Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:18][Mg]Cl.ClC1C=C(C=C(F)C=1)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Cl[Mg]Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cc(F)cc(Cl)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) was reacted with 3,4-dichlorobenzylmagnesium chloride (0.25 M in diethyl ether, 28.0 mL, 7.0 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3,4-dichlorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pt2O). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane to afford the title compound. 0.064 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][N:12]=[C:13]([C:20](=[O:22])[CH3:21])[CH2:14][C:15](OCC)=[O:16])[C:5]([OH:7])=[O:6].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15](=[O:16])[CH2:14][C:13]([C:20](=[O:22])[CH3:21])=[N:12]1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(=NNc1ccc(C(=O)O)cc1C)C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)C1=NN(c2ccc(C(=O)O)cc2C)C(=O)C1

Procedure:
To a solution of a 5 g. (34 mmoles) of 3-methyl-4-[N′-(2-ethoxycarbonyl-1-acetylethylidene)hydrazino]benzoic acid in 25 ml. of ethanol and 25 ml. of water was added with stirring 34.3 ml. of a 1 M sodium carbonate solution. The mixture was stirred at room temperature for 24 hours. The resulting mixture was acidified to pH 3 with 6 M hydrochloric acid and the resulting solid was collected by filtration, washed with water and dried. The 3-methyl-4-(3-acetyl-5-oxo-2-pyrazolin-1-yl)benzoic acid has melting point of >250° C.
Reaction SMILES: N#N.N[C@H](C(N[C@@H](C[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H](O)C[C@@]1(C(N)=O)CCCN1C(C)(C)C)=O)CC(=O)N.C(OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)=O)C1C=CC=CC=1.O[C:59]1[C:67]2[N:66]=NN[C:63]=2[CH:62]=[CH:61][CH:60]=1.[CH2:68]([N:70]1CCOCC1)C>>[CH:67]1([N:66]=[C:68]=[N:70][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O)C(N)=O
Reactant: CCN1CCOCC1
Reactant: Oc1cccc2[nH]nnc12
Agent: N#N
Agent: O=C(O)c1ccc2cc(C(=O)OCc3ccccc3)ccc2c1
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
In a manner analogous to that described in Example from 295 mg of N2 -[3(S) [[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide, 204 mg of 6-(benzyloxycarbonyl ) -2-naphthoic acid, 20 mg of hydroxybenzotriazole, 77 mg of N-ethylmorpholine and 151 mgof dicyclohexylcarbodiimide there were obtained, after chromatography on silica gel using System G for the elution, 340 mg of N2 -[3(S)-[[N-[6-(benzyloxycarbonyl)-2-naphthoyl]-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as an off-white solid from ethyl acetate/n-hexane: MS: m/e 736 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C:18]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:20])[CH2:14]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (51 μL, 1.03 mmol) was added to a solution of (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.93 mmol), HATU (391 mg, 1.03 mmol) and DIPEA (410 μL, 2.35 mmol) in DMF and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a pale brown oil (110 mg, 70%). 1H NMR (CDCl3, 400 MHz) δ 4.01 (m, 3H); 3.52-3.41 (m, 3H); 3.25-3.11 (m, 2H); 3.10-2.97 (m, 2H); 2.89 (dt, J=11.4, 7.5 Hz, 1H); 2.11-1.99 (m, 1H); 2.01-1.91 (m, 2H) and 1.93-1.82 (m, 2H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C=CC=CC=1C=C.Cl[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(=O)(O)(O)O>>[CH3:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: ClCCc1ccccc1
Reactant: C=Cc1ccccc1
Agent: C=Cc1ccccc1Cl
Agent: O=P(O)(O)O
Product: CC1CC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 90 parts of styrene, 217 parts of o-chlorostyrene and 83 parts of o-chloroethylbenzene is added to 722 parts of 94 per cent strength by weight phosphoric acid at 35° to 40° C over 5 hours, whilst stirring vigorously. The mixture is then stirred for a further 2 hours at 35° to 40° C and the organic phase is separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation gives 31 parts of 1-methyl-3-phenylindan and 140 parts of 1-methyl-3-(o-chloro)-phenylindan (b.p. 165° to 168° C (10 mm), nD25 : 1.5890).
Reaction SMILES: [C:1]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.[N:26]1(CC(O)=O)[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]1=[O:28]>>[NH:26]1[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]1=[O:28].[C:1]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:28])[CH3:2]
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CC(=O)N1CCNCC1
Product: Cc1c[nH]c(=O)[nH]c1=O

