19](=[O:39])[O:20][C:21]2[CH:31]=[C:30]([O:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[C:29]([Cl:38])=[CH:28][C:22]=2[C:23]=1[CH2:24][C:25](=[O:27])[NH2:26]>C(Cl)Cl>[C:25]([CH2:24][C:23]1[C:22]2[CH:28]=[C:29]([Cl:38])[C:30]([O:32][C:33](=[O:37])[N:34]([CH3:35])[CH3:36])=[CH:31][C:21]=2[O:20][C:19](=[O:39])[C:18]=1[CH2:17][C:16]1[CH:40]=[CH:41][CH:42]=[C:14]([NH:13][S:9]([CH3:8])(=[O:11])=[O:10])[CH:15]=1)(=[O:27])[NH2:26]
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(N)c3)c(CC(N)=O)c2cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(C)(=O)=O)c3)c(CC(N)=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
Et3N (13·L, 0.093 mmol) and methanesulfonyl chloride (3.6·L, 0.050 mmol) were added to a solution of dimethylcarbamic acid 3-(3-aminobenzyl)-4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-yl ester (20 mg, 0.047 mmol) in methylene chloride (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled away by concentration under reduced pressure, and the resultant residue was purified by column chromatography to yield the title compound (5.0 mg, 22%) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:11])=[C:6]([F:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13]>O1CCCC1>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=2[NH:11][C:12]1=[O:13])[CH3:2]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCNc1cccc(F)c1N
Solvent: C1CCOC1
Product: CCn1c(=O)[nH]c2c(F)cccc21

Procedure:
To 2,6-difluoroaniline (8 g, 62 mmol) in dimethylformamide (100 mL) was added a 2 M solution in tetrahydrofuran of ethyl amine (93 mL, 186 mmol) and the reaction stirred at room temperature overnight. The reaction was partitioned between 1 N hydrochloric acid and ethyl acetate and dried over sodium sulfate. The product was purified by silica gel using the ISCO (0-100% ethyl acetate/hexane) to give an equal mixture of ethyl-(3-fluoro-2-nitro-phenyl)-amine and N,N′-Diethyl-2-nitro-benzene-1,3-diamine. This mixture was reduced using the parr shaker and a spatula tip of 5% Pd/C in MeOH (100 mL). Upon complete reduction, the reaction was filtered through a pad of celite and concentrated onto silica gel. The desired product was purified on silica gel using the ISCO (0-100% ethyl acetate/hexane) to give N1-Ethyl-3-fluoro-benzene-1,2-diamine (2.48 g, 52%). N1-Ethyl-3-fluoro-benzene-1,2-diamine (2.48 g, 16.1 mmol) and carbonyl diimidazole (4.38 g, 27 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature overnight. Upon disappearance of the starting material, the reaction was partitioned between 1 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The organics were dried over sodium sulfate and concentrated to give 1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one as a white solid in near quantitative yield. MS (ES) m/z 181.1;
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][C:9]([CH3:18])=[C:8]([CH3:19])[N:7]=1.[OH-].[Na+].O>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]([CH3:19])=[C:9]([CH3:18])[N:10]=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]1=[O:5]
Reactant: OCCCl
Reactant: Cc1nc(O)c(-c2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nc(-c2ccccc2)c(=O)n(CCO)c1C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 71.6 %

Procedure:
Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-phenyl-5,6-dimethyl-pyrazine (10.0 g, 50 mM) and 5N NaOH (50 ml) in t-butanol (150 ml), and stirred at 60° C. for 2.5 hours. Water was added to the reaction mixture, the mixture extracted with chloroform, and the extract dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 130 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 109 (8.73 g, yield: 71.5%).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH2:12][CH2:13][NH2:14])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[C:1]1([C:7]2[S:8][C:9]([CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1cnc(-c2ccccc2)s1
Product: O=C(NCCc1cnc(-c2ccccc2)s1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 27 %

Procedure:
This compound was synthesized from 2-(2-phenylthiazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (35 mg, yield 27%) as an off white solid. 1H NMR (400 MHz, MeOD) δ 8.61 (t, J=1.5 Hz, 1H), 8.32-8.29 (dt, J=7.8 Hz, 1.3 Hz, 1H), 8.09-8.06 (dt, J=7.8 Hz, 1.5 Hz, 1H), 7.90-7.88 (m, 2H), 7.73-7.69 (t, J=7.9 Hz, 1H), 7.66 (s, 1H), 7.47-7.45 (m, 3H), 3.75-3.71 (t, J=6.8 Hz, 2H), 3.28-3.25 (t, J=6.8 Hz, 2H). MS (ESI) m/z: Calculated for C21H15F3N4O2S: 444.09. found: 445.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:35][N:36]([CH3:47])[CH2:37][CH2:38][O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>CC(O)C.Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([O:39][CH2:38][CH2:37][N:36]([CH3:47])[CH3:35])[CH:41]=3)[N:7]=2)[CH:18]=1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c1
Temperature: 180 °C
Yield: 26.8 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.150 g, 0.325 mmol) and 3-{[2-(dimethylamino)ethyl]oxy}aniline hydrochloride (PCT Publication No. WO2004/087652) (0.63 g, 0.29 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (5 drops) was added. The vial was sealed and heated in the microwave at 180° C. for 15 min. The crude product was adsorbed onto silica gel and flash chromatographed to give the title compound (0.047 g, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.75 (s, 1H), 9.51 (d, J=6.6 Hz, 1H), 8.26-8.47 (m, 2H), 8.03 (d, J=7.7 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.44-7.54 (m, 2H), 7.31-7.44 (m, 1H), 7.11-7.29 (m, 4H), 7.08 (t, J=6.6 Hz, 1H), 6.62 (d, J=5.3 Hz, 1H), 6.53 (dd, J=8.2, 1.6 Hz, 1H), 3.94 (t, J=5.8 Hz, 2H), 2.55 (t, J=5.7 Hz, 2H), 2.14 (s, 6H). MS (M+H, ES+) 606.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:26]([Cl:39])[C:25]=1[OH:40]>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:27]=[C:26]([Cl:39])[C:25]=1[OH:40]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1NC1CCN(C)CC1
Yield: 53.1 %

Procedure:
Following general procedure II, 1-{6-chloro-4-[(1-methylpiperidin-4-yl)amino]-1,5-naphthyridin-3-yl}ethanone (70 mg, 0.22 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (95 mg, 0.33 mmol) to afford the desired product (52 mg, 53%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.85 (s, 1H), 8.09-8.01 (m, 2H), 7.94 (s, 2H), 5.74-5.70 (m, 1H), 2.95-2.92 (m, 2H), 2.68 (s, 3H), 2.51 (t, J=11.7 Hz, 2H), 2.37 (s, 3H), 2.33-2.25 (m, 2H), 1.73-1.71 (m, 2H); ESI MS m/z 445 [M+H]+; HPLC>99% (AUC), tR=9.03 min.