Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-methylphenol (10 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (8.87 g) and benzylbromide (6.36 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-benzyloxy-1-bromo-2-methylbenzene (14.6 g). This material was dissolved in tetrahydrofuran (200 mL). To the solution was added n-butyl lithium (2.66 mol/L n-hexane solution, 21.7 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (10.1 mL), and the mixture was allowed to warm to 0° C. and stirred for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-benzyloxy-2-methylbenzaldehyde. This material was dissolved in ethanol (100 mL). To the solution was added sodium borohydride (1.99 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with diethylether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=6/1-3/1-1/1) to give the title compound (10.5 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:7]2[C:8](=O)[CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:11][C:6]=2[O:5][CH:4]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl.O>C(O)C>[ClH:27].[F:1][C:2]([F:21])([F:20])[C:3]1[C:7]2[C:8](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:11][C:6]=2[O:5][CH:4]=1
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1CC(=O)c2c(C(F)(F)F)coc2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C(F)(F)F)coc2C1
Yield: 40.6 %

Procedure:
A mixture of 3-trifluoromethyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.15 g), aminoguanidine hydrochloride (0.06 g), concentrated hydrochloric acid (0.025 ml), water (0.025 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 3-trifluoromethyl-4-guanidinoimino-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 52) (0.08 g) as colorless crystals.
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([B:13]([OH:15])[OH:14])=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:17]1[C:26]2[CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22][C:21]=2[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.C(OCC)C>O1CCOCC1.O>[CH3:27][C:24]1([CH3:28])[CH2:23][CH2:22][C:21]2[N:20]=[CH:19][N:18]=[C:17]([N:5]3[CH2:6][C:7]4[CH:12]=[C:11]([B:13]([OH:15])[OH:14])[CH:10]=[CH:9][C:8]=4[O:2][CH2:3][CH2:4]3)[C:26]=2[CH2:25]1
Reactant: CC1(C)CCc2ncnc(Cl)c2C1
Reactant: OB(O)c1ccc2c(c1)CNCCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
To a slurry of 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylboronic acid hydrochloride salt (5.7 g, 25 mmol) (example 8, step 1) and 4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazoline (reagent preparation 3) (3.0 g, 15 mmol) in dioxane (75 mL) and H2O (75 mL) was added DIPEA (17 mL, 100 mmol) and the resulting mixture was heated (90° C.). After 72 hours the solution was concentrated and partitioned between 2M aqueous sodium hydroxide and ethyl ether. The aqueous layer was neutralized and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration with ethyl ether provided [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (4.2 g, 80% yield) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.68 (s, 1H), 7.77 (s, 1H), 7.64 (dd, 1H), 6.86 (dd, 1H), 5.04 (s, 2H), 4.46 (m, 2H), 4.18 (m, 2H), 2.80 (t, 2H), 2.52 (s, 2H), 1.58 (t, 2H), 0.86 (s, 6H); MS (ES) for C19H24BN3O3: 354 (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]2[C:10](=[O:15])[O:11][C:12](=O)[NH:13][C:8]=2[CH:7]=[C:6]([CH3:16])[CH:5]=1>CO>[NH2:13][C:8]1[CH:7]=[C:6]([CH3:16])[CH:5]=[C:4]([CH3:3])[C:9]=1[C:10]([O:11][CH3:12])=[O:15]
Reactant: Cc1cc(C)c2c(=O)oc(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(C)cc(C)cc1N
Temperature: 60 °C
Yield: 86 %

Procedure:
To a stirred solution of sodium hydroxide (0.013 g, 0.33 mM) in methanol (1.7 mL) was added 5,7-dimethyl-2H-3,1-benzoxazine-2,4(1H)-dione (0.67 g, 3.5 mM). The mixture was heated to 60° C. and maintained at that temperature for 45 min during which vigorous gas evolution ensued and all solids dissolved completely. The solution was cooled and concentrated using a rotary evaporator. The residue was dissolved in ethyl acetate, and the ethyl acetate solution was washed with water, dried (Na2 SO4), filtered and concentrated to provide the title compound (0.54 g, 86%) as a tan solid; MS(CI); 180 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:34])[CH3:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][C:32](=[O:34])[CH3:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(=O)Nc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and N-(2-bromophenyl)acetamide. MS (ESI): mass calcd. for C18H15FN4O, 322.12; m/z found, 322.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.91 (m, 1H), 7.53-7.21 (m, 6H), 6.73 (s, 2H), 1.92 (s, 3H).
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13](I)=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][Cl:20])[C:10]1=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:9]1[C:14](=[O:15])[C:13]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][Cl:20])[C:10]1=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCl)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(c1ccccc1)n1c(=O)c(-c2cccnc2)cn(CCCCl)c1=O
Yield: 20.3 %