Procedure:
According to the general procedure, the title compound was prepared using PS-trityl-piperazine resin (Novabiochem) and thymine-1-acetic acid (Aldrich): HPLC/MS M+H=253 fnd., (0.29 min, 100%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:13]1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O.[C:44]([OH:56])(=[O:55])CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C.CO>[CH3:13][O:56][C:44]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[OH:1])=[O:55]
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: Oc1ncnc2ccc(I)cc12
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ncnc(O)c2c1

Procedure:
4-Hydroxy-6-iodoquinazoline (250 mg), a catalytic amount of palladium (II) acetate and 1,3-bis(diphenylphosphino)propane were dissolved in N,N-dimethylformamide (3.8 ml) and methanol (1.5 ml) and 1.5 ml of triethylamine was added. After the interior of a reaction vessel was sufficiently replaced with a carbon monoxide gas, a reaction was performed at 80° C. for 20 hours under the carbon monoxide atmosphere. After completion of the reaction, the reaction mixture was poured into 10% aqueous citric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluting with ethyl acetate) to obtain 4-hydroxyquinazoline-6-carboxylic acid methyl ester (XII-1, 157 mg) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17](O)=[O:18])=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CC[N:23]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([NH2:23])=[O:18])=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(C(N)=O)c(Nc2ccc(Br)cc2F)cc1=O
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.069 g, 0.202 mmol), EDCI (0.12 g, 0.61 mmol), and HOBt (0.082 g, 0.61 mmol) in DMF (5 mL) was stirred for 30 minutes. NH4Cl (0.033 g, 0.61 mmol) was added followed by Et3N (0.085 mL, 0.61 mmol). After 1 hour, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 52 mg (76%) clean desired product as an off-white solid. MS APCI (+) m/z 340, 342 (M+, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 10.39 (s, 1H), 8.34 (s, 1H), 7.67 (dd, 1H), 7.43 (m, 2H), 3.36 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O[C:19](=O)[CH3:20])(=O)C.[C:22](=[O:24])=O>C(N(CC)CC)C>[O:24]=[C:22]1[C:19]2[C:20](=[CH:10][CH:5]=[CH:6][CH:7]=2)[C:12](=[O:14])[CH:11]1[C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Reactant: O=C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C

Procedure:
A mixture of (4-acetylamino-phenyl)-acetic acid (15 g, Reference Example 15) phthallic anhydride (15.8 g) and triethylamine (42.3 mL) was heated at 70° C. for 3 minutes then treated with acetic anhydride (105.8 mL). The mixture was heated on a steam bath at approximately 70° C. until evolution of carbon dioxide ceased. The resulting deep red solution was evaporated and the residue was treated with water (750 mL) then heated on a steam bath for 2 hours. The insoluble material was filtered, dried under vacuum and then subjected to chromatography on silica eluting with mixtures of dichloromethane and methanol (99:5 to 50:50, v/v) to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.[H-].[Na+].Cl[C:33]1[C:42]2C(=CC=C(S(N[C@H]3CC[C@H](C(OCC)=O)CC3)(=O)=O)C=2)C(Cl)=CN=1>COCCOC.CC(N(C)C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:33][CH3:42])=[O:24])[CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H]3CC[C@H](C(=O)O)CC3)cc12
Reactant: CCOC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: COCCOC
Product: CCOC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CC1
Temperature: 60 °C

Procedure:
trans-4-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride ##STR59## Guanidine hydrochloride (273 mg, 2.86 mmol) was added in one portion to a stirred suspension of NaH (55 mg, 80% dispersion by wt in mineral oil, 1.82 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of ethyl trans-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (370 mg, 0.78 mmol) in DMA (10 mL) was added and the mixture heated at 90° C. for 3 h. The solvents were evaporated in vacuo, the residue was partitioned between Et2O (100 mL), aqueous NH4Cl (10 mL), and water (150 mL). The separated aqueous phase was extracted with Et2O (3×100 mL) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using toluene-i-PrOH-0.880NH3 (100:0:0 to 90:10:0.05) as eluant to give ethyl trans-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (70 mg, 0.15 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>O>[CH:15](=[N:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[S:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)CCCSc1ccccc1N
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CN(C)CCCSc1ccccc1N=Cc1ccccc1

