Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(OCC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](/[N:8]=[CH:13]/[N:14]([CH3:16])[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Product: CN(C)/C=N/C(=O)c1ccc(Br)cc1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
4-Bromo benzamide (28.0 g, 0.140 mol) was suspended in 1,1-dimethoxy-N,N-dimethylmethanamine (50 mL, 420 mmol) and the solution was stirred and heated to 90° C. for 2 hours. The solution was then cooled to ambient temperature and diethyl ether (150 mL) was added. The solution was cooled to 0° C. overnight and filtered to give (E)-4-bromo-N-((dimethylamino)methylene)benzamide as a colorless solid (25.6 g). This material was then dissolved in acetic acid (50 mL) and hydrazine (3.50 g, 110 mmol) was added slowly (exotherm) to the stirred solution, which solidified. The mixture was heated to 90° C. and a stir bar was added. The solid slowly dissolved over 8 hours and was then cooled to ambient temperature and the solution was diluted with water (35 mL). The resulting white solid was filtered and dried in vacuo to furnish the title compound as a colorless solid (19.8 g, 88%): 1H NMR (400 MHz, DMSO-d6) δ 13.91 (s, 1H), 8.51 (s, 1H), 8.01-7.93 (m, 2H), 7.73-7.67 (m, 2H; ESIMS m/z 224, 226 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]([CH3:15])=[C:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[N:10][C:5]2=[N:4][C:3]=1[C:16](=[O:27])[C:17]#[C:18][CH2:19][O:20]C1CCCCO1.C(=O)(O)[O-].[Na+]>CO.Cl>[Br:1][C:2]1[N:6]2[C:7]([CH3:15])=[C:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[N:10][C:5]2=[N:4][C:3]=1[C:16](=[O:27])[C:17]#[C:18][CH2:19][OH:20]
Reactant: CCc1c(OC)nc2nc(C(=O)C#CCOC3CCCCO3)c(Br)n2c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCc1c(OC)nc2nc(C(=O)C#CCO)c(Br)n2c1C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A solution of 5.0 g (11.5 mmol) of 1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one in a mixture of 100 ml of methanol and 35 ml of 2N hydrochloric acid stood at room temperature for 30 minutes and then was neutralized with aqueous sodium bicarbonate. Extraction with chloroform gave an oil which was chromatographed over silica (chloroform:ether:methanol 100:0:0 gradually changing to 0:95:5) to obtain 1.3 g (32%) of 1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-hydroxy-2-butyn-1-one as off-white crystals melting at 212°-3° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([SH:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.CC(O[CH2:16][C:17]1[CH2:26][S:25][C@@H:20]2[C@H:21]([NH2:24])[C:22](=[O:23])[N:19]2[C:18]=1[C:27]([OH:29])=[O:28])=O.B(F)(F)F>C(#N)C>[NH2:24][C@@H:21]1[C:22](=[O:23])[N:19]2[C@@H:20]1[S:25][CH2:26][C:17]([CH2:16][S:8][C:6]1[N:5]3[N:9]=[CH:10][CH:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=1)=[C:18]2[C:27]([OH:29])=[O:28]
Reactant: Cc1cc(S)n2nccc2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nccc2n1

Procedure:
1.1 g of 5-methylpyrazolo[1,5-a]pyrimidine-7-thiol and 1.80 g of (7R)-7-aminocephalosporanic acid were stirred for 1 hour in 18 ml of a 20 percent solution of boron trifluoride in acetonitrile. The reaction mixture was concentrated, the residue was taken up in 15 ml of water, and the pH was adjusted to 2.5 with 2N sodium hydroxide solution. The precipitated product was filtered off under suction and dried. There was obtained (6R,7R)-7-amino-3-[[(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]#[N:14].[H-].[Na+].[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:22][CH3:23])[C:13]#[N:14]
