Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([CH2:32][CH2:33][OH:34])[CH:27]=[CH:26]4)=[N:19][CH:20]=2)=[CH:11][CH:10]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1.N1C=CC=CC=1>[CH3:35][S:36]([O:34][CH2:33][CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([C:22]#[C:21][C:18]3[CH:17]=[CH:16][C:15]([C:12]4[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)=[CH:20][N:19]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1)(=[O:38])=[O:37]
Reactant: OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere 7.1 mL (51.5 mmol) triethylamine are added to a solution of 16.0 g (42.9 mmol) 2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethanol in 480 mL THF and 30 mL pyridine and this is cooled to 0° C. Then a solution of 4 mL (51.5 mmol) methanesulphonic acid chloride in 20 mL THF is slowly added dropwise, the mixture is allowed to warm up to RT and stirred for a further 2 h at RT. The reaction solution is filtered and evaporated down i.vac. The residue is combined with 1 L DCM, washed with 400 mL water and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is suspended with 600 mL PE/DCM (5:1), suction filtered and finally dried in the air until a constant weight is obtained.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[N:9]([CH2:18][O:19][CH3:20])[C:8]=2[CH:21]=1)[CH3:3]>C(O)C.ClCCl.[Pd]>[OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[NH:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10](=[O:17])[N:9]([CH2:18][O:19][CH3:20])[C:8]=2[CH:21]=1)[CH3:3]
Reactant: COCn1c(=O)c2cccnc2c2ccc(C(C)O)cc21
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COCn1c(=O)c2c(c3ccc(C(C)O)cc31)NCCC2
Reaction time: 24 h
Yield: 48.5 %

Procedure:
The compound (650 mg, 2.29 mmol) prepared in step 4 was dissolved in ethanol (10 ml)/dichloromethane (10 ml) and added with 10%-palladium (Pd) (200 mg) at room temperature. The resulting mixture was stirred for one day under hydrogen gas and 10%-palladium was removed by using celite-filter. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (chloroform:methanol=30:1) to obtain the title compound (320 mg, yield: 49%, white solid).
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.CCCCCCC.CCO.[Cl:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]2[C:64]3[C:63]([CH:65]4[CH2:67][CH2:66]4)=[N:62][N:61]([CH3:68])[C:60]=3[C:59](=[O:69])[N:58]2[C:70]2[CH:71]=[C:72]([CH3:80])[C:73]3[N:74]([C:76]([CH3:79])=[N:77][N:78]=3)[CH:75]=2)=[CH:53][CH:52]=1>C(OCC)C>[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([C@@H:57]2[C:64]3[C:63]([CH:65]4[CH2:67][CH2:66]4)=[N:62][N:61]([CH3:68])[C:60]=3[C:59](=[O:69])[N:58]2[C:70]2[CH:71]=[C:72]([CH3:80])[C:73]3[N:74]([C:76]([CH3:79])=[N:77][N:78]=3)[CH:75]=2)=[CH:55][CH:56]=1
Reactant: Cc1cc(N2C(=O)c3c(c(C4CC4)nn3C)C2c2ccc(Cl)cc2)cn2c(C)nnc12
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CCO
Solvent: CCCCCCC
Solvent: CCOCC
Product: Cc1cc(N2C(=O)c3c(c(C4CC4)nn3C)[C@H]2c2ccc(Cl)cc2)cn2c(C)nnc12

Procedure:
The title compound (26 mg, 34% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: VWR prep HPLC; column: Chiralpak AD-H 20 μm, 76.5×393 mm; mobile phase: heptane/EtOH 60:40; flow: 80 mL/min; detection UV: 240 nm) of the racemic mixture of 4-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 129) followed by trituration in diethyl ether.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:19]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:20]4[C:21]([N:42]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30](B5OC(C)(C)C(C)(C)O5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)S(O[C:57]1[CH2:58][CH2:59][S:60][CH2:61][CH:62]=1)(=O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1.C(=O)=O.CC(C)=O>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:19]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:48])([CH3:50])[CH3:49])[C:20]4[C:21]([N:42]=3)=[N:22][C:23]([C:27]3[CH:28]=[CH:29][C:30]([C:57]5[CH2:62][CH2:61][S:60][CH2:59][CH:58]=5)=[CH:31][CH:32]=3)=[C:24]([Cl:26])[CH:25]=4)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1(C)OB(c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O[Si](C)(C)C(C)(C)C)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)OC1(C)C
