Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[NH:21][C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1.[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:31])[C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Reaction time: 0.25 h

Procedure:
A mixture of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisoxazol-5-yl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (10.5 g, 0.0255 mol) and potassium carbonate (7.04 g, 0.051 mol) in N,N-dimethylformamide is stirred for 15 minutes, treated with methyl iodide (7.24 g, 0.051 mol), stirred overnight, and poured onto ice. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a brown glass. Dry column chromatography of the glass using silica gel and a hexanes/ethyl acetate solution (3:1) gives the title product as an off-white solid which is identified by NMR spectral analyses.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[N+:5]([CH2:24][C:25]2[CH:26]=[C:27](C)[CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[CH:16]=2)[C:11]1=[O:23].[BH4-].[Na+].[CH3:34]O>C1COCC1>[Br:2][C:3]1[CH2:4][N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:34])[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[CH:16]=2)[C:11]1=[O:23]
Reactant: CO
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3cccc(C)c3)cc1Br)C2
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)C(CC1=C(Br)CN(Cc3ccccc3C)C=C1)C2
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of compound 146 (45 mg, 0.08 mmol) in a mixture of methanol and THF (5 mL, respectively 1:4) was added sodium borohydride (3 mg, 1 equiv) in one portion at 0° C. The reaction mixture was then stirred at this temperature for 1 h and quenched with 35% aqueous ammonia solution (3 mL). The mixture was extracted with dichloromethane (3×) and the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. The crude residue was purified by column chromatography on silica gel (petroleum ether/EtOAc: 2/3) to afford the title compound 168 as a yellow solid (Yield 21.9 mg, 60%).
Reaction SMILES: [CH:1](=O)[CH:2]=O.[NH2:5][N:6]1[C:10]([NH2:11])=[N:9][N:8]=[C:7]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[N:9]1[N:8]=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[N:6]2[C:10]=1[N:11]=[CH:2][CH:1]=[N:5]2
Reactant: O=CC=O
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Product: Oc1ccc(Cc2nnc3nccnn23)cc1

Procedure:
General procedure A was followed with the reaction of ethanedial and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol to provide 4-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl-phenol (example 7).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:20][N:21](C=O)C>C(Cl)Cl.[C-]#N.[C-]#N.[Zn+2].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>[O:17]=[C:12]1[CH2:13][CH2:14][CH2:15][C:16]2[C:7]([C:20]#[N:21])=[CH:8][CH:9]=[CH:10][C:11]1=2
Reactant: O=C1CCCc2c(OS(=O)(=O)C(F)(F)F)cccc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: N#Cc1cccc2c1CCCC2=O
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of compound 5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (8.6 g, 30.8 mmol), Zn(CN)2(7.2 g, 61.6 mmol) and Pd(PPh3)4(0.8 g) in anhydrous DMF was stirred at 120° C. under N2 overnight. The reaction was cooled to ambient temperature, and then diluted with DCM. Filtered off solids and the orgainic filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with silica gel cloumn chromatography to give 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carbonitrile.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:7][CH2:6]2.[F:19][C:20]([F:32])([F:31])[C:21]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][NH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][CH:16]([S:13]([NH:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH2:2][N:23]3[CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([C:20]([F:19])([F:31])[F:32])=[N:22]3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)(=[O:15])=[O:14])[CH3:18]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(CCl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc3c(c2)CCC3NS(=O)(=O)C(C)C)nc1C(F)(F)F
Yield: 52.4 %