Procedure:
A mixture of 51g of 2-(3-dimethylaminopropylthio)aniline, 26g of freshly distilled benzaldehyde and 200 ml of xylene is refluxed under an atmosphere of nitrogen. The water formed in the reaction is collected in a Dean-Stark tube; the theoretical quantity is collected after 4 hours of refluxing. The xylene and any unchanged benzaldehyde are removed on the steam bath at 30 mm of Hg, finally at 2 mm of Hg. Fractionation of the residue yields 56g of the title compound, boiling point 182°-189° C. at 0.4 mm of Hg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][C:6]=1[CH3:14].Cl[C:16](OC1C=CC=CC=1)=[O:17].C(N(CC)CC)C.[CH2:32]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])[CH3:33]>C(#N)C>[CH2:32]([C:34]1[S:38][C:37]([NH:39][C:16]([NH:13][S:10]([C:8]2[S:9][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:14])[CH:7]=2)(=[O:12])=[O:11])=[O:17])=[N:36][C:35]=1[CH3:40])[CH3:33]
Reactant: COCCc1sc(S(N)(=O)=O)cc1C
Reactant: CCc1sc(N)nc1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1sc(NC(=O)NS(=O)(=O)c2cc(C)c(CCOC)s2)nc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
5-(2-Methoxy-ethyl)-4-methyl-thiophene-2-sulfonic acid amide (0.1556 g, 0.661 mmol) was dissolved in 4 mL of abs. acetonitrile and treated successively with phenyl chloroformate (0.103 g, 1.00 eq.) and triethylamine (0.229 mL, 2.5 eq.), and the mixture kept at ambient temperature for 1 h. The above prepared 5-ethyl-4-methyl-thiazol-2-ylamine (0.094 g, 1.00 eq.), dissolved in a tiny amount of acetonitrile, was then added, and the mixture heated to 60° C. over night. Cooling, pouring onto crashed ice/NH4Cl, twofold extraction with ethyl acetate, washing with brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, ethyl acetate), yielded eventually 0.089 g of the title compound as light brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:18]=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:31]([F:42])[CH:30]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:18][NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:31]([F:42])[CH:30]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Reactant: CC(C)COc1ccc(C=O)cc1Cn1nc(C(C)(C)C)cc1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CCc1ccc(NCc2ccc(OCC(C)C)c(Cn3nc(C(C)(C)C)cc3C(C)(C)C)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of 3-[(3,5-di-tert-butyl-1H-pyrazol-1-yl)methyl]-4-isobutoxybenzaldehyde (0.43 g, 1.16 mmol) and ethyl 3-(4-amino-2-fluorophenyl)propanoate (0.25 g, 1.16 mmol) in 1,2-dichloroethane (8.6 mL) was added acetic acid (0.20 mL, 3.48 mmol), and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (0.74 g, 3.48 mmol) was added, and the mixture was further stirred for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried, and concentrated under reduced pressure to give the title compound (0.62 g, yield 100%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@@H:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21]CCC(C)(C)C)=[O:20])[C:14]([C:28]([O-:30])=[O:29])=[CH:13]3)[CH2:4][O:3]1.[Li+].[OH-].[CH2:34]1[CH2:38]OC[CH2:35]1.[CH3:39]O>>[CH3:31][C:2]1([CH3:1])[O:6][C@@H:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:34]([CH3:35])([CH3:38])[CH3:39])=[O:20])[C:14]([C:28]([OH:30])=[O:29])=[CH:13]3)[CH2:4][O:3]1
Reactant: CC(C)(C)CCOC(=O)n1c(C(=O)[O-])cc2cc(OCC[C@H]3COC(C)(C)O3)ccc21
Reactant: CO
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCC[C@H]3COC(C)(C)O3)ccc21

Procedure:
To a solution of 1-(1,1-dimethylethyl)2-ethyl 5-({2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}oxy)-1H-indole-1,2-dicarboxylate (167 mg, 0.385 mmol) in MeOH (2 mL) was added 1N LiOH (0.58 mL). A precipitate appeared and THF (2 mL) was added. The solution was stirred until TLC showed the starting material had been consumed. The reaction mixture was quenched with 1N HCl (0.58 mL) and the solvent evaporated. The residue was dissolved in EtOAc and extracted with 1N NaOH. The aqueous layer was acidified with conc. HCl until a precipitate formed and then partitioned with EtOAc. The organic layer was separated, dried over MgSO4 and the solvent evaporated. The crude material was directly with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:17][CH2:18][CH:19]1[CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH:19]2[CH2:21][O:20]2)[CH2:8][CH2:7]1
Reactant: BrCCC1CO1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(OC2CCN(CCC3CO3)CC2)cc1Cl
Temperature: 50 °C
Reaction time: 12 h
Yield: 97.3 %

