Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH2:24]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O1CCOCC1>CO.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]>[CH2:24]([O:31][C:32]1[CH:37]=[C:36]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3cccc(OCc4ccccc4)c3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 150 mmol), 3-Benzyloxyphenylboronic Acid (70 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 0.5 microliters of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 60-80% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (9.7 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 5.21 (s, 2H) 6.59 (d, J=2.27 Hz, 1H) 7.27-7.32 (m, 1H) 7.36 (d, J=7.33 Hz, 1H) 7.39-7.44 (m, 1H) 7.49-7.54 (m, 2H) 7.49-7.57 (m, 1H) 7.54-7.59 (m, 1H) 7.60-7.67 (m, 3H) 7.75-7.79 (m, 1H) 8.01-8.06 (m, 3H) 8.19 (d, J=2.27 Hz, 1H) 11.26 (s, 1H). ESI-MS: m/z 479.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[CH:25]=[C:24]([NH:26]CC5C=CC(OC)=CC=5)[N:23]=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[CH:25]=[C:24]([NH2:26])[N:23]=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(CNc2cc3c(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)ncnc3cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Nc1cc2c(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 97.3 %

Procedure:
To a stirred heterogeneous mixture of compound 211 (2.27 g, 4.48 mmol) and DCM (45 ml) was added trifluoroacetic acid (3.45 ml, 44.8 mmol), followed by anisole (0.99 ml, 8.96 mmol), and the mixture was stirred further at room temperature for 5 days. It was poured into petroleum ether (500 ml) and stirred at room temperature for ca. 20 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (300 ml). To the solid left behind was added 5M NH3 (80 ml) at 0° C. and stirred at room temperature for 15 min. The solid was collected and washed successively with water (6×10 ml), petroleum ether-ethyl acetate=3:1 (3×20 ml), and dried to give N4-(1-(3-fluorobenzyl)-1H-indazol-5-yl)pyrido[3,4-d]pyrimidine-4,6-diamine (220) (1.68 g, 97%), mp 241-244° C.; 1H NMR δ [(CD3)2SO] 9.72 (s, 1H), 8.67 (s, 1H), 8.30 (s, 8.27 (br s, 1H), 8.15 (s, 1H), 7.75-7.68 (m, 2H), 7.41-7.33 (m, 14, 7.18 (s, 1H), 7.14-7.01 (m, 3H), 6.20 (s, 2H), 5.69 (s, 2H). Anal. Calcd for C21H16FN7.1.5H2O: C, 61.16; H, 4.64; N, 23.77. Found C, 61.23; H, 4.71; N, 23.87.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.N1CCNCC1.[F:24][C:25]([F:29])=[C:26](F)F.C(=O)([O-])[O-:31].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:24][CH:25]([F:29])[C:26]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:31]
Reactant: O=C([O-])[O-]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: FC(F)=C(F)F
Agent: C1CNCCN1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 80 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 5.0 mmol) and piperazine (0.52 g, 6.0 mmol) in toluene (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow intothe flask (ca. 0.7 liter/hr), with vigorous stirring at 80° C. for 48 hours. After cooling to an ambient temperature, the reaction mixture was poured into saturated aqueous sodium carbonate solution, and extracted with toluene. The toluene layer was washed with water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 3.8 mmol, yield 77% ).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](SC)[S:4][N:3]=1.[CH:9]1C=C(Cl)C=C(C(OO)=O)C=1.[S:20]([O-:23])([O-])=[O:21].[Na+].[Na+].O>ClCCl>[Br:1][C:2]1[N:6]=[C:5]([S:20]([CH3:9])(=[O:23])=[O:21])[S:4][N:3]=1