Reactant: Cc1ccc(C)c(OCc2ccccc2CC#N)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C#N)c1ccccc1COc1cc(C)ccc1C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A solution of 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]acetonitrile (2.00 g, 8.0 mmol) in N,N-dimethyl-formamide (20 ml) was stirred at 0° C. 60% oily sodium hydride (0.38 g, 9.5 mmol) was added thereto, and then ethyl iodide (1.37 g, 8.8 mmol) was added dropwise over 5 minutes. After 1 hour, water was added, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=19/1) to give the desired compound 2-[2-(2,5-dimethylphenoxymethyl)phenyl]butyronitrile (1.91 g, 86%) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([NH:5][NH2:6])=O.CO[C:12]1[CH2:17][CH:16]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:19]=2)[CH2:15][CH2:14][N:13]=1.C(=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]([C:3]1[N:13]2[CH2:12][CH2:17][CH:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=3)[CH2:15][C:14]2=[N:6][N:5]=1)([CH3:9])[CH2:7][CH3:8]
Reactant: CCC(C)(C)C(=O)NN
Reactant: COC1=NCCC(c2nc(-c3ccccc3)no2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC(C)(C)c1nnc2n1CCC(c1nc(-c3ccccc3)no1)C2
Yield: 59.3 %

Procedure:
Reflux 2,2-dimethyl-butyric acid hydrazide (0.053 g, 0.48 mmol) and 5-(2-methoxy-3,4,5,6-tetrahydropyridin-4-yl)-3-phenyl-1,2,4-oxadiazole (0.1 g, 0.39 mmol) in methanol (1.55 mL) overnight. Remove the methanol under reduced pressure and replace with acetic acid (2 mL). Reflux the reaction for 3 hours and pour over aqueous saturated sodium bicarbonate. Extract with dichloromethane and dry the organics over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography eluting with 5-15% ethyl acetate in dichloromethane. Recrystallize from ethyl acetate and hexane to afford the title compound as a crystalline solid (0.078 g). Mass spectrum (m/z): 338 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[C:34]([F:35])=[CH:33][CH:32]=[C:31]([F:36])[C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[C:31]([F:36])=[CH:32][CH:33]=[C:34]([F:35])[C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Fc1ccc(F)c(CBr)c1Cl
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2c(F)ccc(F)c2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as in the preparation of compound 10, except that 2-chloro-3,6-di-fluoro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H NMR (400 MHz, CDCl3-CD3OD 10:1) δ ppm 6.98-7.06 (m, 2H), 6.90 (m, 2H), 5.31 (s, 1H), 5.01-5.20 (ABq, J=24.2, 14.4 Hz, 2H), 3.28-3.37 (m, 2H) 3.13 (s, 3H), 3.01-2.94 (m, 1H), 2.6-2.9 (m, 2H), 2.10 (m, 1H), 1.92 (m, 2H), 1.73 (s, 1H), 1.6-1.75 (m, 2H). MS (ES) [m+H] calc'd for C17H20ClF2N4O2, 385.1. found 385.1.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[Cl:24][C:21]1[N:20]=[N:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(Cl)nn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccc(Cl)nn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of [6-(6-chloro-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.2 g, 0.55 mmol) in THF:H2O (1:1, 10 mL) at 0° C. was added a solution of LiOH (0.026 g, 1.10 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 2 with 1N HCl (1 mL) at 0° C. and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-chloro-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.1 g, 54%). 1H NMR (400 MHz, DMSO): δ 9.21 (s, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.15 (d, J=1.6 Hz, 1H), 5.52 (dd, J=2.4, 9.2 Hz, 1H), 3.10 (dd, J=2.0, 15.6 Hz, 1H), 2.31 (s, 3H), 2.18-2.12 (m, 1H). MS (ESI) m/z=333 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[I:11][C:10]1[C:5]2[C:6](=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: Cc1ncc2cn[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Cc1ncc2c(I)n[nH]c2n1
Temperature: 80 °C

Procedure:
2.180 g (purity 73%, approx. 11.82 mmol) of 6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 3.987 g (17.72 mmol) of N-iodosuccinimide were dissolved in 30 ml of DMF and the mixture was heated at 80° C. for 2 h. After cooling, the mixture was concentrated on a rotary evaporator and the residue was stirred with dichloromethane, filtered off with suction and dried under high vacuum. 7.950 g (38% purity, 100% of theory) of the target compound were obtained.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:19]=[CH:18][C:17]2[NH:16][C:15]3[C:14]([CH:20]=[O:21])=[C:13]4[CH:22]=[CH:23][N:24]=[CH:25][C:12]4=[C:11]([CH3:26])[C:10]=3[C:9]=2[CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:19]=[CH:18][C:17]2[NH:16][C:15]3[C:14]([CH:20]=[O:21])=[C:13]4[CH:22]=[CH:23][N:24]=[CH:25][C:12]4=[C:11]([CH3:26])[C:10]=3[C:9]=2[CH:8]=1
