Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[CH3:19][NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([N:20]([CH3:19])[CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:8]
Reactant: CNCC(O)CO
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)N(C)CC(O)CO)c1I
Yield: 97 %

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride was reacted with N-methyl-2,3-dihydroxypropylamine according to the conditions in Example 24g. The product was isolated in 97% yield.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=S)[NH2:21]>CO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([NH:2][NH2:3])=[NH:21]
Reactant: NN
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(N)=S)c1Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=N)NN)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Hydrazine hydrate (430 μl) is added dropwise to a room temperature solution of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzene thioamide (1.71 g, 5.48 mmol) in 30 ml of methanol. The solution is stirred at room temperature under nitrogen for five hours, then concentrated in vacuo to half its original volume. This material is chromatographed, eluting with ethyl acetate:hexane (gradient of 1:1 to 3:1) to give 1.15 g (68%) of a glassy pale yellow solid. This material darkens and softens after two days at room temperature.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[C:24](OC)=[N:23][S:22](=[O:27])[N:21]=1>CO>[NH2:19][C:20]1[C:24]([NH:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)=[N:23][S:22](=[O:27])[N:21]=1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: COC1=NS(=O)N=C1N
Solvent: CO
Product: NC1=NS(=O)N=C1NCCCOc1cc(CN2CCCCC2)ccn1
Yield: 66.8 %

Procedure:
A solution of the product of Step A (6.5 g; 26.0 mmoles) in 90 ml of methanol was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (3.84 g; 26.0 mmoles) according to the general procedures described in U.K. Patent Application 2,067,987 to give 6.33 g of product. Recrystallization from methanol-acetonitrile yielded the title compound, mp 154°-158° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:18]=23)[CH:14]=[N:13]1)([CH3:11])[CH2:8][CH2:9][OH:10].C(Cl)Cl>>[CH3:1][S:2]([O:10][CH2:9][CH2:8][C:7]([CH3:6])([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=[CH:25][C:18]=23)[CH:14]=[N:13]1)[CH3:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
TEA (38.0 μL, 0.000273 mol) and methanesulfonyl chloride (21.1 μL, 0.000273 mol) were added sequentially to a solution of 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol (prepared as in Example 58) (81 mg, 0.00020 mol) in DCM (4 mL, 0.05 mol) at 0° C. The reaction mixture was held at this temperature for 1.5 hours, then was quenched by the addition of water. The reaction mixture was extracted with DCM four times. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford crude 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (87 mg). MS (ES): 479 (M+1).
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[C@H:11]([CH3:24])[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)CO>O>[CH3:24][C@H:11]1[C@@H:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][CH2:14][NH:9][CH2:10]1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CC[C@@H]1c1c[nH]c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: C[C@@H]1CNCC[C@@H]1c1c[nH]c2ccccc12
Temperature: 130 °C
Yield: 80 %