Procedure:
3-Benzoyl-1-(3-chloro-propyl)-5-iodo-1H-pyrimidine-2,4-dione (Prep 41,500 mg, 1.2 mmol) was dissolved in degassed DME-water solution (5-1, 35 mL). Pyridine-3-boronic acid (629 mg, 1.8 mmol), Na2CO3 (380 mg, 3.6 mmol), 2-(dicyclohexylphosphino)biphenyl (84 mg, 0.24 mmol) and Pd(PPh3)4 (250 mg, 0.24 mmol) were added and the mixture was refluxed for 3 hours. The solvents were evaporated under vacuum and the residue was filtered over a SCX cartridge washing with MeOH and eluting with MeOH/NH3 95:5. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (from 98-2-0.2 to 95:5:05) to give the title compound (90 mg, 20% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:9]2([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([NH2:32])=O.CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CO.O.O1CCOCC1>[NH2:32][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: NC1=N[C@](CF)(c2cc(Br)cnc2F)C[C@@H](C(F)(F)F)O1
Reactant: NC(=O)C(F)(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: NC1=N[C@](CF)(c2cc(N)cnc2F)C[C@@H](C(F)(F)F)O1
Temperature: 120 °C
Yield: 80.4 %

Procedure:
In a microwave tube was added (4S,6S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.90 g, 2.406 mmol), potassium carbonate (1.330 g, 9.62 mmol) and copper(I) iodide (0.092 g, 0.481 mmol), 2,2,2-trifluoroacetamide (0.544 g, 4.81 mmol) and molecular sieves. The vial was purged with nitrogen followed by addition of dioxane 15 mL and trans-N,N′-dimethyl-1,2-cyclohexanediamine (0.152 ml, 0.962 mmol). The vial was sealed and heated at 120° C. for 2.5 h. To this mixture were added MeOH/water (8/4 mL) and the resulting mixture was heated at 80° C. for 3 h. The mixture was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography on silica gel using a gradient of 0-5% 2M NH3 in MeOH/methylene chloride to afford (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.60 g, 1.934 mmol, 80% yield). MS m/z=311.0 [M+H]+. Calculated for C11H11F5N4O: 310.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH:47][CH3:48])=[CH:42][CH:41]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:47]([CH2:46][C:43]2[CH:44]=[CH:45][C:40]([C:36]3[NH:37][CH2:38][CH2:39][N:35]=3)=[CH:41][CH:42]=2)[CH3:48])=[O:21])[CH:16]=1)[CH3:13])(=[O:10])=[O:11]
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Reactant: CNCc1ccc(C2=NCCN2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2c(Cl)cccc2Cl)c1

Procedure:
5-({[(2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (51 mg, 0.14 mmol) was dissolved in DMF (1 mL) and CDI (34 mg, 0.21 mmol) was added. The mixture was stirred until acid activation was complete. 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.HCl (32 mg, 0.14 mmol) and DIPEA (0.074 mL, 0.42 mmol) were sonicated in DMF (0.5 mL) for 15 min. 0.5 mL of activated acid solution was added to 0.25 mL of amine solution and the reaction was stirred at ambient temperature for 18 h, then microwaved (120° C., 200 W) for 2×20 min. The reaction was concentrated, dissolved in DCM and washed with water (3×1.5 mL) and saturated brine (1 mL)). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude product was purified using prep method A.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)/[CH:6]=[C:7](\O)/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2].[CH3:17][NH:18][NH2:19].C(Cl)Cl.CO>CCO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:18]([CH3:17])[N:19]=1)=[O:16])[CH3:2]
Reactant: CNN
Reactant: CCOC(=O)C(=O)/C=C(\O)c1ccccn1
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccccn2)n(C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.8 %

