Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH2:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([NH:16][CH2:1][CH:3]2[O:5][CH2:4]2)([CH3:14])[CH3:15])=[CH:11][CH:12]=1
Reactant: ClCC1CO1
Reactant: CC(C)(N)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NCC1CO1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Epichlorohydrin (8.05 ml) was added dropwise to a solution of 1-(4-chlorophenyl)-1-methylethylamine (17.38 g) in methanol (17.5 ml) at 0° C. with stirring. The solution was warmed to ambient temperature and stirred for 48 hours. Sodium hydroxide solution (50%) (17.5 ml) was added and the mixture stirred for 15 minutes. The product was extracted with ether to give an oil which was purified by flash column chromatography on silica using petroleum ether, b.p. 40°-60° C./ethyl acetate/triethylamine (8:2:1) as the mobile phase with gradually increasing amounts of ethyl acetate to give N-[1-(4-chlorophenyl)-1-methylethyl]-2,3-epoxypropylamine as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1.C([N:19](CC)CC)C.S(Cl)(Cl)=O>O1CCCC1>[O:1]=[C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]c1=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(-c2ccccc2)n[nH]c1=O
Reaction time: 6 h

Procedure:
In an alternate procedure, a mixture of 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarboxylic acid (1.92 g), triethylamine (3.0 ml), and thionyl chloride (5.0 ml) in tetrahydrofuran is allowed to stir at 20°-25° C. for 6 hours. The mixture is concentrated on the rotary evaporator and the residue is treated with 50 ml of cold ammonium hydroxide solution. The solid product is collected and recrystallized from acetic acid to give 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarboxamide.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][N:16]=[CH:15][C:14]=2[C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][N:16]=[CH:15][C:14]=2[C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9]
Reactant: C=COCCONC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a suspension of 4-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide (258 mg, 0.52 mmol) in methanol (10 mL) was added hydrochloric acid (1.0 mL, 1M solution, 1.0 mmol) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was separated and washed with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% ethyl acetate in cyclohexane) to give the title compound as a white solid (140 mg, 57%). LCMS (Method A): RT=9.72 min, [M+H]+=474. 1H NMR (CD3OD, 400 MHz) 8.57 (1H, s), 7.71 (1H, d, J=8.53 Hz), 7.69-7.61 (1H, m), 7.51 (1H, dd, J=10.43, 1.94 Hz), 7.33 (1H, d, J=8.54 Hz), 6.67 (1H, t, J=8.63 Hz), 3.92 (2H, t, J=4.60 Hz), 3.70 (2H, t, J=4.60 Hz).
Reaction SMILES: [CH:1]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[S:15]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:1]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1)(=[O:17])(=[O:16])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC1Cc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCC1Cc2ccccc21
Yield: 96 %

Procedure:
4-(benzocyclobutan-1-yl)-butyl mesylate was prepared, in a yield of 96%, by treating 4-(benzocyclobutan-1-yl)butanol (oil) with CH3SO2Cl in the presence of triethylamine in methylene chloride.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:7]=[C:8]2[N:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]2[C:26]=1[CH2:27]O>C(Cl)Cl>[Cl:3][CH2:27][C:26]1[N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[N:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]2=[N:7][C:6]=1[CH3:5]
Reactant: Cc1cc(C)c(-n2c3ncccc3n3c(CO)c(C)nc23)c(C)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C)c(-n2c3ncccc3n3c(CCl)c(C)nc23)c(C)c1
Reaction time: 2 h

