Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c2) the title compound is obtained as off-white solid.
Reaction SMILES: O.[O-][C:3]#[N:4].[Na+].[CH:6]([N:19]1[CH2:22][CH:21](OS(C)(=O)=O)[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:6]([N:19]1[CH2:22][CH:21]([C:3]#[N:4])[CH2:20]1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 65 °C
Reaction time: 9 h
Yield: 92.3 %

Procedure:
Water (7.2 ml) and sodium cyanate (3.48 g) were added to a solution of 1-benzhydryl-3-(methanesulfonyloxy)azetidine (7.52 g) in N,N-dimethylformamide (60 ml), followed by stirring at 65° C. for 9 hours. Water, sodium carbonate and ethyl acetate were added to the reaction mixture, which was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, and the resultant crystals were suspended by addition of diethyl ether (10 ml). The crystals were collected by filtration, and washed with diethyl ether. This was dried under aeration to give the title compound (5.43 g, 92.3%) as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([O:10]CC2C=CC(C(OC)=O)=CC=2)[N:7]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].O1CCCC1>[C:1]([C:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(COc2cc(C(C)(C)C)nn2Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2N=C(C(C)(C)C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A mixture of methyl 4-[(3-tert-butyl-5-{[4-(methoxycarbonyl)benzyl]oxy}-1H-pyrazol-1-yl)methyl]benzoate (6.90 g, 15.8 mmol), 10% palladium-carbon (50% water-containing product, 0.35 g) and tetrahydrofuran (50 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off and the obtained filtrate was concentrated to give the title compound (3.70 g, yield 81%) as colorless crystals. melting point 161-162° C.
Reaction SMILES: Cl.O1CCCCC1[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C@@H:17]([NH2:19])[CH3:18])=[CH:16][C:11]=2[N:10]=[CH:9]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:35][CH2:34]3)[CH:29]=2)[CH:24]=[CH:23][N:22]=1.CCCCO.CCN(C(C)C)C(C)C>CCOC(C)=O.CO.O>[NH:8]1[C:12]2[CH:13]=[CH:14][C:15]([C@@H:17]([NH:19][C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[C:30]([CH:33]5[CH2:35][CH2:34]5)[NH:31][N:32]=4)[CH:24]=[CH:23][N:22]=3)[CH3:18])=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: C[C@H](N)c1ccc2c(c1)ncn2C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: C[C@H](Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1ccc2[nH]cnc2c1
Temperature: 140 °C

Procedure:
A 5 mL microwave tube was charged with 126 (208.2 mg, 0.85 mmol), 53 (100 mg, 0.42 mmol) and n-BuOH (1.2 mL) then DIPEA (0.371 mL) was added, the tube sealed and heated to 140° C. for 18 h in an oil bath. The reaction cooled and diluted with EtOAc (50 mL). Water (25 mL) and some MeOH (1 mL) were added and the phases were separated. The organic layer was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by HPLC and SFC to afford 34.4 mg (22%) of I-5 as a white solid: SFC RT=0.72 min.
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:44]1[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][N:45]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:43])[C:22]1[CH:27]=[C:26](C2OC=CN=2)[CH:25]=[C:24]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[CH2:40]OC)=[O:34])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)([C:63](C)([CH3:65])[CH3:64])(C)C.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=CC=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(C(N)C)C=CC=CC=1>ClCCl>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:43])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:33]([NH:35][CH:36]([C:37]3[CH:65]=[CH:63][CH:64]=[CH:39][CH:38]=3)[CH3:40])=[O:34])[CH:23]=2)[C@H:9]([OH:8])[C@H:44]2[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][NH:45]2)[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(N)=O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CC(N)c1ccccc1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)NC(C)c3ccccc3)c2)C1
Reaction time: 0.33 h
Yield: 87 %

