Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29]C(=O)C)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)C>O>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCOC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCCCO)cc2)cc1
Yield: 97.3 %

Procedure:
30 m moles (13.2 g) of the above 4'-(10-acetyloxydecyloxy) biphenyl-4-carboxylic acid ethyl ester and 10 g of sodium hydroxide were stirred for 10 min. at 70° C. in a mixed solvent of 40 ml of ethanol and 80 ml of water. After the reaction, the reaction solution was concentrated to obtain 10.8 g of 4'-(10-hydroxydecyloxy)biphenyl-4-carboxylic acid. (yield: 97%)
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C1C=C(C)C=CC=1S([O-])(=O)=O>O1CCCC1>[CH3:1][NH:2][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:26])([F:3])[C:22]([F:25])([F:24])[F:23]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCCCCCC(F)(F)C(F)(F)F)c1
Solvent: C1CCOC1
Product: CNCCCCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
4.0 g of methylamine is condensed in a solution of 2.9 g of 7,7,8,8,8-pentafluor-octyltosylate in 10 ml of absolute tetrahydrofuran at −20° C., and it is stirred overnight in a pressure vessel at room temperature. After the pressure vessel was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. The reaction solution is taken up in dichloromethane, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 1.58 g of methyl-(7,7,8,8,8-pentafluor-octyl)-amine is obtained as a crude product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([NH:14][N:5]2[N:4]=[C:3]([CH2:2][NH:1][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:13])=[O:24])=[CH:22][CH:21]=1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)NCc2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 42 and 4-methylbenzene-1-sulfonyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.53-11.64 (bs, 1H), 8.19-8.33 (bs, 1H), 8.23 (ddd, J=7.8, 1.5, 0.6 Hz, 1H), 8.06 (ddd, J=8.1, 1.4, 0.7 Hz, 1H), 7.95 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.87 (ddd, J=7.9, 7.2, 1.3 Hz, 1H), 7.57-7.61 (m, 2H), 7.33-7.49 (m, 4H), 7.21-7.25 (m, 2H), 4.22-4.24 (m, 2H), 3.69 (s, 2H), 2.31 (s, 3H); MS (ESI+) M/Z 497 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29](Br)[CH2:30][CH3:31]>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:29][CH2:30][CH3:31])[S:22]([CH2:25][CH3:26])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)NC1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Analogously to Example 11b, 7.5 g (20 mmol) of 6-benzyloxy-4-(ethylsulfonyl)amino-2,2-dimethylchroman (Example 11a) were introduced in portions at 10° C. into a suspension of 0.82 g (27 mmol) of sodium hydride (80% dispersion) in 100 ml of DMA. After stirring at RT for 2 h, 2.4 ml (26.2 mmol) of 1-propyl bromide were added dropwise. After work-up, the residue was chromatographed on silica gel using n-heptane/EA (1:1) and 6.0 g of product were crystallized from appropriate fractions using petroleum ether, m.p. 102-103° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17](Br)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:31]3[C:32]([O:36][CH3:37])=[CH:33][CH:34]=[CH:35][C:30]=3[F:29])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COc1cccc(F)c1B(O)O
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CCCCCNc1ncnc2oc(-c3c(F)cccc3OC)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Dissolve 150 mg (0.34 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 142 mg (0.84 mmol) (2-fluoro-6-methoxyphenyl)boronic acid in 2.0 ml 1,2-dimethoxyethane and add 0.34 ml of 2 M aqueous sodium carbonate solution and 24 mg (0.03 mmol) 1,1′-bis(diphenylphosphano)ferrocene palladium(II) chloride. Next, stir for 15 h at 80° C. Purify the reaction mixture directly by preparative RP-HPLC (gradient: water/acetonitrile). 56 mg (34% of theor.) of the desired product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])(C)C.[NH2:22][C:23]1[C:28]([C:29]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])=[O:30])=[CH:27][N:26]=[C:25](S(CC)(=O)=O)[N:24]=1>>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:25]3[N:24]=[C:23]([NH2:22])[C:28]([C:29](=[O:30])[C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[O:38][CH3:39])=[CH:27][N:26]=3)=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccc(N)cc2)C1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Product: CCOC(=O)N1CCCC(Oc2ccc(Nc3ncc(C(=O)c4cc(F)ccc4OC)c(N)n3)cc2)C1

Procedure:
3-(4-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester ((prepared as described above in Example 139) and the compound of Example 48 were treated as in Example 113, the resulting product was then treated as in Example 114, and then as in Example 115 to give 3-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-phenoxy]-piperidine-1-carboxylic acid ethyl ester. MS(ES) (M+H)+=510.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([N:10]([CH2:18][C:19]2([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21][CH2:20]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[CH2:30]([O:32][C:33](=[O:41])[CH:34](Br)[C:35](OCC)=[O:36])[CH3:31]>C1(C)C=CC=CC=1>[C:13]([O:12][C:11]([N:10]([CH2:18][C:19]1([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:22][CH2:21][CH2:20]1)[C:7]1[N:8]=[N:9][C:4]([CH:1]2[N:2]=[C:35]([OH:36])[CH:34]([C:33]([O:32][CH2:30][CH3:31])=[O:41])[S:3]2)=[CH:5][CH:6]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C(N)=S)nn1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1SC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)N=C1O
