Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([S:56]([NH:59][CH3:60])(=[O:58])=[O:57])[CH:44]=[CH:45][C:46]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([S:56]([NH:59][CH3:60])(=[O:58])=[O:57])[CH:44]=[CH:45][C:46]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CNS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c(OC)c1
Yield: 80.4 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with 3-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (72 mg, 0.22 mmol), sodium carbonate (23 mg, 0.22 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (21 mg, 0.03 mmol) in 1,2-dimethoxyethane (1.60 ml) and water (0.40 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 46 mg (73% yield) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:36][CH2:37][CH2:38][OH:39])=[N:12][N:13](CC4C=CC=CC=4)[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:36][CH2:37][CH2:38][OH:39])=[N:12][NH:13][C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2Cc2ccccc2)cc1
Reactant: [H][H]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2[nH]nc(OCCO)c2-c2ccc3c(c2)OCO3)cc1
Reaction time: 8 h

Procedure:
N-[4-(1,3-benzodioxol-5-yl)-1-benzyl-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 78) (15.8 g) was dissolved in acetic acid (500 ml). Under an atmosphere of nitrogen, Pearlmann's catalyst (JM type 91, 1.6 g) was added and the reaction was stirred for 48 h under 4 bars of hydrogen at 50° C. The reaction mixture was filtered on a short pad of Celite® and concentrated under reduced pressure. To the oily residue was added water (300 ml) and dichloromethane (300 ml). The phases were separated, the organic phase washed with a 5% aqueous solution of sodium bicarbonate (2×150 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (300 ml), solid potassium carbonate (8 g) was added in one portion and the reaction mixture was stirred overnight and then concentrated under reduced pressure. Water (500 ml) was added to the resulting solid and the mixture as extracted with dichloromethane (3×500 ml). The organic fraction was dried on sodium sulfate and concentrated under reduced pressure. The red-yellow solid was re-crystallised in ethyl acetate yielding the title compound as a white solid (7.2 g)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[N:11]1[C:18]([Cl:19])=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13]>C1(C)C=CC=CC=1>[Cl:13][C:12]1[N:11]=[C:18]([Cl:19])[N:17]=[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(Oc2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
An aqueous solution of 52 parts of phenol and 50 parts by volume of a 33% aqueous solution of sodium hydroxide in 250 parts of water is treated, at a temperature of between 30° and 35° C., with a solution of 92.5 parts of cyanuric chloride in 700 parts by volume of toluene, with thorough stirring. The reaction mixture is heated to 50° C. and stirred for a further 1 hour at this temperature. The organic phase is separated off and dried with magnesium sulfate and the bulk of the toluene is distilled off. The distillation residue is filtered off with strong suction and washed with twice 20 parts by volume of toluene. After drying under reduced pressure at 30° C., 80 parts of the compound 2,4-dichloro-6-phenoxy-1,3,5-triazine melting at 111 to 116° C. are obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=O)[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CCC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CCC(=O)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[6-(t-Butyldimethylsilanyloxymethyl)pyridin-2-yl]-propionic acid (1.65 g) was dissolved in 20 mL of methylene chloride, and 584 μL of morpholine, 1.6 g of WSC and 1.56 mL of triethylamine were added to the solution, and then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform, transferred into a separating funnel, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (chloroform-methanol=30:1) to give 1.91 g of 3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]-1-morpholin-4-yl-propan-1-one as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].[N+](=CC(OCC)=[O:41])=[N-].[C:45]1([CH3:51])[CH:50]=CC=C[CH:46]=1>C([O-])(=O)C.[Rh+]>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:46][C:45]([OH:41])([CH3:51])[CH3:50])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[7-butyl-4-(4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.61 g), rhodium(I) acetate (0.006 g) and toluene (30 mL) was added dropwise ethyl diazoacetate (0.62 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained residue was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 1.9 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.22 g, 31%).
Reaction SMILES: [CH2:1]=[O:2].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[OH:21].Cl>C(#N)C>[F:13][C:14]1[C:15]([OH:21])=[C:16]([C:17]([CH3:20])=[CH:18][CH:19]=1)[CH:1]=[O:2]
Reactant: Cc1ccc(F)c(O)c1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(F)c(O)c1C=O
Temperature: 90 °C
Reaction time: 240 h