Procedure:
Step 15 (A): (2R,4R)-tert-Butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid (Step 1 (C), 40 mg, 0.06 mmol) in dichloromethane (1.5 mL) was added Hunig's base (24 mg, 0.18 mmol) to make a clear solution and HATU (28 mg, 0.072 mmol) was then added. After stirring for 20 min, the reaction mixture was added 1-phenylethanamine (15 mg, 0.12 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum and purified by silica gel Flash Chromatography (0% to 15% to 30% EtOAc/Hexane step gradient) to give 40 mg of the title compound (87% yield): 1H NMR (CDCl3, 500 MHz) δ 0.01 (3H, s), 0.05 (3H, s), 0.85 (9H, s), 0.89 (3H, m), 1.46 (9H, s), 1.50 (2H, m), 1.58 (3H, d, J=5 Hz), 2.02-2.05 (1H, m), 2.20 (1H, dd, J=5, 10 Hz), 2.64 (1H, m), 2.88-2.94 (1H, m), 3.30-3.37 (3H, m), 3.78 (1H, dd, J=5, 15 Hz), 4.00 (1H, m), 4.07-4.13 (2H, m), 4.60 (1H, m), 5.33 (1H, m), 6.56-6.61 (2H, m), 6.77 (2H, d, J=10 Hz), 7.25 (1H, m), 7.32 (2H, m), 7.37 (2H, m), 7.48 (1H, m), 7.97-8.01 (2H, m), 8.20 (1H, m), 8.24-8.31 (1H, m). MS (ESI) (M+H)+ 780.49.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=2[OH:33])[CH2:14][C:15]2[C:27]([CH3:28])=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][C:16]=2[CH3:29])(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=2[OH:33])[CH2:14][C:15]2[C:27]([CH3:28])=[CH:26][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][C:16]=2[CH3:29])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1cc(C)c(Cc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC(=O)O)cc(C)c1Cc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
37 mg (0.08 mmol) of ethyl (4-{3-[(4-fluorophenyl)sulphonyl]-4-hydroxybenzyl}-3,5-dimethylphenoxy)acetate (Example 1) are dissolved in 1 ml of ethanol, and a few drops of 1 N aqueous sodium hydroxide solution are added. The mixture is stirred at room temperature for thirty minutes and the solvent is then removed under reduced pressure. Water is added to the residue, and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulphate and concentrated. This gives 32 mg (90% of theory) of (4-{3-[(4-fluorophenyl)sulphonyl]-4-hydroxybenzyl}-3,5-dimethylphenoxy)acetic acid.
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]([NH2:39])=[S:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(OCC)(=O)C>CO.ClCCl>[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]1[S:38][CH:2]=[C:3]([C@@H:5]2[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]2[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[N:39]=1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCC(N)=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.5 %