Procedure:
Thionyl chloride (0.164 mL, 2.25 mmol) was added at 0° C. to a solution of [2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-yl]-methanol (0.36 g, 1.12 mmol) in CH2Cl2 (10 mL). After 2 h, solvents was removed and the title compound was obtained as a brownish oil (100% yield). Mass spec.: 335.24 (M−Cl+OMe+H)+.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([S:27]([NH:30][CH2:31][CH2:32][OH:33])(=[O:29])=[O:28])[CH:24]=[N:25][CH:26]=1>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([S:27]([NH:30][CH2:31][CH2:32][OH:33])(=[O:29])=[O:28])[CH:22]=2)[CH:11]=1)#[N:16]
Reactant: O=S(=O)(NCCO)c1cncc(Br)c1
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: N#Cc1ccc(OCC(=O)O)c(C#Cc2cncc(S(=O)(=O)NCCO)c2)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 5-bromo-N-(2-hydroxyethyl)pyridine-3-sulfonamide (Intermediate 31), the title compound was obtained as a yellow solid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH:5]([C:7]1[N:8]=[C:9]([NH:12][C:13]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:22]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])=[CH:23][CH:24]=2)=[O:14])[NH:10][CH:11]=1)=O>C(Cl)Cl.CO>[CH3:2][N:3]([CH2:5][C:7]1[N:8]=[C:9]([NH:12][C:13]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:22]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])=[CH:23][CH:24]=2)=[O:14])[NH:10][CH:11]=1)[CH3:4]
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1F
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedure described in Example 180 but using dimethylamine hydrochloride (1.5 equiv) instead of N,N,N′-trimethylethylenediamine and 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-formyl-1H-imidazol-2-yl)-amide (Example 7). Title compound: ES-MS: 469 [M+H]+; tR=3.14 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[C:17]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1cc(C(=O)O)ccc1C
Temperature: 70 °C
Yield: 30 %

Procedure:
A solution of 3-hydroxy-4-methylbenzoic acid (3.0 g, 19.7 mmol) in acetic anhydride (5.6 mL) was treated with sulfuric acid (0.03 mL), heated to 70° C., cooled and diluted with water. The resulting solid was collected by filtration yielding 1.14 g (30%) of the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH2:26][CH3:27])[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[CH2:26]([N:17]1[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:11])=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:27]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: CCn1c2ccccc2c2cc(NC(=O)c3cc(Cl)ccc3O)ccc21
Yield: 64.6 %

Procedure:
Using 5-chlorosalicylic acid and 3-amino-9-ethylcarbazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:26])[N:15]([CH3:25])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2n(C)c1=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2cc(F)ccc21
Yield: 86.2 %

Procedure:
Cyclohexylamine (1.98 mL, 17.34 mmol) was added to a solution of Compound 41 (2.3 g, 8.67 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 2.38 g (97%) of white solids. M.P. 193° C. 1H NMR (DMSO-d6): δ 1.28 (m, 1H), 1.36 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.87 (m, 2H), 3.62 (s, 3H), 3.90 (m, 1H), 7.70 (m, 3H), 7.77 (d, J=8.0 Hz, 1H), 10.41 (s, 1H). EIMS m/z 341 (M+23).
Reaction SMILES: I[C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][C:9]([CH:14]=[O:15])=[CH:10][CH:11]=3)[C:4]=2[NH:5][N:6]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)(O)[O-].[Na+]>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>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[C:3]3[CH2:13][C:12]4[C:7](=[CH:8][C:9]([CH:14]=[O:15])=[CH:10][CH:11]=4)[C:4]=3[NH:5][N:6]=2)=[CH:17]1
Reactant: O=Cc1ccc2c(c1)-c1[nH]nc(I)c1C2
Reactant: OB(O)c1ccsc1
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: O
Solvent: COCCOC
Product: O=Cc1ccc2c(c1)-c1[nH]nc(-c3ccsc3)c1C2
Yield: 30 %

Procedure:
A mixture of Example 319 (930 mg, 3.0 mmol), 3-thienylboronic acid (384 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) and sodium bicarbonate (630 mg, 7.5 mmol) in 1,2-dimethoxyethane (18 mL) and water (6 mL) was stirred under nitrogen in a heavy walled process vial in a microwave synthesizer at about 160° C. for about 10 minutes. The mixture was concentrated under vacuum and the residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (3:1) as eluent to provide 240 mg (30%) of the desired product. MS (ESI): m/z 267 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[Cl:9])/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: Clc1cccc(I)c1Cl
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cccc(Cl)c3Cl)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1,2-dichloro-3-iodobenzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.00 (s, 1H), 7.92 (d, 1H), 7.33-7.54 (m, 9H), 7.23 (dd, 1H), 7.10 (t, 1H), 6.74 (t, 1H), 6.66 (d, 1H), 6.55 (d, 1H), 4.95 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:25]([O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1)[CH3:26].Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:14](=[CH:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:15]([NH:36][CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:37])=[CH:34][CH:33]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ccc(CN)cc1
Reactant: COc1cc(C=C(C(=O)O)c2ccc(F)cc2)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CNC(=O)C(=Cc2cc(OC)c(OC)c(OC)c2)c2ccc(F)cc2)cc1
Yield: 50 %