Procedure:
Paraformaldehyde (3.86 g, 133 mmol), magnesium chloride (6.32 g, 66.5 mmol) and triethylamine (11.6 ml, 83.3 mmol) were added to a solution of 2-fluoro-5-methylphenol (4.19 g, 33.3 mmol) in acetonitrile (100 ml), and the mixture was vigorously stirred at 90° C. for 10 days. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. After the organic layer was successively washed with 1N hydrochloric acid, water and a saturated aqueous NaCl solution, and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluting solvent: hexane/ethyl acetate=4/1) to obtain crude 3-fluoro-2-hydroxy-6-methylbenzaldehyde. According to a method similar to Example (28-3) and Example (28-4), from the crude compound obtained in the above, tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-fluoro-6-methylbenzoate was obtained (624 mg, three-step total yield: 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](Cl)(=[O:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:13])[CH2:11][CH3:12])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
3-chloro-4-fluoroaniline (10 g, 67.32 mmol) dissolved in CH2Cl2 was added with propionyl chloride (6.6 mL, 74.10 mmol) and triethyl amine (10.2 mL, 73.58 mmol) dropwise under water bath, and the mixture was stirred for 2 h. The resulting solution was washed with water (2×50 mL) and saturated aqueous NaHCO3 solution (12 mL). The CH2Cl2 layer dried over MgSO4 was evaporated to give title compound as light purple solid (13.01 g, 96.3%). 1H NMR (400 MHz, DMSO-d6) δ 1.06 (t, J=7.6 Hz, 3H), 2.30 (q, J=7.6 Hz, 2H), 7.31 (dd, J=9.2 and 8.8 Hz, 1H), 7.44 (ddd, J=8.8 and 4 and 2.8 Hz, 1H), 7.91 (dd, J=7.2 and 2.8 Hz, 1H), 10.04 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 9.4, 29.4, 116.6, 116.8, 118.8, 119.0, 119.1, 120.2, 136.55, 136.58, 151.5, 153.9, 172.1;
Reaction SMILES: [C:1](=[O:13])([O:5][C:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:2][CH2:3]Cl.N1C(C)=CC=CC=1C.[I-:22].[Na+]>CC(C)=O.CCCCCC>[C:1](=[O:13])([O:5][C:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:2][CH2:3][I:22]
Reactant: [I-]
Reactant: CC1(OC(=O)OCCl)CCCCC1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: CCCCCC
Product: CC1(OC(=O)OCI)CCCCC1
Reaction time: 1.5 h

Procedure:
Chloromethyl 1-methylcyclohexyl carbonate (2.07 g) in acetone (7.5 ml) was treated with 2,6-lutidine (0.116 ml). Sodium iodide (2.25 g) was then added and the mixture was stirred for 1.5 h. More sodium iodide (1.5 g) was then added and stirring was continued. After a total of 2.5 h the acetone was removed and CH2Cl2/water were added and the layers separated. The dichloromethane layer was washed with 5% aqueous Na2S2O3, dried (MgSO4) and evaporated to leave an oil. This was taken up in hexane (50 ml) and loaded onto a silica gel column, and the column was eluted with 5% ethyl acetate in hexane to give iodomethyl 1-methylcyclohexyl carbonate containing some of the starting chloromethyl compound, δ(CDCl3) 1.26-1.35 (2H, m), 1.40-1.65 (9H, m, including s at δ 1.52), 2.10-2.20 (2H, m), 5.69 (s) and 5.91 (s) (together 2H, ratio 1:5) ppm.
Reaction SMILES: [C:1]1([OH:21])[C:2]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[C:22](O)([CH3:25])([CH3:24])[CH3:23].FC(F)(F)S(O)(=O)=O>ClC1C=CC=CC=1Cl.O.CCOCC>[C:22]([C:3]1[CH:4]=[C:5]2[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:1]([OH:21])[C:2]=1[C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Oc1c(-c2ccc3c(c2)CCCC3)ccc2c1CCCC2
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1cc2c(c(O)c1-c1ccc3c(c1)CCCC3)CCCC2
Temperature: 120 °C
Yield: 61.6 %