Procedure:
A mixture of 21 parts of cis-1-benzoyl-4-(1H-indol-3-yl)-3-methylpiperidine, 60 parts of potassium hydroxide 385 parts of 1,2-ethanediol and 80 parts of water was stirred and refluxed (about 130° C.) overnight. After cooling for a while, about 200 parts of water were added whereupon the product was crystallized. The whole was further cooled and the solid product was filtered off, washed with a lot of water and with 2,2'-oxybispropane and dried, yielding 11.2 parts (80%) of cis-3-(3-methyl-4-piperidinyl)-1H-indole (intermediate 23).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([OH:27])=[CH:16][N:15]=2)=[N:6]1.Br[CH2:33][CH:34]([OH:37])[CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([O:27][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[CH:16][N:15]=2)=[N:6]1
Reactant: OCC(O)CBr
Reactant: Oc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCC(O)COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
25.0 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-3, 0.06 mmol, 1 eq.), 28.2 mg of 3-bromo-propane-1,2-diol (0.18 mmol, 3 eq.) and 41.9 mg of potassium carbonate (0.30 mmol, 5 eq.) were suspended in 466 μl of dry DMF. The reaction mixture was stirred at 100° C. oil bath temperature for 18 hours. Then the mixture was partitioned between half saturated aq. sodium chloride solution and ethyl acetate. The phases were separated and the aqueous layer was extracted once more with ethyl acetate and once with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography to yield 2.60 mg (5.34 μmol, 9%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:33]1([C@H:39]([NH2:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:33]1([C@H:39]([NH:46][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:14]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=4)=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH:27]=3)=[O:29])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: N[C@@H](c1ccccc1)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](c1ccccc1)c1ccccn1)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
7-{[2-(4-Trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (30 mg, 0.069 mmol), [S]-C-phenyl-C-pyridin-2-yl-methylamine (15 mg, 0.082 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.082 mmol), 1-hydroxybenzotriazole (10 mg, 0.075 mmol), and triethylamine (0.038 ml, 0.27 mmol) were combined in 1 ml of dichloromethane. After stirring overnight at room temperature, the mixture was diluted with 30 ml of dichloromethane and washed with 2×20 ml of water, the organic layer was dried (magnesium sulfate), filtered and concentrated under vacuum to provide 39 mg of a yellow solid. Purification by preparative thin-layer-chromatography on silica gel eluting with 4% methanol in dichloromethane. The product-containing band was collected and eluted with 5% methanol in ethyl acetate to afford 22 mg of the title compound as a colorless solid.
Reaction SMILES: [NH:1]([C:6]([NH2:8])=[O:7])[NH:2][C:3](N)=[O:4].[CH2:9](N)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CN1CCCC1=O>[CH2:9]([N:8]1[C:3](=[O:4])[NH:2][NH:1][C:6]1=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCN
Reactant: NC(=O)NNC(N)=O
Solvent: CN1CCCC1=O
Product: CCCCCCn1c(=O)[nH][nH]c1=O

Procedure:
60 g of hydrazodicarboxamide and 56 g of n-hexylamine in 100 ml of N-methylpyrrolidone are stirred at 150° C. for 6 hours, at 175° C. for 20 hours and at 180° C. for 20 hours. The solvent is then distilled off in vacuo and the residue is triturated with 100 ml of 10% strength sodium hyroxide solution. The precipitate is filtered off and the filtrate is neutralised with 10% strength hydrochloric acid. A precipitate thereby separates out, and is filtered off, washed with water and dried in vacuo. 75 g (81% of the theoretical yield) of 4-(n-hexyl)-1,2,4-triazolidine-3,5-dione are obtained as colourless crystals of melting point 144°-145° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH:21]([S:22]([NH:11][CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])(=[O:24])=[O:23])=[CH2:20]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-Boc ethylenediamine (1.24 g, 7.74 mmol) in methylene chloride (35 ml) at −10 C, was added triethylamine (2.37 ml, 17.0 mmol). 2-chloro-1-ethanesulfonyl chloride (0.809 mL, 7.74 mmol). After 4 hr at −10 C the cold bath was removed and the reaction was stirred for 12 hr at room temperature. The reaction was quenched by the addition of Na2CO3 (sat aq.) and extracted with methylene chloride. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo to afford the title compound as an oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:31]2[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(B(O)O)cc1
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+]
Product: CN(Cc1cc(-c2ccc(C#N)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (4-cyanophenyl)boronic acid (176 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57.8 mg), the title compound was obtained as a pale-yellow oil (yield 382 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O>CC(O)=O.[Fe]>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[NH2:12]
Reactant: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cc(N)c(C)c([N+](=O)[O-])c1
Temperature: 110 °C