Reactant: CSc1nc(Br)ns1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1nc(Br)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of 3-bromo-5-methylsulfanyl-[1,2,4]thiadiazole (0.8 g, 3.8 mmol) in dichloromethane (20 mL) was added dropwise mCPBA (1.97 g, 11.4 mmol) in DCM (10 mL) at 0° C. After addition, the resulting mixture was stirred at room temperature overnight. TLC (Petroleum ether:EtOAc 10:1) indicated the reaction was completed. The reaction mixture was added excess sodium sulfite and water (50 mL) to decompose the excess mCPBA. The mixture was separated and the separated organic layer was washed with brine (50 mL×3), dried over sodium sulfate and concentrated in vacuo to give residue, which was purified by a silica gel column to yield the title compound (0.58 g, 63.2%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]2[CH2:25][CH2:24][S:23][CH2:22]2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH:21]2[CH2:25][CH2:24][S:23][CH2:22]2)[C:33](=[O:35])[CH3:34])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCNC1CCSC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2cnc3ccccc3c2n1CCCCN(C(C)=O)C1CCSC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [4-(2-Ethyl-imidazo[4,5-c]quinolin-1-yl)-butyl]-(tetrahydro-thiophen-3-yl)-amine in dichloromethane was added triethyl amine (1.5 eq.) and acetic anhydride (1.5 eq.) and stirred at ambient temperature for 4 hrs. Reaction mixture was then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford N-[4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-(tetrahydro-3-thienyl) acetamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.Cl[C:41]([O:43][CH3:44])=[O:42]>ClCCl>[CH3:44][O:43][C:41]([N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1)=[O:42]
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a trifluoroacetic acid salt (57.1 mg, Example 59) in dichloromethane (2 mL) were added triethylamine (58 mg, 8 equiv, Aldrich) and methyl chloroformate (6.7 mg, 1 equiv, Aldrich) at 0° C. After stirring for ˜2 hours at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid methyl ester (23.7 mg). MS (M+H)+, 404.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:11][C:12]2[C:20]([N:21]=1)=[C:19]([CH3:22])[C:18]1[C:17](=[O:23])[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:15](=[O:31])[C:14]=1[CH:13]=2.[ClH:32]>O1CCOCC1>[ClH:32].[Cl:32][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:10]1[NH:11][C:12]2[C:20]([N:21]=1)=[C:19]([CH3:22])[C:18]1[C:17](=[O:23])[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:15](=[O:31])[C:14]=1[CH:13]=2.[ClH:32].[I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:10]1[NH:11][C:12]2[C:20]([N:21]=1)=[C:19]([CH3:22])[C:18]1[C:17](=[O:23])[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:15](=[O:31])[C:14]=1[CH:13]=2
Reactant: COc1nccc(I)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Product: Cc1c2c(cc3[nH]c(-c4c(I)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-Iodo-2-methoxy-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (1.48 g, 2.78 mmol) in 1,4-dioxane (30 mL) was added conc. HCl (3 mL) and the resulting solution was stirred at room temperature for overnight. The solid precipitated was isolated by filtration, washed with THF (10 mL) and dried in vacuo to afford 2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione Hydrochloride and 2-(4-Iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione Hydrochloride (1.5 g, quant.) as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:14].[Cl:15][NH:16][CH2:17][CH2:18][N:19]([C:21](=[O:23])[CH3:22])[Cl:20].[OH:24][CH:25]1O[C@@H](CO)[C@H](O)[C@H](O)[C@H:26]1O>C(#N)C>[Cl:15][NH:16][CH2:17][CH2:18][N:19]([C:21](=[O:23])[CH3:22])[Cl:20].[O:23]=[C:21]1[NH:19][CH2:18][CH2:17][NH:16][C:25](=[O:24])[CH2:26][NH:14][CH:9]2[CH:8]([CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:7][CH2:22]1
Reactant: OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)N(Cl)CCNCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1CNC2CCCCC2NCC(=O)NCCN1