Reactant: COc1ccc2[nH]c3c(C=O)c4ccncc4c(C)c3c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c2cnccc2c(C=O)c2[nH]c3ccc(O)cc3c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.6 g (0.6 mL) of boron bromide in 5 mL of dry methylene chloride was added dropwise to a stirred suspension of 200 mg of the methoxyaldehyde 38 in 50 mL of dry CH2Cl2 at -78° C. The stirred suspension was allowed to warm to room temperature and stirred for an additional 6 hours. The mixture was cooled in an ice bath and about 5 mL of ice-water was added after 30 minutes the methylene chloride layer was separated under nitrogen. The aqueous brown suspension was cooled in an ice-bath and made alkaline with 15 mL of 10% sodium hydroxide under nitrogen. The dark red solution was taken to pH 7-8 with the aid of acetic acid, sodium bicarbonate solution. The brown precipitate was collected on a filter, washed with water and dried. The dry solid was triturated with methylene chloride-hexane (1:1) and filtered to give the desired crude phenolic aldehyde. Wt. 170 mg, m.p. 346°-349° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8]1)=[O:6])[CH3:3].[CH2:21]1COCC1.[OH-].[K+].CI>CN(C=O)C>[CH2:2]([O:4][C:5]([C:7]1([CH3:21])[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl -1-benzyl-4-oxo-piperidine-3-carboxylate hydrochloride (150 g, 0.504 mol) was suspended in a solvent mixture of 750 ml THF and 750 ml DMF at room temperature. Addition of powdered KOH (56 g, 1.0 mol) was made in two equal lots keeping half an hour interval between two additions. To a clear reaction mixture methyl iodide (78 g, 0.55 mol) was added over period of 10 minutes and it was stirred for three hours at room temperature. The reaction was quenched by adding 4 ltr water followed by 1.5 ltr diethyl ether. Layers were separated. Organic layer was washed with water and dried over Na2SO4. Evaporation of organic solvent afforded a liquid, which was passed through a silica gel column to give 86 g (61%), titled compound.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[Cl:14][C:15]1[C:16]([CH3:27])=[N+:17]([O-])[CH:18]=[C:19]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)[CH:20]=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:14][C:15]1[C:16]([CH2:27][OH:4])=[N:17][CH:18]=[C:19]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)[CH:20]=1
Reactant: Cc1c(Cl)cc(C2OCCO2)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCc1ncc(C2OCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
Trifluoroacetic anhydride (231 μl, 1.635 mmol) was added to a solution of 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine 1-oxide (225 mg, 1.043 mmol) in DCM (4 ml) at 0° C. and the mixture was stirred at room temperature for 48 h. Full conversion was observed by HPLC. MeOH (0.5 ml, 12.36 mmol) was added and, after stirring for 10 min, DCM and 10% Na2CO3 solution were added. Extraction, drying (MgSO4), and filtration afforded 223.2 mg of crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded [3-chloro-5-(1,3-dioxolan-2-yl)-2-pyridinyl]methanol (142.7 mg, 63%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:18][O:19][CH3:20])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#N.CC(C[AlH]CC(C)C)C.C1C[O:33]CC1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:18][O:19][CH3:20])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:33]
Reactant: C1CCOC1