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 17.2 %

Procedure:
t-Butyl 6-carbamothioylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1.0 g, 2.4 mmol), diethylbromomalonate (2 mL, 12 mmol), and toluene were added to a round bottom flask, heated to 90° C., and stirred for 40 min. The reaction was concentrated and purified using reverse phase chromatography to yield 219 mg of ethyl 2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxylate as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:21]([S:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[S:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>C(C(C)=O)C>[Cl:13][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[CH:12][C:3]([CH2:2][O:14][C:15]3[CH:16]=[C:17]([CH:21]([S:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[S:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:18]=[CH:19][CH:20]=3)=[N:4]2)=[CH:9][CH:8]=1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
A mixture of 2-bromomethyl-7-chloroquinoline (2.5 g) (Step 2), phenol (Step 1) (3.4 g) and K2CO3 (3 g) was heated at reflux for 4 hours in methyl ethyl ketone (100 ml). The reaction mixture was cooled and ether (100 ml) was added. The suspension was filtered and evaporated. Flash chromatography of the residue using 30% ethyl acetate in hexane afforded the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[CH3:38]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[C:23]2[CH3:38])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCN
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCNCC(O)COc1ccc(CCOCC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([OH:25])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[F:35][C:36]([F:41])([F:40])[CH2:37][CH2:38]O.C(C=P(CCCC)(CCCC)CCCC)#N.O>C1(C)C=CC=CC=1>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([O:25][CH2:38][CH2:37][C:36]([F:41])([F:40])[F:35])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: OCCC(F)(F)F
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(O)c2)ncn1)C1CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCCC(F)(F)F)c2)ncn1)C1CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-hydroxypyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (57 mg) in toluene (1.2 mL) were added 3,3,3-trifluoro-1-propanol (21 μL) and cyanomethylenetributylphosphorane (64 uL), and the mixture was stirred at 100° C. for 4 hr. After allowing to cool to room temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (53 mg) as a pale-yellow amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][CH:9]([F:25])/[C:10](=[N:18]\[S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]>C1COCC1.[Cu]Cl.[Zn]>[CH3:23][C:21]([CH3:24])([S@@:19]([NH:18][C@:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([CH:9]([F:25])[F:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:20])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[S@](=O)/N=C(/c1ccccc1F)C(F)F
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@](N[S@@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
In a dry flask under an inert atmosphere copper(I) chloride (2.74 g, 27.7 mmol) and activated zinc powder (14.5 g, 221 mmol) were mixed and heated to 130° C. After cooling to r.t. dry THF (80 ml) was added and under stirring the dispersion was heated to reflux for 30 min. The external heating was removed and a solution of ethyl 2-bromoacetate (11.5 g, 7.65 ml, 69.1 mmol) in dry THF (40 ml) was added dropwise in a manner that the temperature was maintained at 55° C. After complete addition stirring at 55° C. was continued for 30 min. Thereafter, the mixture was cooled to 5° C. and a solution of the (S,Z)—N-(2,2-difluoro-1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (7.67 g, 27.7 mmol) in dry THF (40 ml) was added dropwise within 10 min while the temperature was kept below 5° C. In order to complete the reaction stirring was continued at 0° C. for 1 h. For the workup, the reaction mixture was filtered through a layer of Dicalite® which was washed with TBME. The filtrate was extracted with a saturated solution of NH4Cl, the organic layer was dried over MgSO4 and evaporated at reduced pressure. The crude product was purified by 2 consecutive chromatographies on silica gel (eluent: heptane/AcOEt 4:1, then 3:1 for the mixture of isomers) to give the (R)-ethyl 3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluoro-3-(2-fluorophenyl)butanoate (XV-1) (yellow oil, 5.17 g, 51.2% yield) as the first eluting isomer and the (S)-ethyl 3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluoro-3-(2-fluorophenyl)butanoate (XV-2) (orange solid, 2.59 g, 25.7% yield) as the second eluting isomer.