Procedure:
To a stirred solution of p-xylene (10.4 g, 97.9 mmol) in concentrated sulfuric acid (20 mL), cooled in an ice bath, was added 90% nitric acid (12.4 mL, 264 mmol) dropwise over 50 min. The resulting mixture was heated to 80° C. for 2 h, then poured onto ice and extracted with CH2Cl2 (2×400 mL). The combined organic extracts were washed with saturated aqueous NaHCO3, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40. The resulting solid was recrystallized from CH2Cl2 to yield 2,5-dimethyl-1,3-dinitrobenzene as a white solid. 2,5-Dimethyl-1,3-dinitrobenzene (3.68 g, 18.8 mmol) was dissolved in AcOH (35 mL) and iron powder (1.95 g, 34.9 mmol) was added. The mixture was heated to 110° C. for 3 h, then filtered through a pad of Celite, washing with EtOAc and H2O. The filtrate was concentrated in vacuo to remove most of the solvent and the residue was partitioned between saturated aqueous NaHCO3 (200 mL) and EtOAc (200 mL). The organic layer was washed with brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 60:40, to give the title compound. MS: m/z=167 (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9][O:10]CC1C=CC=CC=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:4][C@H:5]([CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@H](C)CCCCOCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCO
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
Next, the alkali-stable group was converted to a primary hydroxyl group in one of two representative alternative processes. Palladium (10%) on carbon (3.2 g) was added to a Pyrex® hydrogenation vessel and a solution of 5-(R)-acetoxy-1-benzyloxyhexane (65.5 g, 0.26 mole) in acetic acid (65 ml) was added under an argon atmosphere. The reaction vessel was filled with hydrogen gas (75 psi), shaken for five minutes, evacuated, and this process was repeated again and finally the reaction vessel was brought to 75 psi with hydrogen and hydrogenated for 12 hours. Exothermic reaction and rapid absorption of hydrogen was observed during first 2-3 hours. The vessel was replenished with hydrogen whenever the hydrogen was consumed. After 12 hours the reaction mixture was filtered, and the solids were washed with ethyl acetate (75 ml). The combined filtrates were concentrated under reduced pressure and then the residue was dissolved in ethyl acetate (200 ml). The solution was washed with saturated aqueous sodium bicarbonate solution (2×100 ml) and saturated aqueous sodium chloride solution (100 ml) and then dried over magnesium sulfate (10 g). Evaporation of the solvent under reduced pressure gave 39.84 g of 5-(R)-acetoxy-1-hydroxyhexane (yield=95%, 91% pure by gas chromotagraphy).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4].[CH2:28]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[CH3:29]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH2:28][CH3:29])[CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4]
Reactant: COC(=O)c1c(C(C)C)nc2c(Cl)cc(Cl)cc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2c(C(=O)OC)c(C(C)C)nc3c(Cl)cc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 72 step C from 6,8-dichloro-2-isopropyl-4-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid methyl ester (prepared as described in example 72 step B) and 3-ethoxyphenylboronic acid. White solid. MS (ESI): 418.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21]C(=S)N[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[OH-:24].[Na+]>>[C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([SH:21])[C:18]([OH:23])=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:1]
Reactant: [OH-]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: [Na+]
Product: CC(C)(C)c1cc(C=C(S)C(=O)O)cc(C(C)(C)C)c1O

Procedure:
A solution of 174.5 g of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-thioxo-4-thiazolidinone in 1250 ml of a 10% sodium hydroxide solution was heated on a steam bath for four hours. Decolorizing carbon was added and the mixture filtered through a high flow diatomaceous earth pad. The filtrate was chilled by adding ice and treated with 6N hydrochloric acid. The precipitated product was recovered by filtration, washed with water, and dried providing 150 g of the desired subtitled intermediate.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[NH:4][C:3](=[O:15])[CH:2]=1.[Cl:16]Cl>C(O)(=O)C>[Cl:16][C:2]1[C:3](=[O:15])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[CH:1]=1
Reactant: ClCl
Reactant: O=c1ccc2c([nH]1)CCc1ccccc1-2
Solvent: CC(=O)O
Product: O=c1[nH]c2c(cc1Cl)-c1ccccc1CC2