Procedure:
Sodium carbonate (226 g., 2.13 mol.) and trans-1,2-diaminocyclohexane (14.1 ml., 117 mmol.) were added to a solution of N,N'-dichloroacetylethylenediamine (25 g., 117 mmol.) in dry acetonitrile (3.75 l.) under nitrogen. N,N'-dichloroacetylethylenediamine was prepared as reported by Lin W.C., Fiqueira, J. A. D and Alt, H. G. in "New multidentate potential inophors of ether-amide type", Monat. Chem., 1985, 116, 217-221. The reaction mixture was refluxed for 20 hours. The insoluble material formed was filtered off and the volume of the filtrate was reduced to 1 l. by evaporation. Crystals of the compound (A) slowly formed at room temperature. They were collected by filtration and the product was purified by crystallization in acetonitrile. The yield was 7.43 g. of a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18].CO>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:18]
Reactant: c1cc2cc[nH]c2cn1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1c(Cl)cccc1Cl)c1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
1H-Pyrrolo[2,3-c]pyridine (0.5 g, 4.2 mmol) was added to a stirred suspension of aluminium chloride (2.82 g, 21.1 mmol) in dry dichloromethane (100 mL) and the mixture was stirred at room temperature for 1 hour. This was followed by drop-wise addition of 2,6-dichloro benzoyl chloride (4.42 g, 21.1 mmol). The resulting reaction mixture was stirred at room temperature for 8 hours. Methanol (25 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The resulting residue was neutralized using aqueous sodium bicarbonate solution followed by partitioning with ethyl acetate (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography using ethyl acetate and hexane gradient as eluent afforded (2,6-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (0.5 g, 41.66%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][CH:39]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([O:25][C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:11]2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: O=C(CNc1noc2ccc(OC(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3noc4ccc(OC(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethoxy-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-oxo-cyclohexane carboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Cl)[N:11]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc(OCc3ccccc3)n2)cc1

Procedure:
Benzyl alcohol (5.1 g; 0.05 mols) was reacted with 2,6-dichloropyridine (3.5 g; 0.024 mols) utilizing sodium hydride (1.2 g) and, as solvent, dimethylformamide by the procedure of Example 1 above. Usual work up, chromatography and recrystallisation gave 2,6-dibenzyloxypyridine as a colorless solid (5.5 g; 81%). Melting point: 74° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].C(N(C(C)C)CC)(C)C.C(OC(O)C)C.C(=O)([O-])[O-].[K+].[K+]>O.CCCCCC>[Br:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][CH:28]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: NCc1cccc(Br)c1
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: O
Product: CCOc1cc2ncc(C#N)c(NCc3cccc(Br)c3)c2cc1OCC
Yield: 68.5 %

Procedure:
A stirred mixture of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile (0.69 g, 2.5 mmol), 3-bromobenzylamine (0.78 g, 3.5 mmol), diisopropylethyl amine (1.05 ml, 6.0 mmol), and 7.5 ml of ethoxyethanol was refluxed for 4 h, cooled, and stirred with a mixture of hexane and water containing 0.4 g of potassium carbonate for 3 h. The resulting solid was filtered, washed with water, and dried. Recrystallization from acetone-hexane gave 0.73 g of off-white solid, mp 156-159° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([O:26][C:27]1[C:34]([Br:35])=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([Cl:36])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:19]([O:26][C:27]1[C:34]([Br:35])=[CH:33][C:30]([CH:31]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=2)[OH:32])=[C:29]([Cl:36])[CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCOCCc1ccc(Br)cc1
Reactant: O=Cc1cc(Br)c(OCc2ccccc2)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCCc1ccc(C(O)c2cc(Br)c(OCc3ccccc3)cc2Cl)cc1
Reaction time: 0.17 h
Yield: 24.6 %

Procedure:
To a tetrahydrofuran solution (6 mL) of 1-bromo-4-[2-(methoxymethoxy)ethyl]benzene (1.52 g, 6.20 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M hexane solution of n-butyllithium (2.38 mL, 6.20 mmol), and the mixture was stirred for 10 minutes at the same temperature. Then a tetrahydrofuran solution (6 mL) of 4-(benzyloxy)-5-bromo-2-chlorobenzaldehyde (2.02 g, 6.20 mmol) was added dropwise over 10 minutes, and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain the title compound (750 mg, 25%) as a colorless oily compound.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.C(OP([C:19]([Cl:22])([Cl:21])Cl)(=O)OCC)C.[CH2:23]([O:25][C:26]([CH:28]1[CH:30]([CH:31]=O)[C:29]1([CH3:34])[CH3:33])=[O:27])[CH3:24]>O>[CH2:23]([O:25][C:26]([CH:28]1[CH:30]([CH:31]=[C:19]([Cl:21])[Cl:22])[C:29]1([CH3:33])[CH3:34])=[O:27])[CH3:24]
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Reactant: CCOP(=O)(OCC)C(Cl)(Cl)Cl
Agent: CN(C)P(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 90 °C
Yield: 88 %

