Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]=[C:8]2[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]OS(F)(=O)=O.[OH-].[Na+]>C(Cl)Cl>[C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:14])[C:8]2=[NH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NC(=O)CN1c1ccccc1
Reactant: COS(=O)(=O)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1C(=N)N(c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1.2 g. of 1-phenyl-2-amino-4-oxo-2-imidazoline, 15 ml. methylene chloride and 3.6 ml. of methylfluorosulfonate was left to stir at room temperature for 20 hours. The reaction was stopped and filtered to give 1.9 g. (94%) of the acid salt of the product. The isolation of the free base (m.p. 164°) is made by treating the salt with aqueous sodium hydroxide.
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][C:15]1[CH:27]=[CH:26][C:18]([O:19][CH:20]([CH3:25])[C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=1)[CH:8]=[N:7]2.[OH-].[Na+]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:25])[C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1)[CH:8]=[N:7]2
Reactant: COC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)O
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Into a mixture of methanol (10 ml) and tetrahydrofuran (14 ml), methyl 2-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]propionate (0.6 g) was dissolved, and lN sodium hydroxide solution (2.5 ml) was added thereto. The reaction was carried out at room temperature while stirring for 2 hours. After removal of methanol and tetrahydrofuran by distillation, the aqueous layer was washed with dichloromethane (1 ml), made acidic with conc. hydrochloric acid and extracted with ethyl acetate. The extract was concentrated to remove ethyl acetate to give 2-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]propionic acid (0.44 g). Yield, 76%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][O:79][CH2:78][CH2:77]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a mixture of 0.060 g (0.139 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0212 g (0.209 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0532 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(tetrahydro-pyran-4-yl)-benzamide (I-187) as a white solid.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]=C)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].I([O-])(=O)(=O)=[O:43].[Na+]>O1CCCC1.O.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]=[O:43])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOCC(COCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(COCC=O)OCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
Osmium tetroxide (90 mg., 0.354 mmoles) was added to a solution of 1,2-di-O-(n-hexadecyl)-3-O-allyl-glycerol (4.5 g., 7.75 mmoles) in tetrahydrofuran:water (3:1, 120 ml.), and the resulting solution stirred for 5 minutes at room temperature. Sodium periodate (9 g., 42 mmoles) was then added and the reaction solution stirred for 16 hours at room temperature under nitrogen. The reaction solution was then diluted with water (150 ml.) and extracted with ether (2×150 ml.). The combined ether extract was washed with water (150 ml.), dried (MgSO4) and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene:ethyl acetate) [2.6 g., 57% yield, waxy solid, ir (CHCl3) 1735 cm-1, n.m.r. (CDCl3) δ9.38 (t, J=1 Hz, 1, --OCH2CHO) and 4.07 (d, J=1 Hz, 2, --OCH2CHO)].
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:18])[C:6]2[C:11]([CH3:12])=[C:10]([C:13]([O:15]CC)=[O:14])[S:9][C:7]=2[N:8]=1.[NH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>>[CH3:12][C:11]1[C:6]2[C:5](=[O:18])[NH:4][C:3]([CH2:2][N:19]3[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]3)=[N:8][C:7]=2[S:9][C:10]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1sc2nc(CCl)[nH]c(=O)c2c1C
Reactant: O=C1CCNCC1
Product: Cc1c(C(=O)O)sc2nc(CN3CCC(=O)CC3)[nH]c(=O)c12

Procedure:
Using ethyl 2-chloromethyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate and piperidin-4-one, a substitution reaction was carried out similarly to later appearing Production Example 21. Successively the reaction product was hydrolyzed similarly to Example 33, without intervening isolation of the reaction product, to provide the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[C:13]([N:15](C)[C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[CH3:13][NH:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(C)C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCc2ccc(C(=O)OC)cc21
Reaction time: 1 h
Yield: 92 %

Procedure:
TFA (25 ml) was added dropwise at 0° C. to a solution of (R)-methyl 3-(tert-butoxycarbonyl-(methyl)amino)-2,3-dihydro-1H-indene-5-carboxylate (11.0 g, 36.60 mmol, 1.0 eq.) in DCM (100 ml) and stirring was carried out for 1 hour at RT. After monitoring by TLC, the reaction solution was concentrated under reduced pressure and the residue was taken up in sat. sodium hydrogen carbonate solution and extracted with ethyl acetate (3×1000 ml). The combined org. phases were dried over sodium sulfate, concentrated and used in the next stage without being purified further. Yield: 92% (6.8 g, 33.17 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)[C@@H:3]([C@H:5]1[CH2:14][C:13]2[C:8](=[C:9]([O:16][CH3:17])[CH:10]=[CH:11][C:12]=2[Br:15])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[OH:4].C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>O1CCCC1>[C:41]([NH:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)[C@@H:3]([C@H:5]1[CH2:14][C:13]2[C:8](=[C:9]([O:16][CH3:17])[CH:10]=[CH:11][C:12]=2[Br:15])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[OH:4])(=[O:43])[CH3:42]
Reactant: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)C2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)C2
Yield: 88 %