Procedure:
To a solution of (2S, 4R)-2-bromoacetyl-4-methanesulfonyloxy-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (20 g) in a mixture of methanol (200 ml) and dichloromethane (200 ml) was added 2-(N-t-butoxycarbonylamino)thioacetamide (20 g) at room temperature. After stirring at ambient temperature for 12 hours, the mixture was poured into ethyl acetate, washed with saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated, and the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of acetone and dichloromethane (1:5, V/V) to give (2S,4R)-2-[2-(N-t-butoxycarbonylamino) methylthiazol-4-yl]-4-methanesulfonyloxy-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (9.7 g).
Reaction SMILES: [NH2:1][OH:2].CC[O-].[Na+].[Cl:7][C:8]1[C:20]([CH3:21])=[C:19]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:22]([OH:24])=O)[C:17]=3[NH:18]2)=[CH:10][CH:9]=1>C(O)C>[Cl:7][C:8]1[C:20]([CH3:21])=[C:19]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:22]([NH:1][OH:2])=[O:24])[C:17]=3[NH:18]2)=[CH:10][CH:9]=1
Reactant: Cc1c(Cl)ccc2c1[nH]c1c(C(=O)O)cccc12
Reactant: NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Cl)ccc2c1[nH]c1c(C(=O)NO)cccc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
Under cooling, a solution of 200 mg. of hydroxylamine in 15 ml. of ethanol is combined with 10 ml. of a sodium ethylate solution containing 1% sodium, as well as, in incremental portions, with 1.0 g. of the ethyl ester of 7-chloro-8-methylcarbazole-1-carboxylic acid. The mixture is stirred for one hour at 0° C. and for another 12 hours at room temperature and is then concentrated under vacuum. The residue is taken up in water, acidified to pH 1 with hydrochloric acid, extracted with ethyl acetate, and the extract is washed and concentrated. The residue is recrystallized from ethanol - water, thus obtaining in a 20% yield, 7-chloro-8-methylcarbazole-1-carbohydroxamic acid, m.p. 200° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:3])[N:33]([C:32]4[CH:34]=[CH:35][C:29]([O:28][C:27]([F:36])([F:37])[F:26])=[CH:30][CH:31]=4)[CH2:23][CH2:22][CH2:21]3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCCC12CCN(S(=O)(=O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
1-Benzenesulfonyl-4-(3-methoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (0.3 g) was dissolved under an argon atmosphere in toluene (10 ml), 4-(trifluormethoxy)-aniline (0.173 g) was added followed by dimethylaluminium chloride in heptane (1.8 ml, 0.9 molar). The mixture was refluxed 3 hours, more 4-(trifluormethoxy)-aniline (0.173 g) and dimethylaluminium chloride in heptane (1.8 ml) were added and refluxing was continued for further 3 hours. The reaction mixture was then cooled to RT, water (1 ml) was added and the mixture was stirred for 10 minutes. The solvent was evaporated off, the residue absorbed on silica gel and purified by flash-chromatography (AcOEt/heptane, gradient from 0 to 25%) to give the desired 9-benzenesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,9-diaza-spiro[5.5]undecan-1-one (0.215 g) as a white solid. MS (ESI): 469.13 (MH+)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O

Procedure:
To a stirred solution of methyl 2-allyloxy-4-(1-tertbutyloxycarbonyl-4-piperidinyloxy)benzoate (2.50 g, 6.39 mmol) from Step 1 above in methanol (40 mL) was added 2N NaOH (15.9 mL, 31.9 mmol). The reaction mixture was refluxed for 30 minutes and cooled in a ice water bath. The solution was acidified with 5% citric acid and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAC and washed with water (2×75 mL). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure to give 2-allyloxy-4-(1-tertbutyloxycarbonyl-4-piperidinyloxy)benzoic acid as a white solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[C:10]([CH3:13])([OH:12])[CH3:11])=[CH:5][CH:4]=1.C(OCCC1C=CC(OC)=CC=1)(=O)C.C[Mg]Br>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)C(C)(C)O)cc1
Agent: COc1ccc(CCOC(C)=O)cc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(CC(C)(C)O)cc1