Procedure:
16.3 g (0.1 mole) of tris-dimethylaminophosphine were added dropwise to a mixture of 25.5 g (0.1 mole) of trichloromethanephosphonic acid diethyl ester and 17.2 g (0.1 mole) of 3-formyl-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester at a temperature of 40° C. The reaction mixture was then warmed to 90° C. for 3 to 4 hours. It was subsequently cooled and poured into 200 ml of water. This suspension was extracted twice with 100 ml of methylene chloride each time. The combined extracts were dried over sodium sulphate and then concentrated. 3-(2,2-Dichloro-vinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester was obtained in a yield of 88% of theory.
Reaction SMILES: Cl.Cl.[CH:3]1([NH2+:9][C:10]2[C:14]3([CH2:19][CH2:18][NH2+:17][CH2:16][CH2:15]3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[Br:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O.C(Cl)Cl>ClCCCl>[Br:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][N:17]1[CH2:16][CH2:15][C:14]2([N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=[C:10]2[NH:9][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:19][CH2:18]1
Reactant: O=C1N=C([NH2+]C2CCCCC2)C2(CC[NH2+]CC2)N1c1cccc(F)c1
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC2CCCCC2)C2(CCN(Cc3cccc(Br)c3)CC2)N1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 600 mg (1.44 mmol) 4-(cyclohexylammonio)-1-(3-fluorophenyl)-2-oxo-1,3-diaza-8-azoniaspiro[4.5]dec-3-ene dihydrochloride, 376 μL (2.16 mmol) diisopropylethylamine, and 427 mg (2.01 mmol) triacetoxy sodium borohydride in 20 mL DCE was added dropwise a 4 mL DCE solution of 251 μL (2.16 mmol) 3-bromobenzaldehyde and the resulting heterogeneous mixture was stirred at rt overnight under a nitrogen atmosphere. The reaction mixture was treated with 50 mL CH2Cl2 and washed with 20 mL saturated NaHCO3 (aq), 20 mL brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by automated flash chromatography (0-5% MeOH in CH2Cl2 over 25 m) afforded the product as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.75 (d, J=8.15 Hz, 1H), 7.45 (m, 2H), 7.36 (m, 1H), 7.22 (m, 1H), 7.15 (d, J=7.69 Hz, 1H), 7.02 (m, 3H), 3.97 (m, 1H), 3.50 (s, 2H), 2.76 (m, 2H), 2.43 (m, 2H), 2.09 (m, 4H), 1.95 (m, 2H), 1.75 (m, 2H), 1.68 (m, 1H), 1.41 (m, 2H), 1.23 (m, 3H). High resolution mass spec (FT/ICR): calc M+H=513.1660. found 513.1697
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:35][C:36](Cl)=[O:37].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>CN(C)C=O>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36](=[O:37])[CH2:35][N:43]4[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]4)[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2c1
Yield: 40.1 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyano-1-methylethyl)benzamide (230 mg, 0.50 mmol) produced in Example A21(iv), chloroacetyl chloride (225 mg, 2.00 mmol), 1-methylpiperazine (200 mg, 2.00 mmol) and N,N-dimethylformamide, and in the same manner as in Example A20, the title compound (120 mg, 40%) was obtained as a pale-yellow powder.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1)=[O:21].[Cl-].[NH4+]>C1COCC1.CCCCCC>[OH:21][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:27]=1)[CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: Cc1ccccn1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(C(O)Cc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 5.4 %

Procedure:
With cooling with ice, a hexane solution (48 mL) of 2.6 N n-butyllithium was added to a THF solution (300 mL) of diisopropylamine (18 mL), stirred at 0° C. for 5 minutes, and then cooled to −78° C. Next, 2-picoline (10 g) was dropwise added thereto, and stirred at that temperature for 30 minutes. THF solution (100 mL) of methyl 4-formylbenzenecarboxylate (17.6 g) was added thereto, and stirred at −78° C. for 30 minutes and then at room temperature for 4 hours. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the entitled compound (1.5 g) as a colorless solid.