Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.C1COCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Nc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 2-amino-5-nitropyridine (4.17 g, 30 mmol) in pyridine (30 mL) is stirred at rt and a solution of phenylacetyl chloride (4.64 g, 30 mmol) in THF (30 mL) is added dropwise. The mixture is stirred for 24 h and then poured into ice-water (250 mL) to afford a brown solid, which is used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:12]=1[CH2:25][C:26](Cl)=[N:27][OH:28].C(N(CC)CC)C>O1CCCC1>[F:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:12]=1[CH2:25][C:26]1[CH:2]=[C:1]([C:3]2[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=2)[O:28][N:27]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1F
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2F)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of the 3-ethynyl-pyridin-2-ylamine (38.4 mg, 0.325 mmol) described in Manufacturing Example 1-2-3 and (2-fluoro-4-(pyridin-2-yloxymethyl)-phenyl)acetohydroximoyl chloride (150 mg, 0.509 mmol) described in Manufacturing Example 204-1-8 was added triethylamine (97.2 μL, 0.697 mmol), which was stirred for 2 hours at 60° C. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2, then 1:1) to obtain the title compound (46 mg, 24%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[S:3][CH2:4][C:5](=[N:7][OH:8])[CH3:6].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.ClCCl>[CH3:11][NH:12][C:13]([O:8][N:7]=[C:5]([CH3:6])[CH2:4][S:3][C:2]([F:10])([F:9])[F:1])=[O:14]
Reactant: CN=C=O
Reactant: CC(CSC(F)(F)F)=NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)ON=C(C)CSC(F)(F)F

Procedure:
A mixture of 1-trifluoromethylthio-2-propanone oxime (0.02 mole) from Step 2, methyl isocyanate (0.22 mole) and 2 drops of triethylamine in 25 ml of dichloromethane was heated at its reflux temperature overnight. The solvent was removed by evaporation under vacuum. The residual oil was recrystallized from a mixture of petroleum ether and diethyl ether to give a pure sample of 1-trifluoromethylthio-2-propanone O-methylcarbamoyl oxime, m.p. 56°-58°C. The structure of the product was confirmed by elemental and spectral analyses.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH:3]12[O:25][CH:4]1[CH2:5][CH:1]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC1CC=CC1)OCc1ccccc1
Solvent: ClCCl
Product: O=C(NC1CC2OC2C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 152 %

Procedure:
To a solution of benzyl cyclopent-3-en-1-ylcarbamate (920 mg, 4.23 mmol) in DCM (20 mL), was added m-CPBA (2.0 g, 7.6 mmol) in portions at 0° C. The mixture was warmed up to RT and stirred at RT for 2 hours. The reaction was quenched by addition of sat. aqueous solution of K2CO3, and the resulting mixture was extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, and then concentrated in vacuo to afford the crude benzyl 6-oxabicyclo[3.1.0]hex-3-ylcarbamate (1.5 g), which was used in the next step directly.
Reaction SMILES: [CH:1]([O:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].S(O)(O)(=O)=O.Cl[C:24]1[NH:25][CH2:26][CH2:27][N:28]=1>ClCCl>[CH:1]([O:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:24]3[NH:28][CH2:27][CH2:26][N:25]=3)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Cc2ccc(N)cc2)s1
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(Cc2ccc(NC3=NCCN3)cc2)s1
Temperature: 80 °C
Yield: 89.7 %

Procedure:
To a solution of 4-(5-isopropoxythien-2-ylmethyl)-phenylamine (131 mg, 0.53 mmol) in aceonitrile (8 ml) was added 2-chloro-2-imidazoline sulfate (121 mg, 0.59 mmol) at 20-25° C. under argon. The mixture was heated at 80° C. for 1.5 hours. The mixture was diluted with dichloromethane and washed with sodium hydroxide, water, dried (Na2SO4) and concentrated to dryness. Purification by preparative TLC, eluting with ethyl acetate/methyl alcohol/isopropylamine, gave 2-[4-(5-isopropoxythien-2-ylmethyl)phenyl]amino-imidazoline (150 mg, 90%) as a thick yellow oil; 1H NMR (300 Mhz, CDCl3δ 7.13 (d,J=8.4 Hz, 2H) 6.93 (d,J=8.4 Hz, 2H), 6.37 (dt, J=3.7, 1.0 Hz, 1H), 6.02 (d, J=3.7 Hz, 1H), 4.28 (quintet, J=6.2 Hz, 1H), 3.93 (bs, 2H), 3.52 (5, 4H), 3.24-3.5 (broad, 2H), 1.32 (d, J=6.2 Hz, 6H). MS m/e (%):316 (M+1, 100%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.ClCl>ClC1C=CC=CC=1>[Cl:1][C:7]1[CH:8]=[C:3]([NH2:2])[C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: Cc1ccccc1N
Reactant: Cl
Agent: ClCl
Solvent: Clc1ccccc1
Product: Cc1ccc(Cl)cc1N