Procedure:
Slurry tert-butyl (3R)-3-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxy-propyl]-5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (59.4 mg, 0.000113 mol) in tetrahydrofuran (1.00 mL). Add triethylamine (15.7 uL, 0.000113 mol) and acetic anhydride (10.6 uL, 0.000113 mol) and stir for 45 minutes. Dilute dichloro-methane (25 mL) and wash with water (1×10 mL), 0.1N HCl (1×10 mL), saturated aqueous sodium bicarbonate (1×10 mL), saturated aqueous sodium chloride (1×10 mL) and dry over magnesium sulfate. Concentrate the filtrate to give the desired product (57.9, 88%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[N:5]([C@@H:12]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[CH2:13]2)[CH:4]=1)[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[C:35]([O:39][C:40](=[O:46])[NH:41][S:42](Cl)(=[O:44])=[O:43])([CH3:38])([CH3:37])[CH3:36]>C(C#N)(C)=O>[C:35]([O:39][C:40](=[O:46])[NH:41][S:42]([O:18][CH2:17][C@@H:15]1[C@@H:14]([OH:19])[CH2:13][C@H:12]([N:5]2[C:6]3[N:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:3]([CH2:1][CH3:2])=[CH:4]2)[O:16]1)(=[O:44])=[O:43])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c2ncncc12
Agent: CC(=O)C#N
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)NC(=O)OC(C)(C)C)O2)c2ncncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a solution of (2R,3S,5R)-5-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol (0.0560 g, 0.213 mmol) and 2,6-di-tert-butyl-4-methylpyridine in AcCN (4 mL) at 0° C. was added tert-butyl(chlorosulfonyl)carbamate (0.0573 g, 0.266 mmol), the solution was warmed to room temperature and stirred for 1 hour. The reaction was quenched with 7N ammonia in methanol (2 mL) and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/DCM) to give the title compound as a white solid (39 mg, 29%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)#[N:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:7]2[C:6](=[O:8])[CH:5]=[N:4][N:3]([C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)[C:2]2=[O:1])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(=O)Nc1cccc(-n2ncc(=O)[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1cccc(-n2ncc(=O)n(Cc3ccc(C#N)cc3)c2=O)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 35.4 %

Procedure:
According to Scheme 5 Step 5: A suspension of N-(3-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (50 mg, 0.203 mmol), 4-cyanobenzylbromide (40 mg, 0.203 mmol) and potassium carbonate (31 mg, 0.223 mmol) in acetonitrile (2 mL) was stirred at 60° C. for 15 h The reaction mixture was then partitioned between AcOEt and water The organic layer was washed twice with water and once with brine. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by flash chromatography over silica gel (Merck Flashmart prepacked column 10 g SiO2) using DCM/MeOH 98/2 as eluent to afford N-(3-(4-(4-cyanobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 9(E) (26 mg, 35%) as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]2[CH:11]=[CH:12][O:13][C:9]=2[C:8]=1[CH3:16].Cl[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:27]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[C:12]1[O:13][C:9]2[C:8]([CH3:16])=[C:7]([CH3:6])[CH:15]=[CH:14][C:10]=2[CH:11]=1)[CH2:28][CH2:29][CH3:30]
Reactant: Cc1ccc2ccoc2c1C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2ccc(C)c(C)c2o1

Procedure:
A solution of 1.5 M hexane (21 ml) of n-butyllithium was added dropwise to a solution of 6,7-dimethyl-benzofuran (4.1 g) in tetrahydrofuran (100 ml) at −78° C. under an argon atmosphere, and the mixture was stirred for half an hour. Then, chloro tri-n-butyltin (8.4 ml) was added to the mixture, and the mixture was stirred for one hour. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane) to obtain tri-n-butyl(6,7-dimethyl-benzofuran-2-yl) tin (10.8 g).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:17](O)=[O:18])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][C@@H:62]([C:64]([NH2:66])=[O:65])[NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][C@@H:16]([CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:17](=[O:18])[NH:63][C@H:62]([C:64](=[O:65])[NH2:66])[CH2:61][S:60][C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
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: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
3.00 g (5.30 mmol) of the compound from example 13A was dissolved in 120 ml dichloromethane. 1.92 g (5.30 mmol) S-Trityl-L-cysteinamide, 0.92 ml (5.30 mmol) N,N-diisopropylethylamine and 2.02 g (5.30 mmol) HATU were added. The reaction mixture was split into 6 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 800 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.91 g (3.73 mmol, 70% of theory, 69% purity) of the desired product.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[C:9]([NH:34][C@@H:35]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:36][S:37](O)(=[O:39])=[O:38])=[CH:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)=[N:12][CH:13]=1.CN(C=O)C>ClCCl>[F:7][C:8]1[C:9]([NH:34][C@@H:35]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:36][S:37]([Cl:4])(=[O:39])=[O:38])=[CH:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)=[N:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CS(=O)(=O)O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CS(=O)(=O)Cl)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (3.5 mL, 38.7 mmol) was added to a solution of (S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3yl)pyridin-4-ylamino)-3,3-dimethylbutane-1-sulfonic acid, 57a, (7.3 g, 12.9 mmol) in dichloromethane (130 mL), followed by the slow, dropwise addition of DMF (2 mL). The yellow colored solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to afford 8.4 g of the desired product as a foamy yellow solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 585.72 (M+H) RT=2.30 minutes.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:33])[C:16]([OH:32])([C:21]2[CH:22]=[CH:23][C:24]3[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=3[CH:31]=2)[C:17]([F:20])([F:19])[F:18])=[C:11]([Cl:34])[CH:10]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].O.Cl>C1COCC1>[Cl:34][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH:15]([CH3:33])[C:16]([OH:32])([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)[C:17]([F:19])([F:18])[F:20])[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(OC(C)(C)C(=O)O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reaction time: 3 h
Yield: 16 %