Procedure:
To a stirred solution of (Z)-4-hydroxy-2-oxo-4-pyridin-2-yl-but-3-enoic acid ethyl ester (2.32 g, 10 mmol) at r.t. in EtOH (15 ml) under an argon atmosphere was added methylhydrazine (0.55 ml, 10 mmol). The mixture was heated to reflux and stirring was continued for 90 min. The mixture was cooled to r.t. and concentrated to leave a brown paste. After silica gel chromatography using a CH2Cl2/MeOH gradient, the product (1.43 g, 59%) was obtained as yellow waxy solid. MS: M=232.1 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28](F)=[C:27]([Cl:32])[CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:32][C:27]1[CH:26]=[C:25]([S:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:23])=[O:24])[CH:30]=[CH:29][C:28]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 29 step (i).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[C:7]2[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:4]=1.[NH4+].[OH-].Cl.O.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C1COCC1>[F:32][C:2]([F:1])([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:37](=[O:39])[CH3:38])=[N:18][CH:19]=3)=[C:7]2[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)[CH:4]=1
Reactant: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 5-[7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-ylethynyl]-pyridin-2-ylamine (example 55) (2.00 g, 4.47 mmol) in acetic anhydride (15 mL) was stirred at 120° C. for 1 h. Cooled to 60° C., concentrated in vaccumn to dryness (water bath temperature 60° C.) and dried in HV to give an orange solid (2.465 g, 113%, mixture of mono- and diacetylated compound). Suspended in THF (30 mL) at 23° C., added NH4OH (25%, 13.3M, 1.0 mL, 13.4 mmol) and stirred at 23° C. for 1.5 h resulting in a clear red solution, adjusted pH with 1N HCl until pH 1, added H2O (total volume 200 mL), filtered the precipitate off, washed with H2O and dried in HV, followed by trituration with ether and drying in HV to give the title compound as an orange solid (2.130 g, 97%). MS [ISN] 488.1 [(M−H)−]; mp 266° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: COC(=O)c1cccc(N)c1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-amino-2-fluorobenzoate (21.8 g, 129 mmol) in DCM (300 mL) were added pyridine (30.6 g, 387.6 mmol) and a catalytic amount of DMAP. The mixture was cooled to 0° C. 2,5-Difluorobenzene-1-sulfonyl chloride (28.8 g, 136 mmol) in DCM (20 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. The reaction mixture was washed with water (300 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether to afford the title compound of Step A. (16 g, 35.9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.71-10.91 (br, 1H), 7.65-7.73 (m, 1H), 7.48-7.62 (m, 4H), 7.20-7.28 (m, 1H), 3.77 (s, 3H).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH2:5][C:6](=[CH:8][CH2:9][C:10](=[O:19])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:7]=1.N1C=CC=CC=1.[CH3:26][N:27]=[C:28]=[O:29]>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]([CH2:9][CH:8]=[C:6]2[CH2:5][S:4][C:3]([NH:2][C:28]([NH:27][CH3:26])=[O:29])=[N:7]2)=[O:19])=[CH:13][CH:14]=1
Reactant: CN=C=O
Reactant: NC1=NC(=CCC(=O)Nc2ccc(Cl)cc2)CS1
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)NC1=NC(=CCC(=O)Nc2ccc(Cl)cc2)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
A reaction flask was charged with 3.9 g (0.011 mole) of 2-amino-4-(4-chlorophenylcarbamoylethylidene) thiazole hydrobromide (M.P. 112°-16°; prepared from 4-bromo-4'-chloro-2-methylacetoacetanilide and thiourea in ethanol), 30 ml of pyridine and 1.1 g (0.018 mole) of methyl isocyanate. The solution was allowed to stir overnight at ambient temperature. On the following morning, the pyridine solution was poured into water. The water was decanted from the residual oil. With stirring, the addition of fresh water caused the residue to solidify. The solid was dissolved in hot ethanol. The crystalline material in the cooled mixture was collected on a vacuum filter. There was obtained 1.4 g (38%) of white solid, M.P. 203°-205°. N.M.R. (dimethyl-d6 sulfoxide, CDCl3) ∂1.3-1.6 (CH3, doublet), 2.5-2.8 (NCH3, doublet), 3.5-3.8 (CH), 6.5 (hetero-aromatic), 7.1-7.7 (aromatic), 9.9 and 10.4 [NHC(O)NH].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[I-].[Na+]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)CN
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CNc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 44.4 %