Procedure:
To a solution of 3-(3,4,5-trimethoxyphenyl)-2-(4-fluorophenyl)acrylic acid (0.6 g, 18 mmol) in DMF (5 mL) was added ethyl-4-aminomethylbenzoate.HCl (0.375 g, 21.6 mmol), EDCI (0.69 g, 36 mmol) and HOBt (0.24 g, 18 mmol). TEA (0.75 mL, 36 mmol) was added dropwise with constant stirring to the above reaction mixture and stirred overnight at room temperature. Subsequently the reaction mixture was evaporated to dryness, the residue was dissolved in ethyl acetate and washed successively with 1N HCl (3×50 mL), saturated NaHCO3 (3×50 mL) and brine solution (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the pure compound (0.4 g, 50% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][C:6]=1[CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:18]
Reactant: Cc1csc2ccccc12
Reactant: O=Cc1ccccc1
Product: Cc1c(C(O)c2ccccc2)sc2ccccc12

Procedure:
Using general procedure B, 3-methyl-benzo[b]thiophene was reacted with benzaldehyde to give (3-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol as a pale yellow solid. MS: 236.8 ([M+H—H2O]+).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=1)[C:12]([OH:14])=O.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[O:14]=[C:12]1[C:11]2[C:10](=[CH:9][C:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:20])=[CH:16][CH:15]=2)[C:17](=[O:19])[N:21]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: Cc1ccccc1Oc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: NCC(=O)O
Product: Cc1ccccc1Oc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Temperature: 230 °C

Procedure:
A mixture of 4-(o-tolyloxy)phthalic acid (9.5 g, 35.0 mmol) and glycine (2.6 g, 35.0 mmol) was ground thoroughly in a mortar. The powder was then transferred to a flask and heated to 220-240° C. under high vacuum for 30 minutes. The reaction crude was cooled to room temperature to give the title compound in 10.2 g. 1H NMR (DMSO, 200 MHz): δ=7.89 (d, 1H, J=8.0 Hz), 7.42-7.08 (m, 6H), 4.27 (s, 2H), 2.14 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.[NH:20]1[CH2:24][CH2:23][C@@H:22]([CH2:25][OH:26])[CH2:21]1.C(=O)([O-])O.[Na+]>C(O)CCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([N:20]3[CH2:24][CH2:23][C@@H:22]([CH2:25][OH:26])[CH2:21]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: Clc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Reactant: OC[C@@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: OC[C@@H]1CCN(c2ccc3ncc(-c4cc5ccccc5o4)n3n2)C1

Procedure:
150 mg (0.56 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine, 135 mg (1.34 mmol) (3R)-pyrrolidin-3-ylmethanol and 112.1 mg (1.34 mmol) sodium hydrogencarbonate in 4.0 mL butan-1-ol were stirred 72 h at 150° C. The solvent was removed. The residue was purified by HPLC to yield 92 mg (48%).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:17]=2[N:18]=1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Reactant: NCc1ccc2c(c1)OCO2
Product: Clc1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine Mp. 222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[ClH:9].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[Cl-].[Zn+2:16].[Cl-]>C(O)CCC>[ClH:1].[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:12]([CH3:13])[CH:11]=[CH:10]2.[Cl-:9].[Zn+2:16].[Cl-:1]
Reactant: C/C=C/C=O
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCO
Product: Cc1ccc2cc(Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
(Method A) 4-Chloroaniline (2.55 g, 20 mmol), concentrated hydrochloric acid (5 cm3), tetrachloro-1-4-benzoquinone (5.9 g, 20 mmol), and n-butanol (5 cm3) were mixed and heated to reflux giving a yellow suspension. Crotonaldehyde (1.68 g, 24 mmol) in butanol (2 cm3) was added over 1 hr giving a dark brown solution. After a further 30 mins reflux, zinc chloride (0.5M in THF, 40 cm3, 20 mmol) was added in three portions and reflux continued for 20 mins before cooling slowly to 0° C. and standing for 1 hr. The dark solid was filtered off, washed with ether, IPA and THF before drying in vacuo to give 6-chloro-2-methylquinoline hydrochloride/zinc chloride salt (3 g, 10.6 mmol, 62%). See, for example, Song et al., 1993.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:21])[NH:12][C:13]2[S:14][CH:15]=[C:16]([S:18]([CH3:20])=[O:19])[N:17]=2)=[CH:7][CH:6]=1)(=O)C.[C:22]([O:25]C1C=CC=C(C(=O)NC2SC=C(SC)N=2)C=1)(=[O:24])[CH3:23]>>[C:22]([O:25][C:6]1[CH:5]=[CH:10][CH:9]=[C:8]([C:11](=[O:21])[NH:12][C:13]2[S:14][CH:15]=[C:16]([S:18]([CH3:20])=[O:19])[N:17]=2)[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CSc1csc(NC(=O)c2cccc(OC(C)=O)c2)n1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2nc(S(C)=O)cs2)cc1
Product: CC(=O)Oc1cccc(C(=O)Nc2nc(S(C)=O)cs2)c1