Procedure:
At step 3, the deprotected electrodes 53 were reblocked with a MPMP-diol reprotection unit 54. For this example, 2-(4-methoxyphenyl)ethyl acetate was allowed to react with excess methylmagnesium bromide in tetrahydrofuran (THF) to provide after aqueous workup 1-(4-methoxyphenyl)-2-methylpropan-2-ol. This was brominated with NBS in carbon tetrachloride at reflux for 12 hours. Hydroylsis of the resulting 1-bromo-1-(4-methoxyphenyl)-2-methylpropan-2-ol was performed with freshly prepared silver carbonate in aqueous acetone. The resulting 1-(4-methoxy-phenyl)-2-methyl-propane-1,2-diol (MPMP-diol) was identical spectroscopically with that reported in the literature. See J. Yan et al., Tetrahed. Lett. 46, 8503 (2005). The unblocked electrode was then treated with 100 μl of 10 mM MPMP-diol reprotection unit in anhydrous toluene for 30 min to provide the reprotected electrode 55. The reprotected electrodes 55 comprised para-methoxybenzyl groups 56 that provide a protecting group that can be removed through oxidation. The MPMP-diol protecting group has been previously used to protect borate esters. See J. Yan et al., Tetrahed. Lett. 46, 8503 (2005).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH:26]([OH:28])[CH3:27])[O:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:29]([O:28][CH:26]([C:24]1[O:23][N:22]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[CH:25]=1)[CH3:27])(=[O:31])[CH3:30]
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide (28 mg, 0.070 mmol) and DMAP (0.864 mg, 7.00 μmmol) were dissolved in pyridine under nitrogen atmosphere. The reaction mixture was cooled to 0° C., acetic anhydride (7.51 mg, 0.074 mmol) was added and the reaction mixture stirred for 2 h. The solvent was evaporated. Yield 82%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), δ 1.64 (d, 3H), 2.11 (s, 3H), 4.25 (dd, 1H), 4.43 (dd, 1H), 4.54-4.63 (m, 1H), 6.05 (q, 1H), 6.63 (d, 1H), 6.65 (d, 1H), 7.48 (d, 1H), 7.70 (d, 1H), 7.84 (dd, 1H), 7.89 (d, 1H), 8.06 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([CH:21]([NH2:24])[CH2:22][CH3:23])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CCC(N)CC
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC(CC)CC

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 1-ethyl-propylamine following general procedure B to afford 4-(1-ethyl-propylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (160 mg) following general procedure E.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][C:5]([SH:8])=[N:6][CH:7]=1.Br[CH2:10][CH:11]([C:34]1[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=1)[CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[N:15]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:14]=1>CN(C)C=O>[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[N:15]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[N:14]=[C:13]([CH2:12][CH:11]([C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)[CH2:10][S:8][C:5]3[NH:4][N:3]=[CH:7][N:6]=3)[CH:17]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: Sc1ncn[nH]1
Reactant: COc1ccc(-n2nc(CC(CBr)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(CC(CSc3ncn[nH]3)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a suspension of sodium hydride (4.0 mg, 60% dispersion in oil) in N,N-dimethylformamide (1.0 mL) at 0° C. was added a solution of 2H-[1,2,4]triazole-3-thiol (10.0 mg, 0.1 mmol, 1.1 equiv) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at 0° C. for 30 min then a solution of 3-(3-bromo-2-m-tolyl-propyl)-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole (48 mg, 0.09 mmol, 1.0 equiv) in N,N-dimethylformamide (1.0 mL) was added. The reaction mixture was brought to room temperature then was stirred for 2 h. The reaction was quenched with satd aq ammonium chloride (1.0 mL), and the resulting mixture was diluted with water (10.0 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) then brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by reversed-phase HPLC to yield the title compound (39 mg, 80%). HPLC: Rt=3.26 (Method B). MS (ESI): mass calculated for C28H25Cl2N5OS, 549.12; m/z found, 550.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.32 (br s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.07-7.04 (m, 5H), 6.95 (dd, J=8.4, 21. HZ, 2H), 6.89 (d, J=9.0 Hz, 2H), 6.31 (s, 1H), 3.70 (s, 3H), 3.48 (dd, J=12.9, 6.3 Hz, 1H), 3.36 (dd, J=12.7, 8.2 Hz, 1H), 3.26 (m, 1H), 3.07 (dd, J=14.9, 6.4 Hz, 1H), 2.91 (dd, J=14.9, 8.2 Hz, 1H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][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.Br[C:42]1[CH:43]=[C:44]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][OH:59])[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH2:57][CH2:58][OH:59])[CH2:55][CH2:56]6)=[O:50])[CH:45]=[CH:46][CH:47]=5)[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:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=C(Cc1cccc(Br)c1)N1CCN(CCO)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CC(=O)N4CCN(CCO)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(3-bromo-phenyl)-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethanone (143 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[3-(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]-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-186) as a yellow powder (56 mg, 28%).