Reactant: O=S(=O)(OC1=CCSCC1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C=O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(C4=CCSCC4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Placed 2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)-oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (500 mg, 0.672 mmol), 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (250 mg, 10.8 mmol), and 1M aqueous potassium phosphate tribasic (2.02 ml, 2.02 mmol) under nitrogen in dioxane (7.0 ml). Cooled in dry-ice/acetone bath, pulled a hard vacuum, then introduced nitrogen (3×). Added [1,1′-bis(diphyenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.067 mmol) to the frozen mixture, pulled a hard vacuum, then introduced nitrogen (3×). Removed ice bath and stirred mixture at 80° C. for 6 hours. The mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate (50 ml). The mixture was extracted with ethyl acetate (2×100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The resultant dark oil was chromatographed using a 40 g silica gel cartridge eluted with 0-40% EtOAc in hexanes over 20 column volumes. The desired product fractions were combined and concentrated under reduced pressure to provide the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH2:36](I)[CH2:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:36][CH2:37][CH3:38])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: CCCI
Product: CCCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 64 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and propyl iodide was used in place of methyl iodide. As a result, 209.9 mg (yield: 64%) of Compound 3 was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)O)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([N:42]([CH3:50])[CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])=[O:41])=[CH:36][CH:35]=1>>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([N:42]([CH3:50])[CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:41])=[CH:38][CH:39]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1cn(-c2ccc(OC(F)(F)F)cc2)nc1OCc1ccccc1)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccc(OC(F)(F)F)cc3)nc2OCc2ccccc2)C2CCCCC2)cc1
Yield: 50.8 %

Procedure:
Using {3-(benzyloxy)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}(cyclohexyl)methanol (0.50 g) synthesized in Example 60(2) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.28 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.37 g, 52%) was obtained as a white solid.
Reaction SMILES: Cl.[C:2]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH:28]([F:30])[F:29])[CH:25]=4)[N:20]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:19]=3)[N:16]=2)[N:11]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:10]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH2:45](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:2]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH:28]([F:29])[F:30])[CH:25]=4)[N:20]([CH:31]4[CH2:32][CH2:33][N:34]([CH3:45])[CH2:35][CH2:36]4)[N:19]=3)[N:16]=2)[N:11]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:10]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCNCC4)c4ccc(OC(F)F)cc34)nc12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCCl
Product: CN1CCC(n2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round-bottomed flask, 2-(5-difluoromethoxy-1-piperidin-4-yl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide hydrochloride (91 mg, 0.14 mmol) was suspended in 1,2-dichloroethane (1.5 ml) and triethylamine (0.03 ml, 0.22 mmol) was added. The mixture was stirred room temperature for 10 min then formaldehyde (37% aqueous solution, 13 μl, 0.175 mmol) and sodium triacetoxyborohydride (119 mg, 0.56 mmol) were added. The yellow suspension was stirred at room temperature for 1.5 h then quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 2-[5-difluoromethoxy-1-(1-methyl-piperidin-4-yl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a yellow foam which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4](S)[N:3]=1.Br[CH2:23][C:24]([NH2:26])=[O:25].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:19]([C:5]1[C:4]([CH2:23][C:24](=[O:25])[NH2:26])=[N:3][C:2]([NH2:1])=[C:7]([C:8]#[N:9])[C:6]=1[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)#[N:20]
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cc(Cl)c(O)c(Cl)c1
Reactant: NC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(CC(N)=O)c(C#N)c1-c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
337.2 mg (1 mmol) of 2-amino-4-(3,5-dichloro-4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile and 207 mg (1.5 mmol) of bromoacetamide are dissolved in 4 ml of DMF, 336 mg (4 mmol) of NaHCO3 are added and the mixture is stirred at RT for 8 hours. The mixture is diluted with water and washed with ethyl acetate. The aqueous phase is acidified with 1N HCl and the resulting crystals are filtered off with suction and dried.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[CH3:17].[OH-].[Na+]>C(O)C>[O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH3:17]