Procedure:
Using the above procedure for compound (3), 513 (0.61 g, 2.0 mmol) gives crude 5 as a white solid. The crude product is stirred in diethyl ether (30 mL) for 30 minutes, filtered and air dried to give 5 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[NH:6][C:5]2([C:17]#[C:18][CH:19]1[CH2:21][CH2:20]1)[C:13]([F:16])([F:15])[F:14].C([O-])([O-])=O.[Na+].[Na+].NC(N)=[S:30]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:30])[NH:6][C:5]2([C:17]#[C:18][CH:19]1[CH2:21][CH2:20]1)[C:13]([F:16])([F:15])[F:14]
Reactant: NC(N)=S
Reactant: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)C1(C#CC2CC2)NC(=S)Nc2ccc(Cl)cc21
Temperature: 95 °C
Yield: 39 %

Procedure:
A solution of (+/-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (0.33 g, 1.0 mmol) in phosphorous oxychloride (5 mL) containing Na2CO3 (160 mg, 1.5 mmol) was heated at 95° C. overnight. After cooling to room temperature, the phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in ethanol (5 mL) and thiourea (0.35 g, 4.6 mmol) was added. The resulting mixture was heated at reflux for 24 hours, cooled to room temperature and concentrated. The material was dissolved in EtOAc (75 mL) and washed sequentially with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL). The organic extract was dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (25% EtOAc/hexanes) to afford the title compound as a white solid (129 mg, 37%): mp 259-260; 1H NMR (300 MHz, acetone-d6) δ 10.3 (br s, 1H), 8.95 (br s, 1H), 7.56 (d, J=1.1 Hz, 1H), 7.48 (dd, J=8.4, 2.6 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 1.49-1.44 (m, 1H), 0.93-0.85 (m, 2H), 0.80-0.76 (m, 2H); 19F NMR (282 MHz, acetone-d6) δ -82; MS (CI) calc'd for C14H10ClF3N2S: m/z 330.020533, found 330.019821; 331 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CCCCCC>[Cl:1][CH2:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: CC[SiH](CC)CC
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(CCCl)ccc2N1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
5-Chloroacetyl-2-oxindole (7.0 g) was added to 25 mL of trifluoroacetic acid and the mixture cooled in an ice bath with stirring. Triethylsilane (12.3 mL) was added dropwise over 2 minutes. The reaction was then stirred at room temperature for 4 hours and poured into ice water. Hexane was added, the mixture stirred vigorously, and the solid collected by vacuum siltation and washed with hexane to give 5.9 g (91% yield) of the product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C[Si]([N:47]=[N+:48]=[N-:49])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:35]1([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]3[NH:49][N:48]=[N:47][N:2]=3)=[CH:42][CH:41]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCc2ccccc2)Cc2ccc(C#N)cc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCc2ccccc2)Cc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 295 mg (0.53 mmol) of methyl 4-((4E)-3-(4-cyanobenzyl)-5-{2-[(5-phenylpentyl)oxy]phenyl}pent-4-en-1-yl)benzoate in 20 ml of toluene is mixed with 1.05 ml (7.93 mmol) of trimethylsilyl azide and 198 mg (0.79 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: dichloromethane→dichloromethane/methanol 10:1). 284 mg (0.47 mmol, 89% of theory) of a white foam are obtained.