Reaction SMILES: C(O)(=O)C.[C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH2:14])=[NH:13].C[O:22][C:23](=O)/[C:24](/[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[C:25](\O)/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C[O-].[Na+]>CO>[C:29]([O:28][C:26]([C:25]1[C:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:23]([OH:22])[N:14]=[C:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: N=C(N)Cc1ccccc1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a stirred solution of 2-biphenyl-2-yl-acetamidine acetate salt (5-01) (2.5 g, 9.2 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (4.2 g, 13.88 mmol) in methanol (60 mL) was added sodium methoxide (1.5 g, 27.77 mmol) at 0° C., then the reaction mixture was allowed to warm to room temperature and was stirred for 16 h. After completion of the reaction, it was quenched with 1N HCl, evaporated and w ater was added. The mixture was extracted with ethyl acetate and the separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get a crude product, which was purified using a normal silica column using 30% ethyl acetate in hexane to get 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01) (2.5 g, 57.63%) as a white solid.
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([CH3:28])=[C:23]([C:25](O)=[O:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([N:4]([CH:32]2[CH2:33][CH2:34]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([CH3:28])=[C:23]([C:25]([N:36]([CH3:37])[CH3:35])=[O:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CNC
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)O)c(C)s3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)N(C)C)c(C)s3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A mixture of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-5-methylthiazole-4-carboxylic acid (43A, 30 mg, 0.063 mmol), dimethylamine, 40% aqueous (0.016 mL, 0.125 mmol) and HATU (35.7 mg, 0.094 mmol) in DMF (1 mL) was stirred at room temperature for 3 h. The solvent was evaporated off and the residue purified by silica gel chromatography (2-10% MeOH/dichloromethane). The material was further purified by preparative HPLC to give of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N,N,5-trimethylthiazole-4-carboxamide (20 mg, 62.5% yield) as off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([NH:8][CH:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:23])[C:20]([OH:22])=[O:21])=[CH:17][C:18]=1[Cl:28])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(CCOc1ccc(C(=O)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(CCOc1ccc(C(=O)C(=O)O)cc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18.7 h
Yield: 118 %

Procedure:
DL-p-(3-tert-Butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxylic acid (750 mg.) was dissolved in a mixture of chloroform (15 ml.) and methanol (10 ml.), and to the solution was added 1,3,5-trichloroisocyanuric acid (180 mg.) in the course of 5 minutes, whereafter the mixture was stirred at ambient temperature for 18.7 hours. The insoluble materials were filtered off from the reaction mixture and the filtrate was evaporated to dryness under reduced pressure. The resultant residue was dissolved in ethyl acetate, and the solution was washed with water and then dried over magnesium sulfate. This solution was evaporated to dryness under reduced pressure to give a residue, which was subjected to column chromatography on silica gel (11 g.). Elution was carried out with a mixture of chloroform and methanol (99:1 by volume) and the fractions containing a desired compound were collected. The solvent was removed by evaporation from the eluate under reduced pressure to give DL-p-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)-3-chlorophenylglyoxylic acid (380 mg.).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][N:7]=1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:3])=[CH:8][N:7]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Cl)nc1

Procedure:
Thionyl chloride (14.6 ml, 0.2 mol) was added extremely carefully in dropwise manner to a rapidly stirred mixture of 2-chloro-5-hydroxymethylpyridine (18.6 g, 0.13 mol) and chloroform (150 ml) at ambient temperature (20° C.). After addition was complete the resulting mixture was heated under reflux for 12 hours. The reaction mixture was then allowed to cool to ambient temperature (20° C.) and chloroform was evaporated off under reduced pressure to give a brown oil. The product, 2-chloro-5-chloromethyl-pyridine was isolated from this brown oil by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with dichloromethane as eluent, as a yellow oil which solidified on standing (17.45 g, 82.9%).