Procedure:
2-{3-Chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-phenoxy}-2-methyl-propionic acid ethyl ester (99 mg, obtained in Example 229) was dissolved in THF (2.3 mL) under argon. LiOH solution (1M, 0.31 mL) was added and the mixture was stirred for 3 hours. Another 0.19 mL of the LiOH solution was added and stirring was continued at r.t. for 48 hours. The reaction mixture was poured into water containing ice and the aqueous solution was acidified with 1M HCl to pH 1. The aqueous mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate, then ethyl acetate containing 0.25% acetic acid) to provide the title compound 2-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-phenoxy}-2-methyl-propionic acid as a light brown foam (15 mg). MS (m/e, ISP neg. ion)=486.5 [M−H+].
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:18]=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([C:19]4[S:23][C:22]([CH:24]=O)=[CH:21][CH:20]=4)=[CH:14][C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([CH2:32][C:33]([OH:35])=[O:34])#[N:31].N1CCCCC1>C(#N)C>[C:30]([C:32](=[CH:24][C:22]1[S:23][C:19]([C:13]2[CH:12]=[CH:11][C:10]3[C:9]4[C:17](=[CH:18][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:7][CH:8]=4)[CH2:16][C:15]=3[CH:14]=2)=[CH:20][CH:21]=1)[C:33]([OH:35])=[O:34])#[N:31]
Reactant: N#CCC(=O)O
Reactant: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(-c3ccc(C=O)s3)ccc1-2
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(-c3ccc(C=C(C#N)C(=O)O)s3)ccc1-2
Temperature: 90 °C

Procedure:
Under N2 atmosphere, 0.18 parts of 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a), 0.05 parts of cyanoacetic acid, and 0.017 parts of piperidine were added into acetonitrile, followed by stirring and mixing. Then, the reaction mixture was heated to 90° C. and reacted for 6 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was filtrated to obtain a solid. Then, the solid was washed with water, ether, and acetonitrile sequentially to obtain a dark red solid. Finally, this crude was purified with column chromatography method by using dichloromethane/methanol co-solvent as an eluent, to obtain a compound (13a) of the present example. This compound was in a form of a dark red solid, and the yield of this compound was 73%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:40])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C@@H:36]([OH:39])[CH2:37][OH:38])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:40])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C@@H:36]([OH:39])[CH2:37][OH:38])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(C[C@@H](O)CO)S(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(C[C@@H](O)CO)S(=O)(=O)c3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-25 (100 mg) and lithium hydroxide (20 mg) were added to tetrahydrofuran (5 ml) and water (2 ml), and the same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 58 mg (60%); MS APCI+ve 567 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[CH:8]=[N:7][CH:6]=1)[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1>[N+](C1C=CC=CC=1)([O-])=O.CCOCC>[CH2:1]([O:3][C:4]([C:5]1[C:10]2[N:11]=[C:19]([C:18]3[CH:21]=[CH:22][C:15]([F:14])=[CH:16][C:17]=3[C:23]([F:25])([F:24])[F:26])[NH:12][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:13])[CH3:2]
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)c1cncc(N)c1N
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cncc2[nH]c(-c3ccc(F)cc3C(F)(F)F)nc12
Temperature: 220 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
A mixture containing ethyl 4,5-diaminonicotinate (79; 0.9 g, 5 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (82; 1.0 g, 5.2 mmol) in nitrobenzene (50 mL) was stirred at 220° C. for 18 h. Upon cooling to room temperature, the reaction mixture was diluted with ether. The resulting solids were collected by filtration, washed with ether, and dried to provide 2-(4-fluoro-2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester 83 (600 mg, 39%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18](=[O:20])[NH:24][C:23]1[C:22]([F:21])=[CH:28][CH:27]=[CH:26][C:25]=1[F:29])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To the solution of (S)-3,4-dihydro-1H-isoquinoline-1,2-dicarboxylic acid 2-tert-butyl ester (500 mg, 1.8 mmol, Eq: 1.00) and 2,6-difluoroaniline (279 mg, 2.16 mmol, Eq: 1.2) in pyridine (10.0 mL) at 0° C. was added POCl3 (415 mg, 252 μL, 2.7 mmol, Eq: 1.5). The mixture was warmed to RT and stirred for 2 h. The solvent was evaporated, water was added and the mixture extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (380 mg) as a white foam.