Procedure:
A mixture of 4-(3,4-dichlorophenoxy)piperidine (WO 0058305, WO 0177101) (2.00 g), 2-(2-bromoethyl)oxirane (J. Am. Chem. Soc. 1981, 103, 7520-8) (1.36 g) and potassium carbonate (2.2 g) in acetone (20 ml) was stirred at 50° C. for 12 h. The solvent was removed under vacuum. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate. The mixture was filtered and the solvent was evaporated to afford the subtitle compound as a yellow oil (2.50 g) which was used without further purification in the next step.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH:13]1([CH2:16][N:17]2[C:25]([N:26]3[CH2:31][C@H:30]([CH3:32])[NH:29][C@H:28]([CH3:33])[CH2:27]3)=[N:24][C:23]3[C:18]2=[N:19][C:20]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)=[N:21][C:22]=3[N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:15][CH2:14]1>ClCCl.ClCCl.CO>[CH:13]1([CH2:16][N:17]2[C:25]([N:26]3[CH2:31][C@H:30]([CH3:32])[N:29]([S:9]([CH3:8])(=[O:11])=[O:10])[C@H:28]([CH3:33])[CH2:27]3)=[N:24][C:23]3[C:18]2=[N:19][C:20]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)=[N:21][C:22]=3[N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH2:15][CH2:14]1
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H](C)N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H](C)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.1 %

Procedure:
Triethylamine (127.1 μl, 0.91 mmol) and methanesulfonyl chloride (35.3 ml, 0.46 mmol) were added to a dichloromethane suspension (2.0 ml) of 5-[9-(cyclopropylmethyl)-8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (105.9 mg, 0.23 mmol) with ice cooling and the resulting mixture was stirred at the same temperature for 2.5 hours and at room temperature for 4 hours. Triethylamine (127.1 μl, 0.91 mmol) and methanesulfonyl chloride (35.3 ml, 0.46 mmol) were added at room temperature and the resulting mixture was stirred for 16 hours followed by the addition of dichloromethane-methanol (10:1) and washed with water. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in 1,2-dichloroethane (2.0 ml). Triethylamine (127.1 μl, 0.91 mmol) and methanesulfonyl chloride (35.3 ml, 0.46 mmol) were added at room temperature and the resulting mixture was stirred for 19 hours followed by the addition of dichloromethane and washed with 10% aqueous citric acid solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1) to give the title compound (16.3 mg, 13%) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:14][O:15][C:16](Cl)=[O:17])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]C)C(O)=O.[C:30]([OH:33])(=[O:32])[CH3:31]>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[C:1]1([CH2:14][O:15][C:16]([NH:19][CH2:20][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:31][C:30]([OH:33])=[O:32])=[O:17])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Reactant: CCCCCCC(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)CCCCCCCNC(=O)OCc1cccc2c1Cc1ccccc1-2
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Fluorenylmethoxycarbonyl chloride (4.87 g, 0.02 mol) to a mixture of aminooctanoic acid (3.0 g ,0.02 mol) in 200 mL of 10% Na2CO3 (aq) and dioxane (150 mL) at 0° C. The mixture was stirred for 2.5 h at 0° C., acidified to pH 5 with acetic acid and extracted three times with CHCl3. The combined organic extracts were washed with H2O, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, CHCl3 →95:5 CHCl3 --MeOH) to afford 8-fluorenylmethoxycarbonylaminooctanoic acid (6.4 g) as a solid: MS 382 (MH+). The product was dissolved in CH2Cl2 (40 mL), cooled to 0° C., and treated with methoxymethyl amine hydrochloride (2.05 g, 21.1 mimol), triethylamine (8.1 mL) and BOP reagent (8.0 g). This mixture was stirred for 12 h at 0° C., washed sequentially with 3N HCI, NaHCO3 (sat"d. aq.) and brine. The organic phase was dried (Na2SO4) and concentrated. in vacuo. The residue was purified by flash column chromatography (silica gel; CHCl3 →98:2 CHCl3 --MeOH) to afford 8-fluorenylmethoxycarbonyl-aminooctanoic acid N,N-methoxymethyl amide (7.1 g): MS m/z 425 (MH+). A solution of the product (6.8 g) in THF (80 mL) was cooled to -40° C. and treated dropwise with 1.0M DIBAL/THF (48.5 mL). The mixture was stirred an additional 15 min, quenched with 3N HCI (50 mL) and warmed to room temperature. The resulting aqueous layer was extracted repeatedly with CHCl3 and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (silica gel; CH2Cl2 →2% MeOH--CH2Cl2) to afford aldehyde 13a as a solid: 5.2 g; MS m/z 366 (MH+).