Procedure:
To N-(5-(chloromethyl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (0.250 mmol, 72 mg) in DMF (4 mL) was added ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.250 mmol, 52.1 mg) and Potassium carbonate (0.750 mmol, 104 mg). The resultant solution was heated to 60° C. with stirring. After 1.5 h the reaction mixture was concentrated to remove DMF before partitioning between EtOAc/H2O and the phases mixed and separated. The organic layer was washed with water (×4) and brine before drying and concentration to a yellow oil. Purification on 10 g Si eluting with 1% MeOH/DCM gave the desired compound as an off-white solid (60 mg, 0.131 mmol, 52.2%). 1H NMR (400 MHz, CDCl3) δ 1.33 (t, 3H) 1.44 (d, 6H) 1.95 (m, 1H) 2.65 (m, 1H) 2.85 (m, 1H) 3.00 (m, 1H) 3.25 (m, 1H) 4.15 (d, 1H) 4.29 (q, 2H) 4.95 (m, 1H) 5.30 (s, 2H) 7.14 (s, 1H) 7.18 (d, 1H) 7.48 (d, 1H) 7.88 (s, 1H).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[C:8]([O:15]COC)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])([CH3:6])([CH3:5])[CH3:4]>CO>[Br:1][C:13]1[CH:14]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]([OH:15])=[C:9]([CH:12]=1)[CH:10]=[O:11]
Reactant: BrBr
Reactant: COCOc1c(C=O)cccc1C(C)(C)C
Solvent: CO
Product: CC(C)(C)c1cc(Br)cc(C=O)c1O
Temperature: 20 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
Bromine (747 g) was gradually added to a solution of the 3-(tert-butyl)-2-(methoxymethoxy)benzaldehyde (1247 g, 4.67 mol) in methanol (4000 ml) while cooling on ice. After stirring at 20° C. for 1 hour, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, the mixture was washed with water, saturated sodium aqueous hydrogencarbonate and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to yield a crude product of the title compound (1333 g) as a red oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][S:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[S:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(SCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CSc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To a solution 2-[4-(4-hydroxy-butyl)-benzylsulfanyl]-3-methyl-chromen-4-one (300 mg, 0.85 mmol) dissolved in anhydrous dichloromethane (8.0 mL) was added TsCl (194 mg, 1.01 mmol), DMAP (124 mg, 1.01 mmol) and TEA (0.213 mL, 1.52 mmol). The reaction mixture continued stirring at room temperature. After 3 hours the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material was purified using silica gel chromatography (1:1 pentane: ethyl acetate) to yield toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-chromen-2-ylsulfanylmethyl)-phenyl]-butyl ester (280 mg, 0.55 mmol) in moderate yield (65%).1H (CDCl3, 600 MHz): δ 8.18 (1H, dd, J=7.9, 1.3 Hz), 7.77 (2H, d, J=8.2 Hz). 7.62 (1H, m), 7.39 (2H, t, J=8.0 Hz), 7.33 (2H, d, J=8.0 Hz), 7.30 (2H, d, J=8.0 Hz), 7.07 (2H, d, J=8.0 Hz), 4.37 (2H, s), 4.02 (2H, t, J=5.8 Hz), 2.55 (2H, t, J=7.3 Hz), 2.05 (3H, s), 1.65 (4H, m); 13C (CDCl3, 150 MHz): δ 175.5, 162.2, 156.7, 144.9, 141.5, 134.1, 133.4, 133.0, 130.0, 129.1, 129.0, 128.1, 126.5 125.3, 122.9, 117.5, 117.0, 70.5, 35.3, 34.9, 28.6, 27.2, 21.8, 10.8.; HRMS calcd for C28H28O5S2 509.1450:, found 509.1441
Reaction SMILES: Cl.Cl.[CH:3]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[N:19]=4)=[C:13]3[CH:12]=[CH:11][C:10]=2[C:37]([OH:39])=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.S(Cl)(Cl)=O.[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>ClCCl>[CH:3]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[N:19]=4)=[C:13]3[CH:12]=[CH:11][C:10]=2[C:37]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylic acid dihydrochloride (19 mg, 0.033 mmol) was added to a dry flask and cooled to −78° C. Thionyl chloride (14 μL, 0.19 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under a stream of nitrogen then placed under high vacuum. To a solution of the crude residue in dichloromethane (600 μL) was added pyrrolidine (150 μL, 1.80 mmol). The reaction mixture was stirred at room temperature for 10 minutes then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes:ethyl acetate to 100% ethyl acetate) provided N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-6-(1-pyrrolidinylcarbonyl)pyrazolo[1,5-a]pyridin-7-amine (9 mg, 49%) as a clear oil. Rf 0.13 (1:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H), 7.72 (d, 1H), 7.62 (m, 2H), 7.26 (d, 1H), 7.14 (t, 2H), 6.54 (d, 1H), 6.30 (d, 1H), 5.11 (d, 1H), 4.31 (m, 1H), 4.19 (m, 1H), 3.66 (broad, 2H), 3.38 (broad, 2H), 2.11-1.88 (m, 8H), 1.80-1.50 (m, 12H); MS m/z 554 (M+1). To a solution of the product in ether was added 1 M HCl in ether. The precipitated solid was isolated to give the corresponding HCl salt.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH:33]=[CH:34][C:35]=1[CH:36]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:35]3[CH:34]=[CH:33][C:32]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[CH:31][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(-c2ccc(C=O)c(F)c2)cc1
Product: COc1ccc(-c2ccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)c(F)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-fluoro-4′-methoxy-biphenyl-4-carbaldehyde according to the procedure of Example 66. MS (ESI) m/z 593.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7]([N:12]1[C:18](=[O:19])[CH:17]2[CH:13]1[S:14][C:15]([CH3:21])([CH3:20])[NH:16]2)[CH2:8][C:9]([OH:11])=[O:10])(C)(C)C.F[C:24](F)(F)C(O)=O>>[CH3:1][O:5][C:6](=[O:22])[CH:7]([N:12]1[C:18](=[O:19])[CH:17]2[CH:13]1[S:14][C:15]([CH3:21])([CH3:20])[NH:16]2)[CH2:8][C:9]([O:11][CH3:24])=[O:10]
Reactant: CC(C)(C)OC(=O)C(CC(=O)O)N1C(=O)C2NC(C)(C)SC21
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)CC(C(=O)OC)N1C(=O)C2NC(C)(C)SC21
Reaction time: 18 h