Procedure:
57 g of hydrogen chloride (= 1.56 mols) were introduced, while thoroughly stirring, into a solution of 160 g of distilled o-toluidine (= 1.5 mols) in 1300 ml of chlorobenzene in the course of 30 - 45 minutes. It is advisable but not necessary to cool the reaction mixture slightly in a water bath. 105 g of chlorine gas (= 1.48 mols) were introduced at 35°C within 13/4 hours. Then, the hydrogen chloride still in solution was blown out with air. The hydrochloride was suction-filtered through a Buchner funnel and dried in the air. To isolate the free 5-chloro-2-toluidine the dried filter residue was introduced portionwise into 350 g of sodium hydroxide solution (18%). The temperature rose to about 40° - about 50°C. Then, the crude amine was separated in a separating funnel and subjected to a fractionated distillation under reduced pressure. The amount of product obtained was 60.1 g of 2-toluidine (= 0.56 mol), which was reused, 101.0 g of 5-chloro-2-toluidine (= 0.71 mol) corresponding to 75.5 % calculated on reacted 2-toluidine (introduced 2-toluidine minus 2-toluidine recovered) and 14.3 g of 3.5-dichlorotoluidine (= 0.08 mol).
Reaction SMILES: [CH3:1][C:2]#[N:3].[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:5].[NH4+].[Cl-]>C1COCC1>[OH:6][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[CH2:1][C:2]#[N:3]
Reactant: CC#N
Reactant: CC(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(CC#N)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Dry THF was cooled to −20° C. and 2.5 M n-Bull (100 mL, 0.25 mol) was added. A solution of CH3CN (11.25 g, 0.25 mol) in dry THF was added dropwise over 10 min. Then the mixture was stirred for 1 h at −20° C. and a solution of acetophenone (30 g, 0.25 mol) in THF was added dropwise over 10 min. The mixture was stirred at −20° C. for 15 min and warmed to rt over 15 min. Aq NH4Cl was added to quench the reaction. The solution was extract with EtOAc. The organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3-hydroxy-3-phenylbutanenitrile (30 g, yield 75%). 1H NMR (CDCl3, 400 MHZ): δ=1.76 (s, 3H), 2.83 (s, 2H), 7.34 (m, 1H), 7.41 (m, 2H), 7.5 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][CH2:26][Cl:27])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCCl
Temperature: 40 °C
Yield: 54.7 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (957 mg, 3 mmol), (prepared as described for the starting material in Example 2), 1-bromo-3-chloropropane (2.36 g, 15 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (20 ml) was heated at 40° C. for 1.5 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×50 ml). The organic extracts were combined, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with hexane/ethyl acetate, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(3-chloropropoxy)-6-methoxyquinazoline (650 mg, 55%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([OH:14])(=[O:13])[CH3:12].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:14][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)COC(C)=O