Reactant: COCN(c1nccs1)S(=O)(=O)c1ccc(C#N)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-cyano-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (4.5 mmol) in THF (50 mL) at −78° C. under argon was added DIBAL (5.0 mmol, 1M in THF) and the solution was allowed to warm to room temperature overnight. After the reaction was quenched with potassium sodium tartrate solution slowly, the mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography to give 4-formyl-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (3.1 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.C([Li])CCC.[C:24](=[O:26])=[O:25].Cl>C1COCC1.O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]([OH:26])=[O:25])=[CH:3][CH:4]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(Br)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc2ncnc(N)c2c1-c1ccc(C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A −78° C. solution of Example 66A (1.5 g, 4.68 mmol) in THF (50 mL) was treated dropwise with 2.5M n-butyllithium in hexanes (4.7 mL, 11.71 mmol), stirred for 30 minutes at −78° C., then treated with excess dry ice. The reaction was stirred at −78° C. for 30 minutes, warmed to room temperature, diluted with water, adjusted to pH 3 with 2N HCl, and filtered. The filter cake was dried to provide 686 mg (51%) of the desired product. MS (CI) m/e 285 (M+); 1H NMR (300 MHz, DMSO-d6) δ 13.13 (br s, 1H); 8.29 (s, 1H); 8.09 (d, J=8.4 Hz, 2H); 7.53 (d, J=8.4 Hz, 2H); 2.28 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8].[CH:14](O)=[O:15]>O>[CH:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8])=[O:15]
Reactant: COC(=O)C=Cc1cccc(N)c1
Reactant: O=CO
Solvent: O
Product: COC(=O)C=Cc1cccc(NC=O)c1

Procedure:
193 g of methyl 3-aminocinnamate and 900 ml of formic acid were mixed and heated under reflux for 2 hours. The reaction solution was poured into water and the crystals (methyl 3-formamidocinnamate) obtained were collected by filtration. Yield: 127 g.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:12][CH2:11]2)=[CH:6][C:5]=1[Cl:13])=[N+:2]=[N-:3].O=[C:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].C[O-].[Na+]>O>[Cl:13][C:5]1[CH:6]=[C:7]([CH:10]2[CH2:11][CH2:12]2)[CH:8]=[CH:9][C:4]=1[N:1]1[C:15]([CH3:21])=[C:16]([C:17]([OH:19])=[O:18])[N:3]=[N:2]1
Reactant: COC(=O)CC(C)=O
Reactant: [N-]=[N+]=Nc1ccc(C2CC2)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)O)nnn1-c1ccc(C2CC2)cc1Cl
Temperature: 5 °C
Reaction time: 64 h

Procedure:
To crude 1-azido-2-chloro-4-cyclopropylbenzene (0.2 M solution in THF) was added methyl 3-oxobutanoate (146 g, 1254 mmol) and the resulting mixture was cooled to 5° C. NaOMe (232 mL, 1254 mmol) was added slowly forming a precipitate and the mixture was stirred at RT for 64 hrs. The resulting suspension was cooled in an ice bath and water (2 L) was added. The mixture was transferred to a separating funnel and the aqueous layer was extracted with Me-THF (500 mL). The aqueous layer was acidified with 2M HCl (aq) and extracted with EtOAc (2 L) (1×) and (1 L) (2×). The combined organic extracts were washed with water (1 L) and brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give an orange oily residue. Water (300 mL) was added and the mixture was stirred for 30 min, filtered, washed with water and dried under reduced pressure to give the title compound as orange crystals.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[NH2:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](F)(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:8]=1>>[NH2:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:24])(=[O:23])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[CH:20][CH:21]=2)[N:8]=1
Reactant: NC1CCC1
Reactant: N#Cc1cnc(Nc2ccc(S(=O)(=O)F)cc2)nc1N
Product: N#Cc1cnc(Nc2ccc(S(=O)(=O)NC3CCC3)cc2)nc1N
Temperature: 40 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