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH2:7][CH2:6][CH:5]([C:8]([CH3:10])=[CH2:9])[C:4]=1[CH2:11]Cl.[C:13](=[O:15])=[O:14].Cl.[Na]>O1CCCC1.CCOCC>[C:8]([CH:5]1[CH2:6][CH2:7][C:3]([CH3:2])([C:13]([OH:15])=[O:14])[C:4]1=[CH2:11])([CH3:10])=[CH2:9]
Reactant: O=C=O
Reactant: C=C(C)C1CCC(C)=C1CCl
Agent: Cl
Agent: [Mg]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C1CCC(C)(C(=O)O)C1=C
Temperature: -10 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
75 ml of dry tetrahydrofuran and 23 g of magnesium shavings are added to a round flask which is fitted with a stirrer, thermometer, dropping funnel and reflux condenser. Without stirring there is added thereto slowly (within 4 hours) a solution of 112.4 g of 1-methyl-2-chloromethyl-3-(prop-1-en-2-yl)-cyclopent-1-ene in 100 ml of tetrahydrofuran. The mixture is brought to 60°-65° for 1 hour and then cooled to -10°. A carbon dioxide stream is conducted through the solution, which is cooled to -10° C. The amount of carbon dioxide introduced is weighed; it amounts to 29.5 g. The mixture is left to stand at room temperature overnight. The mixture is then cooled to 10° C. and decomposed with 300 ml of a 10% hydrochloric acid solution. The acid solution is extracted with ether, the organic acid formed is taken up as the sodium salt (treatment with 10% sodium hydroxide) from the ether into the aqueous phase, which is washed with ether. After acidifying with 10% orthophosphoric acid, the mixture is extracted with ether and the etherial solution is dried over sodium sulphate. The solvent is evaporated and there are obtained 78.2 g (yield: 66%) of crude 3-isopropenyl-2-methylene-1-methyl-cyclopentanecarboxylic acid, which are recrystallized with hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:4][CH:3]=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(O)(=O)C>ClCCCl>[CH2:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:19][CH:20]=1)[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CCc1ccccc1
Reactant: Nc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(NCCc2ccccc2)cc1

Procedure:
A solution of 4-amino-N-quinolin-3-yl-benzamide (1.0 g, 3.8 mmol), phenylacetaldehyde (0.49 mL, 4.18 mmol), tetramethylammonium triacetoxyborohydride (2.0 g, 7.60 mmol) and acetic acid (a catalytic amount) in 1,2-dichloroethane (40 mL) was heated at reflux for approximately 18 hours. The resultant solution was cooled to room temperature and washed with a saturated solution of aqueous sodium bicarbonate. The solution was applied to a flash silica gel column, and the product was eluted with ethyl acetate (40% to 75%) in hexane to give the product, 0.67 g (48%), as a colorless solid. MS: m/z 368 (MH+). 1H NMR (DMSO-d6): δ 2.88 (t, 2 H), 3.35 (t, 2 H), 6.51 (br t, 1 H), 6.7 (d, 2 H), 7.20-7.27 (m, 1 H), 7.30-7.33 (m, 4 H), 7.55-7.67 (m, 2 H), 7.87 (d, 2 H), 7.95 (m, 2 H), 8.82 (d, J=2 Hz, 1 H), 9.15 (d, J=2 Hz, 1H) and 10.25 (s, 1 H).