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1N1CCCS1(=O)=O

Procedure:
170 mg (0.63 mmol) methyl 4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoate are stirred in 2 ml of ethanol at ambient temperature for 3 hours with 0.6 ml of 2-molar sodium hydroxide solution. Then the reaction solution is evaporated down i. vac., combined with water and 0.6 ml 2-molar hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue is further reacted without any more purification.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]2=[O:24])(=O)=O)=CC=1.[CH:26]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(C)(C)C>[CH:26]([CH:39]1[CH2:44][CH2:43][N:42]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:18](=[O:24])[CH2:19][O:20][CH2:21][C:22]2=[O:23])[CH2:41][CH2:40]1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Solvent: CC(C)(C)O
Product: O=C1COCC(=O)N1CCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Yield: 149.6 %

Procedure:
To a solution of 9.75 grams (26.39 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate (prepared as described in Example IX) in 160 milliliters of warm tertiary butyl alcohol was added portionwise at temperatures in the range of 30°-32° C. over a period of about 23 minutes, 63 grams (26.38 millimoles) of 4-benzhydrylpiperidine in 160 milliliters of tertiary-butyl alcohol. The reaction mixture was heated at reflux temperature for about 22 hours and thereafter the solvent removed by vaporization to obtain 17.7 grams of a 4-[6-(4-benzhydrylpiperidino)hexyl]-3,5-dioxomorpholine product as a yellow oil. Crystallization (twice) from ethyl acetate produced 4.19 grams of white crystals, m.p., 121°-124.5° C. and having NMR, UV and IR spectral characteristics appropriate for the product.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([OH:26])[CH:22]([OH:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.CCCCCCC.CCOC(C)=O>[C:7]([O:26][CH2:21][CH:22]([OH:25])[CH:23]=[CH2:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of triphenylmethyl chloride (3.31 kg, 11.87 mol, 0.99 equiv) in toluene (6.74 kg) at RT, was added but-3-ene-1,2-diol (1.06 kg, 12.02 mol, 1.0 equiv.). The reaction mixture was cooled down to 0° C. Triethylamine (2.72 kg, 26.91 mol, 2.24 equiv.) was slowly added to the reaction mixture while maintaining temperature below 5° C., followed by 4-dimethylaminopyridine (8.38 g, 0.068 mol, 5.71 mmol). The reaction mixture was allowed to warm up to 10° C. then heated to 40° C. The reaction mixture was stirred at 40° C. overnight. The reaction was followed by TLC (Rf 0.45 in Heptane/EtOAc 20%). The reaction mixture was cooled down to 26.5° C., filtered and the solids were rinsed with toluene (2.72 kg). The filtrate was successively washed with 28% aq. NH4Cl solution (3.38 kg) and saturated aq NaCl solution (1.26 kg). The organic phase was then concentrated under reduced pressure to afford an oil as a crude mixture 3.95 kg). 1H NMR (500 MHz, DMSO) δ ppm 7.42 (dd, J=8.3, 1.0 Hz, 6H), 7.33 (dd, J=10.5, 4.8 Hz, 6H), 7.30-7.19 (m, 3H), 5.94-5.83 (m, 1H), 5.25 (td, J=17.3, 1.8 Hz, 1H), 5.08 (td, J=10.9, 1.8 Hz, 1H), 2.99 (dd, J=8.9, 6.3 Hz, 1H), 2.84 (dd, J=8.9, 5.7 Hz, 1H); 13C NMR (125 MHz, DMSO) δ 144.35, 140.07, 128.78, 128.26, 127.39, 115.04, 86.25, 70.88, 68.27.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[C:21]([C:25]1[O:29]C(=O)[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33](F)[N:32]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:9]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:33]4[N:32]=[C:31]([NH:27][NH:26][C:25](=[O:29])[C:21]([CH3:23])([CH3:22])[CH3:24])[CH:36]=[CH:35][CH:34]=4)=[CH:16][CH:15]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Oc1ccc(CCNc2ncnc3scc(Cl)c23)cc1
Reactant: CC(C)(C)c1nn(-c2cccc(F)n2)c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NNc1cccc(Oc2ccc(CCNc3ncnc4scc(Cl)c34)cc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
To a solution of 4-{2-[(5-chlorothieno[2,3-d]pyrimidin-4-yl)amino]ethyl}phenol (0.152 g, 0.5 mmol) and 5-(tert-butyl)-3-(6-fluoropyridin-2-yl)-3H-[1,3,4]oxadiazol-2-one (0.119 g, 0.5 mmol) in anhydrous DMF (4 mL) was added 60 percent sodium hydride in mineral oil (30 mg, 0.75 mmol) portionwise. The mixture was then stirred at 100° C. overnight. After cooling the reaction was quenched with methanol. The solvent was removed in vacuo and the residue was triturated in CH2Cl2 and water. The organic phase was separated, dried over anhydrous Na2SO4, filtered, concentrated, and purified on preparative HPLC to give the decarboxylated product as a brownish foam, 16 mg, 0.03 mmol, 6.5 percent yield.