Cyclobutylamine (2 ml) was added to 4-amino-5-cyano-2-(4-fluorosulphonylanilino) pyrimidine (Method 1; 250 mg, 0.853 mmol), the mixture was heated at 40° C. for 1 hour and then stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (50:50). The product was triturated with ether/hexane and the resulting solid collected by filtration to give the title compound (91 mg, 31%). NMR: 1.41-1.50 (m, 2H); 1.62-1.78 (m, 2H); 1.82-1.90 (m, 2H); 3.59 (m, 1H); 7.60 (s, 2H); 7.62 (d, 2H); 7.98 (d, 2H); 8.40 (s, 1H); m/z: 345 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[N:6]=1.C(OCC)C.C(=O)(O)[O-].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(OCC)(=O)C>[Cl:22][CH2:23][C:24]([NH:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc2cc(N)ccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1nc2cc(NC(=O)CCl)ccc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methylbenzothiazole-5-ylamine (1.0 g, 4.2 mm) was suspended in a mixture of 1:1 ethyl ether: saturated aqueous sodium bicarbonate. To the suspension was added chloracetyl chloride (0.7 g, 6.5 mm) over a period of 10 minutes. The mixture was allowed to stir at room temperature for 24 hours, and then diluted with 50 ml of ethyl acetate. The organic layer was separated, dried over magnesium sulgate, and filtered. The solvent was evaporated from the filtrate, and the white solid residue obtained was triturated in ether and filtered, to afford 2-chloro-N-(2-methylbenzothiazol-5-yl)acetamide, a compound of formula (1).
Reaction SMILES: CN.[Br:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1.[C:18]([BH3-])#[N:19].[Na+].C(O)(=O)C>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([NH:19][CH3:18])[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1
Reactant: [BH3-]C#N
Reactant: O=C(CN1CCCC1)c1cccc(Br)c1
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(CN1CCCC1)c1cccc(Br)c1
Reaction time: 1 h
Yield: 47.9 %

Procedure:
2.0 M methylamine solution in THF (55 mL, 110.0 mmol) was added to a solution of 1-(3-bromophenyl)-2-(1-pyrrolidinyl)ethanone (7.40 g, 27.62 mmol) in anhydrous THF (30 mL) at room temperature. The reaction mixture was stirred for 1 h and then sodium cyanoborohydride (5.21 g, 82.86 mmol) and acetic acid (3 mL) were added. The resulting reaction mixture was continually stirred at room temperature for 96 h until the starting material was consumed completely. Saturated K2CO3 solution (100 mL) was added and after stirring for 15 min, the solution was extracted with ethyl acetate (2×80 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting residue was isolated by column chromatography on silica gel (MeOH/EtOAc, 1:10) to yield the title compound as a yellow oil (3.75 g, 48%), MS (ES) m/e 283[M+H]+.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]2[O:16][C:2](=[O:3])[S:4][N:17]=2)=[CH:11][CH:12]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)CCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=c1oc(CCc2ccc(Cl)cc2)ns1
Yield: 87.5 %

Procedure:
11.60 g (88.5 mmol) of chlorocarbonylsulphenyl chloride and 13.54 g (73.8 mmol) of 3-(4-chlorophenyl)propionamide are stirred in 25 ml of toluene at 70° C. for 3 h. Subsequently, the mixture is cooled and freed from a solvent under vacuum and the residue is purified by column chromatography. 15.6 g of product are obtained (99.9% purity, 87.6% yield, log P (pH 2.3)=3.36).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][OH:20])=[O:17])=[N:14][CH:15]=1.O[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][O:20][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)NCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)COCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Yield: 34.9 %

Procedure:
A solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-N-(hydroxymethyl)-4-methylpyridine-2-carboxamide (421 mg, 0.935 mmol) obtained from Example 85, ethyl hydroxyacetate (106 μl, 1.12 mmol), p-toluenesulfonic acid monohydrate (18 mg, 0.094 mmol) in benzene (10 ml) was heated to reflux for 30 minutes. The reaction solution was returned to room temperature, and then was concentrated under reduced pressure. Saturated aqueous sodium hydrogencarbonate was added to the resulting concentration residue, and the mixture was extracted from ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with 35% ethyl acetate/hexane was concentrated under reduced pressure, to obtain the title compound (175 mg, 0.326 mmol, 35%) as a white solid.