Procedure:
57.6 g (0.3 mol) of 2,5-dichloronitrobenzene, 26.2 g (0.3 mol) of 2,2-dimethylpropylamine, 82.9 g (0.6 mol) of potassium carbonate and 0.5 g of sodium iodide in 400 ml of dimethylformamide were heated at 80° C. for 10 h. The mixture was then added to a large amount of water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: petroleum ether/toluene=16/1) to yield 32.3 g (50%) of the product. Melting point 78° C.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](OC)=[O:11])[CH:5]=1.CC(C[AlH]CC(C)C)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][OH:11])[CH:5]=1
Reactant: COC(=O)c1cc(OC(F)F)ccn1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1cc(OC(F)F)ccn1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of methyl 4-(difluoromethoxy)picolinate (600 mg; 2.95 mmol) in anh. toluene (12 ml) was treated dropwise with a solution of 1 M DIBAH in toluene (8.90 ml; 8.90 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 5 min., and then at 0° C. for 3 h. The obtained mixture was treated successively with water (50 ml), 1 M aq. NaOH (10 ml), and aq. sat. NaHCO3 (100 ml). The separated aq. layer was further extracted with Et2O (2×100 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded (4-(difluoromethoxy)pyridin-2-yl)methanol as a yellow solid. LC-MS (conditions A): tR=0.20 min.; [M+H]+: 176.17 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][N:3]=1.Cl[C:18]1[C:25]([CH3:26])=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][N:19]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+].C(OC(C)C)(=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:1][C:2]1[CH:7]=[C:6]([C:18]2[C:25]([CH3:26])=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][N:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C=O)cnc1Cl
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)OC(C)C
Solvent: O
Product: Cc1cc(-c2ncc(C=O)cc2C)ccn1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a 5-L four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (34b, 1120 mmol), 6-chloro-5-methylnicotinaldehyde (34c, 174.3 g, 1120 mmol), Pd(dppf)Cl2.CH2Cl2 (4.57 g, 5.6 mmol), K2CO3 (309.6 g, 2240 mmol), and iso-propyl acetate (1120 mL)/water (1120 mL). The mixture was stirred at 75° C. for 4 h, and cooled to 30° C. The organic layer was separated, washed with 10% NaCl (1120 g), and treated with activated charcoal (50 g) at 50° C. for 2 h before cooling to rt and filtered through Celite. Concentration of the filtrate to almost dryness afforded the crude 2′,3-dimethyl-[2,4′-bipyridine]-5-carbaldehyde (34d) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1OC1C.CCOCC>C(COC)OC>[Cl:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]1[N:3]2[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=1
Reactant: Nc1ccc2c(Cl)cccc2n1
Reactant: CCOC(=O)C(=O)CBr
Agent: CC1CO1
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(ccc3c(Cl)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
140 mg of 2-amino-5-chloroquinoline were dissolved in 2.5 ml of dimethoxyethane and then a mixture of 170 mg of ethyl bromopyruvate and 30 mg of propylene oxide was added. The mixture was stirred at room temperature for 2 hours and 2 ml of ether were added. Then, the mixture was cooled in ice and the precipitated quaternary salt was filtered off, was dissolved in 5 ml of ethanol and the solution was heated at reflux for 2 hours. Then, the solvent was removed under vacuum and the residue was partitioned between sodium bicarbonate solution and chloroform. The chloroform solution was dried over magnesium sulfate and was evaporated to dryness. The residue was chromatographed over silica with chloroform as eluent and the purified product was recrystallized from ethyl acetate/petroleum ether to obtain colorless needles of ethyl 6-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 193°-194° C.