Procedure:
A mixture of 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol (1.0 g, 3.4 mmol), tert-butyl alcohol (1.4 g), trifluoromethanesulfonic acid (0.04 g) was dissolved in 2 ml 1,2-dichlorobenzene. The mixture was heated at 120° C. for 2.5 hours. GC showed 97% conversion to 87% mono-butylated product, and 10% bis-butylated product. The mixture was cooled, and diluted with 10 ml water and 10 ml ether. The layers were separated, and the organic layer was washed with sodium bicarbonate solution, dried, and concentrated. The crude product was purified by flash column chromatography (silica gel, 2% ethyl acetate/hexanes) to yield 0.7 g of white solid.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]([O:4][CH2:5][CH2:6][O:7][S:9]([CH3:8])(=[O:11])=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)OCCO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCCOS(C)(=O)=O
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a stirred solution of 2-isopropoxyethanol (2.0 mL, 17.37 mmol) in DCM (100 mL) at ambient temperature add methanesulfonyl chloride (1.48 mL, 18.08 mmol). Add triethylamine (2.70 mL, 19.37 mmol) slowly followed by DMAP (catalytic). Continue stirring overnight and concentrate in vacuo. Add diethyl ether and filter. Wash the filtrate with aqueous 1N aqueous HCl, brine, and saturated aqueous NaHCO3. Dry over anhydrous MgSO4 and concentrate in vacuo to give the desired intermediate (2.97 g, 94%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>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>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH3:15]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Temperature: 85 °C
Reaction time: 36 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzonitrile (5.5 g, 22 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (7.04 g, 22 mmol), potassium carbonate (7.6 g, 55 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.300 g, 0.25 mmol) were combined in DME (40 mL) and H2O (20 mL). The mixture was purged with N2, and then stirred at 85° C. for 36 hours. After standard work-up, the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])[CH2:23][CH2:22]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:27]([N:24]5[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]5)[CH:28]=4)[N:19]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:13][CH:14]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: Fc1ccc(CNc2cccn3nc(Cl)nc23)cc1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5ccc(F)cc5)cccn4n3)c2)CC1

Procedure:
N(8)-(4-Fluoro-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-fluoro-benzyl)-amine (0.288 g, 1.04 mol) and ]3-(4-methylpiperazin-1-yl)aniline (223 mg, 1.17 mol) in a manner analogous to Example 2d. Product isolated as red foam (83.06 mg, 18.5%). 1H NMR (400 MHz, (D3C)2SO, δ, pap): 9.16 (s, 1H), 7.96 (d, J=6.3 Hz, 1H), 7.43 (t, J=12.8, 6.7 Hz, 2H), 7.26 (m, 2H), 7.18-7.06 (m, 3H), 6.72 (t, J=14.3, 7.2 Hz, 1H), 6.45 (m, 2H), 6.32 (d, J=8.4 Hz, 1H), 4.50 (d, J=5.7 Hz, 2H), 3.11 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H). MS=432 (MH)+.
Reaction SMILES: [CH2:1]1[C:6](=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)[CH2:2]1.[CH3:19]CN(CC)CC.[O:26]1[CH2:30][CH2:29][C@H:28]([O:31][C:32](=[O:41])[O:33][N:34]2[C:38](=[O:39])[CH2:37][CH2:36][C:35]2=[O:40])[CH2:27]1>CC#N>[O:26]1[C:27]2([CH2:6][CH2:1][CH2:2][CH:28]2[O:31][C:32](=[O:41])[O:33][N:34]2[C:35](=[O:40])[CH2:36][CH2:37][C:38]2=[O:39])[CH2:19][CH2:29][CH2:30]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CC
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Solvent: CC#N
Product: O=C(OC1CCCC12CCCO2)ON1C(=O)CCC1=O
Yield: 40 %