Procedure:
Add 19.7 gm of 5,6-dihydrobenzo[f]quinolin-3(4H)-one to 300 ml of acetic acid. Bubble chlorine into the reaction solution for 4 hours at 100°. Cool the system and collect the product as a precipate. Dissolve the solid into water and neutralize the solution with 1N NaOH. Extract the product with chloroform. Dry the chloroform over anhydrous magnesium sulfate and filter the solution. Remove the solvent by stripping to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5F)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:49]=[CH:50][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([N:55]6[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]6)=[O:36])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:46][CH:45]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C)CC4)cc3)cn2)cc1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (65.6 mg, 0.0968 mmol) obtained in Step A in Example 1-D-21 and N-methylpiperazine (20.9 μl, 0.194 mmol) instead of 1-pyridin-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone was obtained as a yellow solid (85.0 mg), and then the PMB groups and BOC group were removed according to the above Deprotection method 3, to obtain the desired compound (D-140) as a yellow powder (25.0 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].C(N(CC)CC)C.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:33]([Si:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:10][CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:12])=[C:4]([Cl:11])[CH:5]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCc1cc(Cl)c(O)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCc1cc(Cl)c(O)c(Cl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A solution of 2,6-dichloro-4-(2-hydroxy-ethyl)-phenol (16) (2.0 g, 9.66 mmol) in methylene chloride (20 mL) at 25° C. was treated with triethylamine (1.35 mL, 9.66 mmol) and tert-butyl diphenylsilylchloride (2.48 mL, 9.66 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with methylene chloride. The organics were washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95:5 petroleum ether/ethyl acetate) afforded 4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,6-dichloro-phenol (70) (2.60 g, 60%) as a pale yellow oil; HRMS m/e calcd for C24H26Cl2O2Si (M+Na)+ 467.0971, found 467.0977. Exact Mass=444.1079; Molecular Weight=445.47.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]1=[O:17].N1C=CC=CC=1.[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27]([O:17][C:9]1[CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][C:13](=[O:14])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:28])[CH3:25]
Reactant: CC1(C)CC(=O)C(c2ccccc2Cl)C(=O)C1
Reactant: CCCCC(CC)C(=O)Cl
Solvent: c1ccncc1
Product: CCCCC(CC)C(=O)OC1=C(c2ccccc2Cl)C(=O)CC(C)(C)C1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 1.009 (3.99 mmol) of 2-(2'-chlorophenyl)-5,5-dimethyl-1,3-cyclohexanedione and 0.03 g (8.0 mmol) of pyridine was cooled in an ice bath and stirred under N2. The 2-ethylhexanoyl chloride (0.69 g, 4.25 mmol) was added, the mixture was then allowed to warm to room temperature, stirred at room temperature for one hour and refluxed for one hour. The solvent was removed under reduced pressure and the residue taken up in ether and water. The ether was washed three times with 0.25N NaOH, three times with 10% HCl and with water. The ether was dried over anhydrous MgSO4 and decanted to give 1.23 g (82%) of 3-(2'-ethylhexanoyloxy)-2-(2'-chlorophenyl)-5,5-dimethyl-2-cyclohexenone as a clear colorless oil which was homogeneous by thin layer chromatography.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]>CO>[C:1]([CH2:2][CH2:3][NH:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH3:12])[CH3:5])#[N:4]
Reactant: C=CC#N
Reactant: CN(C)CCCCN
Solvent: CO
Product: CN(C)CCCCNCCC#N
Temperature: 0 °C
Yield: 80 %

Procedure:
A solution of acrylonitrile (1.17 g, 22.07 mmol) in methanol (1.0 ml) was added dropwise to a solution of N,N-dimethyl-1,4-diaminobutane 322 (2.1 g, 18.42 mmol) in methanol (1.0 ml) at 0° C., and the mixture was stirred at 0° C. for sixteen hours. Evaporation of the solvent in vacuo afforded almost pure N-(2-cyanoethyl)-N',N'-dimethyl-1,4-diaminobutane 323 as a colorless oil (2.5 g, 80% yield based on 322). 1H NMR (400 MHz, CDCl3) δ: 1.45 (4H, m, --CH2 --CH2 --CH2 --CH2 --), 2.15 (6H, s, --N(CH3)2), 2.22 (2H, t, --CH2N), 2.47 (2H, t, --CH2CH2CN), 2.60 (2H, t, --CH2CH2NH--), 2.88 (2H, t, --CH2CH2NH--), 3.37 (1H, s, --NH).