Procedure:
71 ml of ethyl 4-chloro-3-oxobutyrate are reacted with 57 ml of acetic acid and 132 ml of triethylamine in 1 l of dimethylformamide by the procedure described in Example 1.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32]3)(=[O:30])=[O:29])=[CH:27][C:13]=2[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C>[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([C:36]([OH:1])=[O:37])=[CH:32]3)(=[O:30])=[O:29])=[CH:27][C:13]=2[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCC(F)CC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone® (0.36 g, 0.53 mmol) was added to a solution of 1-({2-tert-butyl-1-[(4fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-1H-pyrrole-3-carbaldehyde (0.23 g, 0.53 mmol) in DMF (15 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was recovered in DCM, washed with 10% HCl solution, brine and dried over anhydrous Na2SO4. The solvent was concentrated to provide the pure title compound as white solid. Yield: 0.26 g (99%). MS (ESI) (M+H)+=462.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][S:8]2(=[O:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:38][CH2:39][CH:40]1[O:45][CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH:42]1[CH2:43][CH2:44][O:45][CH:40]([CH2:39][CH2:38][N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8]2(=[O:16])=[O:17])[CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CCO)C1
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(CCC2CNCCO2)c2ccccc2N1c1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.2 g, 0.8 mmol) in THF (10 mL) was added triphenylphosphine (0.26 g, 1 mmol), tert-butyl 2-(2-hydroxyethyl)morpholine-4-carboxylate (0.2 g, 0.9 mmol) and DIAD (0.2 g, 1 mmol) at 0° C. The mixture was allowed to warm to ambient temperature overnight then concentrated and chromatographed on silica gel (0 to 40% EtOAC in hexane). The resulting mostly pure carbamate was dissolved in dichloromethane (10 mL) and treated with HCL (4 mL, 4M in dioxane). The resulting salt was chromatographed on silica (0 to 100% of (7N NH3/MeOH) in dichloromethane) giving the desired product as a clear oil (0.23 g, 80%). HRMS: calcd for C18H21N3O3S+H+, 360.1376; found (ESI, [M+H]+), 360.1377.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[Cl-]>CCOCC>[OH:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.0 g, 0.0054 mol) in ether (20.000 mL, 0.19050 mol) was added dropwise a solution of phenylmagnesium bromide (1.12 g, 0.00621 mol) in ether (10.3 mL) at rt under N2. After the addition was complete, the reaction mixture was heated to reflux for 15 min. and then cooled to rt. The reaction mixture was poured into saturated NH4Cl and extracted with ether (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The product was purified by Combiflash eluting with 0-40% EtOAc-hexanes. The product was confirmed by 1H NMR and LC/MS: m/z 286.0 (M+Na)+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][OH:14])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(C=NO)cc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of 4-(dimethylamino)benzaldehyde (5.0 g), hydroxylamine hydrochloride (2.3 g), and sodium acetate (2.7 g) in ethanol (61 mL)/water (11 mL) is heated at reflux temperature for 1 hour. The mixture is cooled to ambient temperature and partitioned between diethyl ether and water. The aqueous layer is back-extracted with diethyl ether and the combined organic extracts are washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.6 g pure white solid as the product. MS: m/z 165 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:8].O>C(O)(=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([N+:1]([O-:4])=[O:2])[CH:16]=2)=[CH:11][CH:10]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Concentrated nitric acid (1.8 ml) was carefully added to a cooled suspension (5-10° C.) of phenol 27 (2.0 mg, 8.8 mmol) in 60 ml of glacial acetic acid. The reaction mixture was stirred for one hour and was then allowed to warm to room temperature and stirred for an additional 30 minutes. Water was added (50 ml) and the reaction mixture was cooled, filtered, and washed with water to yield a yellow powder. The crude product was purified via flash chromatography through a small pad of silica gel with elutions of 80/20 and 50/50 (Hex/EtOAc), respectively. Evaporation of the solvent yielded 2.23 g (93%) of a bright yellow solid.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[C:20]([Cl:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][CH2:35][C:36]#[CH:37])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([Cl:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[N:8]2[CH2:37][CH2:36][CH2:35][C:34]#[CH:33])=[C:4]([NH2:22])[N:3]=1
Reactant: Nc1nc(F)nc2nc(Cc3cc4c(cc3Cl)OCO4)[nH]c12
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc3c(cc2Cl)OCO3)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-Fluoro-8-(6-chloro-benzo[1,3]dioxol-5-ylmethyl)adenine (11 mg, 0.034 mmol), Cs2CO3 (11 mg, 0.034 mmol) and pent-4-ynyl tosylate (10.5 mg, 0.044 mmol) in anhydrous DMF (85 L) was stirred at 50° C. for 1 h. Following solvent removal, the product (4.2 mg, 31.9%) was collected through silica gel column purification (EtOAc:hexanes:CHCl3:i-PrOH at 10:20:20:1). 1H NMR (400 MHz, CDCl3) 6.89 (s, 1H), 6.61 (s, 1H), 5.98 (bs, 2H), 5.96 (s, 2H), 4.27 (s, 2H), 4.13 (t, J=7.5 Hz, 2H), 2.24-2.10 (m, 2H), 2.00-1.91 (m, 3H); 13C NMR (100 MHz, CDCl3) 1597, 158.0, 156.3, 150.6, 147.7, 147.2, 126.2, 125.3, 110.0, 102.0, 82.3, 69.9, 42.2, 31.4, 28.1, 15.8; MS m/z 388.1 (M+H)+. HPLC: (a) 98.1% (65% water-35% acetonitrile); (b) 97.0% (35% to 45% acetonitrile).
Reaction SMILES: Br[C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[S:7][C:8]2[C:14]3[CH:15]=[N:16][NH:17][C:13]=3[CH:12]=[C:11]([C:18]([F:21])([F:20])[F:19])[C:9]=2[N:10]=1)=[O:4].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:41])=[C:29]([CH:40]=1)[C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31].O>C(O)CO>[Cl:41][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:2]([CH3:23])([C:3](=[O:4])[NH:5][C:6]2[S:7][C:8]3[C:14]4[CH:15]=[N:16][NH:17][C:13]=4[CH:12]=[C:11]([C:18]([F:21])([F:20])[F:19])[C:9]=3[N:10]=2)[CH3:22])=[CH:40][C:29]=1[C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31]
Reactant: CC(C)(Br)C(=O)Nc1nc2c(C(F)(F)F)cc3[nH]ncc3c2s1
Reactant: CCOC(=O)CCNC(=O)c1cc(N)ccc1Cl
Solvent: O
Solvent: OCCO
Product: CCOC(=O)CCNC(=O)c1cc(NC(C)(C)C(=O)Nc2nc3c(C(F)(F)F)cc4[nH]ncc4c3s2)ccc1Cl
Temperature: 25 °C
Yield: 13.4 %