Procedure:
The above spiro alcohol (27 mg, 0.19 mmol), N,N′-disuccinimidyl carbonate (52 mg, 0.204 mmol), Et3N (25 mg, 0.25 mmol) in CH3CN (5 mL) were stirred for 12 hours, following the same conditions as described for compound 22 to obtain compound 26 (22 mg, 40%). 1H NMR (CDCl3, 200 MHz): δ 4.7 (m, 1H), 3.8 (m, 2H), 2.8 (s, 4H), 1.5–2.1 (m, 10H).
Reaction SMILES: C([Cl:4])(=O)C.[Br:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[CH:10]=[CH:11][N+:12]([O-])=O.[OH2:19]>ClCCl>[Br:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:9]=1[CH:10]([Cl:4])[C:11](=[O:19])[NH:12]2
Reactant: CC(=O)Cl
Reactant: O
Reactant: O=[N+]([O-])C=Cc1ccccc1CCBr
Solvent: ClCCl
Product: O=C1Nc2cccc(CCBr)c2C1Cl
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a precooled solution of ferric chloride (28.5 kg) in dichloromethane (340 1) at 0° C. was added acetyl chloride (9.2 kg) at such a rate that the reaction temperature did not exceed 5° C. The reaction mixture was stirred at between 0° and 5° C. for 15 minutes. To the mixture was added a pre-dryed solution of 2-(2'-bromoethyl)-β-nitrostyrene [12.88 kg (16.22 kg wet:water content 20.6%)]in dichloromethane (55 litres) at such a rate that the reaction temperature did not exceed 5° C. The reaction mixture was stirred for 5 hours at a temperature between 5 and 10° C. Analysis by TLC confirmed that the reaction had gone to completion. Water (240 1) was then added to the reaction mixture at such a rate so that the temperature did not exceed 20° C. The mixture was then stirred for 30 minutes. The dichloromethane layer was isolated and washed a further three times with water (three times 120 1). The dichloromethane layer was then distilled to a volume of about 60 1. After cooling to 20° C. petroleum ether (60/80 grade. 40 1) was added and the resulting precipitate was stirred at 10° C. for 30 minutes. HPLC analysis of the crude reaction mixture indicated a purity of 93.22% of the required product. 4-(2'-bromo-ethyl)-3-chloro-1,3-dihydro-2H-indol-2-on by filtration, the filtrate washed with petroleum ether (60 1) and dried at 80° C. overnight to give 10.8 kg (78%) of of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH:30]1[C:40]2[C:41]3[CH:32]([CH2:33][C:34](=[O:42])[NH:35][C:36]=3[CH:37]=[CH:38][CH:39]=2)[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24]([N:30]5[C:40]6[C:41]7[CH:32]([CH2:33][C:34](=[O:42])[NH:35][C:36]=7[CH:37]=[CH:38][CH:39]=6)[CH2:31]5)=[O:25])[CH:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=C1CC2CNc3cccc(c32)N1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ccn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC5CC(=O)Nc6cccc4c65)ccn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
67 mg (0.17 mmol) 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid and 30 mg (0.17 mmol) 1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one in 56 μL (0.40 mmol) TEA and 1.8 mL DMF were combined with 58 mg (0.18 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[NH:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1>>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(C)=CCCBr
Product: CC(C)=CCCn1ccc2c(C=O)cccc21
Yield: 86.9 %

Procedure:
The same procedures used in Example 7 were repeated except for using 4.59 g of 5-bromo-2-methyl-2-pentene and 2.00 g of indole-4-carbaldehyde as a starting material to give 2.72 g of 1-(4-methyl-3-pentenyl)indole-4-carbaldehyde as a brown oily substance. The yield thereof was found to be 87%.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16](=[NH:20])OCC)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:21](N)[CH2:22][NH2:23]>C(O)C>[ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[NH:20][CH2:21][CH2:22][N:23]=3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CCOC(=N)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2ccc(C3=NCCN3)o2)cc1
Yield: 86.4 %

Procedure:
A mixture of 39 g (0.13 mole) of ethyl 5-(4-nitrophenyl)-2-furimidate hydrochloride and 8.6 g (0.14 mole) of ethylenediamine in 400 ml of absolute ethanol was heated under reflux for 61/2 hr and stood in a refrigerator overnight. The yellow solid was collected by filtration and washed with anhydrous ether to give 33 g (85%) of product, m.p. > 300°.