Procedure:
A mixture of 0.025 g of the isomer B of α-(3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-α-(carboxymethyl)-acetic acid tert.-butyl ester (Example 39) and 1 ml of trifluoroacetic acid is kept for 18 hours at 0°, is then evaporated under reduced pressure, and the residue containing the α-(3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-α-(carboxymethyl)-acetic acid, is taken up in 1 ml of dioxane and then mixed with an ether solution of diazomethane until saturated. After 3 minutes reaction time, the mixture is evaporated under reduced pressure and the residue is filtered through a silica gel column (diameter: 0.8 cm; hight: 10 cm), a 2:1-mixture of hexane and ethyl acetate being used for elution; the isomer B of α-(3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-α-(carbomethoxymethyl)-acetic acid methyl ester of the formula ##STR56## which is obtained as a crude product, melts at 136°-137° after recrystallisation from a mixture of ether, methylene chloride and hexane.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][O:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][O:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCCC1CCCO1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCCO1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[N:18]=2)=[CH:5][CH:4]=1)#[N:2].[ClH:19].[CH2:20]([OH:22])[CH3:21]>>[ClH:19].[ClH:19].[CH2:20]([O:22][C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[N:18]=2)=[CH:7][CH:8]=1)=[NH:2])[CH3:21]
Reactant: N#Cc1ccc(-c2nc3c(s2)NCCCC3)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(-c2nc3c(s2)NCCCC3)cc1
Reaction time: 8 h

Procedure:
A solution (700 ml) of 2-(4-cyanophenyl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (8.00 g) in ethanol was saturated with hydrogen chloride, and allowed to stand overnight. It was concentrated under reduced pressure, and the residue was washed with ethyl ether and dried to give the title compound as a powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][C:15](Cl)=[O:16].Cl>C(OCC)(=O)C.O>[Cl:13][CH2:14][C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:8])[CH:4]=1)=[O:16]
Reactant: Fc1ccccc1F
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCl)c1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
1,2-Difluorobenzene (150 g) and aluminium chloride (156 g) were charged in a round bottom flask. The reaction mixture is heated to about 60° C. followed by slow addition of chloroacetyl chloride (105 mL) over a period of 1 hour at the same temperature. The reaction mixture was stirred for another 3 hours followed by cooling to about 10° C. The reaction mass was poured into precooled water (1500 mL) followed by addition of hydrochloric acid (36%, 225 mL) at the same temperature and stirring. To this mixture ethyl acetate (750 mL) was charged and layers were separated. The aqueous layer is extracted with ethyl acetate (750 mL). The organic layers were combined and washed with water (750 mL) followed by complete evaporation of organic layer under vacuum at 50-55° C. The residue obtained is cooled to 25-35° C. followed by purification with column chromatography using 0-5% ethyl acetate in petroleum ether to afford the title compound in about 70% yield having HPLC purity of 99.51%.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:10]([NH:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:9][C:8]([CH2:18][S:19](/[CH:22]=[CH:23]/[C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=2[O:34][CH3:35])(=[O:21])=[O:20])=[CH:7][N:6]=1.Cl>O>[CH3:3][O:4][C:5]1[C:10]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][C:8]([CH2:18][S:19](/[CH:22]=[CH:23]/[C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=2[O:34][CH3:35])(=[O:21])=[O:20])=[CH:7][N:6]=1
Reactant: CCOC(=O)CNc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)cnc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(NCC(=O)O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.7 %