Procedure:
0.1 g (0.25 mmol) of 2-bromo-2-methyl-N-(4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-yl)-propionamide and 0.23 g (0.85 mmol) of ethyl 3-(5-amino-2-chlorobenzoylamino)-propionate were heated at 100° C. in 4 ml of ethylene glycol. After the completion of the reaction was confirmed by HPLC, the mixture was cooled to room temperature, and 4 ml of water was added to the mixture. The mixture was extracted with 4 ml of ethyl acetate twice, dried over 3 g of anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 20 mg of ethyl 3-{2-chloro-5-[1-methyl-1-(4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylcarbamoyl)-ethylamino]-benzoylamino}-propionate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([OH:28])=[O:27].C(N(CC)CC)C>CC(C)=O>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([OH:28])=[O:27]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccc(O)c(C(=O)O)c2)cc1

Procedure:
is prepared by dissolving 10.4 grams (0.05 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile and 14 g (0.05 mol + 15% excess) of 4-hydroxy-3-carboxybenzenesulfonyl chloride in 200 ml acetone, cooling in an ice bath and slowly adding thereto 8 ml (0.055 mol) of triethylamine diluted with 25 ml acetone. After filtration and evaporation of the acetone the remaining semi-solid is dissolved in dimethylformamide, dispersed in water and the emulsion extracted with chloroform. After work-up the above sulfonamide is recovered.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:18]([C:8]2[CH:9]=[CH:10][C:5]([O:11][CH3:12])=[CH:6][CH:7]=2)=[O:19])[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
Aluminum chloride (2.20 g, 16.5 mmol) was added to a stirred mixture of anisole (1.63 ml, 15.0 mmol) in anhydrous methylene chloride (20 ml) in an ice bath. Then a solution of 3,5-dimethoxybenzoyl chloride (3.01 g, 15.0 mmol) in anhydrous methylene chloride (10 ml) was added. The mixture was allowed to warm up to rt, then refluxed overnight. After cooling down to rt, the mixture was poured to ice water (50 ml), stirred for 20 min., and extracted with methylene chloride (3-x 50 ml). The combined organic extracts were washed with sat. NaHCO3 (3×50 ml), H2O (2×50 ml), brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (10% EtOAc in hexane) to give (3,5-dimethoxy-phenyl)-(4-methoxy-phenyl)-methanone as a yellow solid (3.11 g, 76%): mp, 90-92° C.; 1HNMR (CDCl3) δ 7.85 (d, J=8.0 Hz, 2H, Ar), 6.96 (d, J=9.0 Hz, 2H, Ar), 6.88 (d, J=2.3 Hz, 2H, Ar), 6.65 (d, J=2.4 Hz, 1H, Ar), 3.89 (s, 3H, OCH3), 3.83 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[K].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>CN(C)C=O>[Cl:16][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:29][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(OC)cc2)cc1
Yield: 85 %

Procedure:
A solution of 510 mg of 4,6-dichloro-5-(p-methoxyphenyl)pyrimidine and 680 mg of p-methoxybenzenesulfonamide potassium in 3 ml of dimethylformamide was heated at 130° C. for 1 hour. After working-up the reaction mixture, there were obtained 690 mg of N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl]-p-methoxybenzenesulfonamide, melting point 165°-167° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6]([N:10]2[CH:14]=[C:13](I)[N:12]=[C:11]2[CH3:16])[CH:5]=[N:4]1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([C:24]#[C:25][Si](C)(C)C)[CH:21]=[CH:20][N:19]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]#[C:25][C:13]2[N:12]=[C:11]([CH3:16])[N:10]([C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:8](=[O:9])[CH:7]=3)[CH:14]=2)[CH:21]=[CH:20][N:19]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Reactant: CCn1ncc(-n2cc(I)nc2C)cc1=O
Product: CCn1ncc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1=O

Procedure:
The title compound, light yellow crystalline solid, MS: m/e=339.1, 340.6 (M+H+), was prepared in accordance with the general method of example 35 from 2-ethyl-5-(4-iodo-2-methyl-imidazol-1-yl)-2H-pyridazin-3-one and 2-chloro-4-trimethylsilanylethynyl-pyridine.