Reaction SMILES: C[S:2]([C:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][N:6]=1)(=O)=O.O.[SH-].[Na+].O.O.CS(OO)(=O)=O.[Na].C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[F:43])[C:32]([F:35])([F:34])[F:33]>CN(C=O)C>[F:43][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([F:42])[C:36]=1[CH:31]([S:2][C:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][N:6]=1)[C:32]([F:35])([F:34])[F:33]
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: Fc1cccc(F)c1C(Br)C(F)(F)F
Agent: CS(=O)(=O)OO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(SC(c2c(F)cccc2F)C(F)(F)F)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (87 mg, 0.49 mmol), sodium hydrosulfide hydrate (73 mg, 0.99 mmol), sodium hydroxy methanesulfonate dihydrate (151 mg, 0.99 mmol) and potassium carbonate (136 mg, 0.99 mmol) were added to DMF (10 ml) at 0° C. and the mixture was stirred at 0° C. for 2 hours. 2-(1-Bromo-2,2,2-trifluoroethyl)-1,3-difluorobenzene (135 mg, 0.49 mmol) was added and the suspension was stirred at room temperature for 5 hours. The reaction was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as a white solid (55 mg, 35% yield). 1H-NMR (400 MHz, CDCl3): 1.41 (3H, s, Me), 1.45 (3H, s, Me), 2.80 (1H, d, CH2), 2.82 (1H, d, CH2), 5.98 (1H, m, CH), 6.97 (2H, m, CH), 7.37 (1H, m, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=2)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:36][CH2:37][CH3:38])[O:39][CH2:40][CH3:41])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 76 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: COCCOC.[CH2:7]([O:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[N:22]([S:30]([C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:19][CH:18]=[C:17]([C:40]([F:43])([F:42])[F:41])[CH:16]=2)=[O:11])[CH3:8].[C:44]1(B(O)O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([O:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[N:22]([S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:19][CH:18]=[C:17]([C:40]([F:43])([F:42])[F:41])[CH:16]=2)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
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+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To 8.5 mL of degassed ethylene glycol dimethyl ether, was added 500 mg (0.85 mmol) of the ester, 110 mg (0.93 mmol) of phenylboronic acid, 80 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium and 1.1 ml (2.2 mmol) of 2M aqueous Na2CO3 and the mixture ws heated to reflux under nitrogen for 36 hr. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give 4-[(biphenyl-4-sulfonyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[O:16][CH3:17])=[O:5].[Cl:23]C(Cl)C>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:23])=[O:12])=[CH:9][C:8]=1[O:16][CH3:17])=[O:5]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)c1cc(F)ccc1Cl
Reactant: CC(Cl)Cl
Product: COc1cc(C(=O)Cl)ccc1NC(=O)c1cc(F)ccc1Cl

Procedure:
In a manner analogous to the process outlined in Example 12, 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoic acid was suspended in dichloroethane and reacted to yield the 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoyl chloride as a white solid.