Procedure:
Sodium hydroxide (4 mg, ° Animal) was added to a solution of (E)-ethyl 2-(2-methoxy-5-((2,4,6-trim ethoxystyrylsulfonyl)methyl)pyridin-3-ylamino)acetate (19 mg, 0.04 mmol) in H2O (10 mL). The mixture was stirred at room temperature for 1 h. The residue was acidified by addition of 2M aq HCl and extracted with EtOAc (3×10 mL). The combined extracts was washed with brine, dried on MgSO4, and filtered. The residue was further purified by silica gel chromatography, eluting with PE/EtOAc (2:3, v/v) to afford pure product as a white solid (24.2 mg, 70%). 1H-NMR (CDCl3): δ 3.82 (s, 6H, 2×OCH3), 3.83 (s, 3H, OCH3), 3.85 (d, 2H, J=1.6 Hz, CH2), 3.90 (s, 2H, CH2), 3.96 (s, 3H, OCH3), 6.08 (s, 2H, Ph-H), 6.72 (s, 1H, Py-H), 7.02 (d, 1H, J=15.6 Hz, CH), 7.43 (s, 1H, Py-H), 7.78 (d, 1H, J=15.6 Hz, CH); HR-MS (ESI+) m/z: 451.1245 [M−H]−, C20H24N2O8S requires 452.1253.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.[Br:19][C:20]1[N:25]=[C:24](Br)[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(O)C>[Br:19][C:20]1[N:25]=[C:24]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[CH2:7][CH2:8]2)[CH:23]=[CH:22][N:21]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Brc1ccnc(Br)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=c1[nH]c2ncccc2n1C1CCN(c2ccnc(Br)n2)CC1

Procedure:
1.4 g (4.8 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one-dihydrochloride, 1.1 g (4.8 mmol) 2,4-dibromo-pyrimidine, a spatula tip of DMAP and 3.3 mL (19.1 mmol) DIPEA in 35 mL ethanol were stirred at RT. After the reaction had ended the precipitate was suction filtered, washed with a little ethanol and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[N:16][CH:17]=1>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:22])([F:10])[F:21])=[CH:17][N:16]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: COc1cccc(NCCc2ccc(C(F)(F)F)cn2)c1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (3-methoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 297.2 [M+H]+) was prepared from 3-bromo-anisol instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14].C([O:23][C:24]([C:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]4)=[CH:40][C:39]=3[O:51][CH3:52])[N:32]=2)[N:28]([CH3:53])[CH:27]=1)=O)C>C1COCC1>[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH:14][C:24]([C:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)=[CH:40][C:39]=3[O:51][CH3:52])[N:32]=2)[N:28]([CH3:53])[CH:27]=1)=[O:23]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCOC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1nccc(-c2cc(C(=O)Nc3c(C)cc(C)cc3C)cn2C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
NaHMDS in THF (1.0 M, 11.0 mL, 11.0 mmol) was added over 30 min to a solution of 2,4,6-trimethylaniline (1.2 mL, 8.32 mmol) and 5-{2-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.25 g, 2.77 mmol) in THF (30 mL) at 0° C. The resulting brown solution was stirred at 0° C. for 10 min and allowed to warm to room temperature over a period of 20 min. After stirring at room temperature for 4 h, the reaction was quenched by the addiction of saturated aqueous NH4Cl (10 mL). The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic solution was washed with brine (50 mL), dried over Na2SO4, filtered and evaporated to dryness, the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) to afford 1.10 g (72% yield) of the title compound.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[C:1]1([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2/[C:13](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:14](=[O:20])[NH:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
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
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3ccccc3)c21
Yield: 23.5 %

Procedure:
Using Method S above, phenyl boronic acid (86 mg, 0.70 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.47 mmol) (Starting Material 7) using (Ph3P)4Pd (27 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.47 mL, 0.94 mmol) and DME (10 mL) at reflux for 2 days to give (Z)-1,3-dihydro-4-phenyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield: 35 mg, 23%).