Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[CH2:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH2:19][CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(C(=O)CCC2CCCC2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCCC2CCCC2)c[nH]1

Procedure:
Triethylsilane (4.28 mL, 26.86 mmol) was added to a stirring, room temperature solution of 74 (2.2816 g, 8.66 mmol) in trifluoroacetic acid (TFA) (20.6 mL, 0.42 M) under N2. When the reaction was judged complete by HPLC, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 30:70 H2O:CH3CN; 20 mL/min.; λ=254 nm. 75 was obtained as a fluffy white solid. 1H (CDCl3, 400 MHz): δ 9.43 (1H, broad s), 6.77 (1H, s), 6.74 (1H, s), 4.32 (2H, q, J=7.1 Hz), 2.46 (2H, t, J=7.6 Hz), 1.83-1.71 (3H, m), 1.64-1.46 (6H, m), 1.35 (3H, t, J=7.1 Hz), 1.36-1.31 (2H, m), 1.14-1.02 (2H, m) ppm. 13C (CDCl3, 100 MHz): δ 161.46, 126.62, 122.33, 120.74, 114.86, 60.10, 40.00, 35.82, 32.65, 30.14, 26.94, 25.13, 14.39 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.39; CH2 carbons: 60.10, 35.82, 32.65, 30.14, 26.94, 25.13; CH carbons: 120.74, 114.86, 40.00 ppm. HPLC: 12.379 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:44]1([CH2:50][CH:51]([N:54]2[CH:58]=[C:57]([C:59]3[C:60]4[CH:67]=[CH:66][N:65](COCC[Si](C)(C)C)[C:61]=4[N:62]=[CH:63][N:64]=3)[CH:56]=[N:55]2)[CH2:52][CH3:53])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C1COCC1>[N:62]1[C:61]2[NH:65][CH:66]=[CH:67][C:60]=2[C:59]([C:57]2[CH:56]=[N:55][N:54]([CH:51]([CH2:52][CH3:53])[CH2:50][N:44]3[CH2:49][CH2:48][N:47]([C:4]([C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[OH:1])=[O:6])[CH2:46][CH2:45]3)[CH:58]=2)=[N:64][CH:63]=1
Reactant: O=C(O)c1ccccc1O
Reactant: CCC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CN1CCN(C(=O)c2ccccc2O)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxybenzoic acid (0.0045 g, 0.033 mmol) in tetrahydrofuran (0.5 mL, 6 mmol) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.012 g, 0.033 mmol) and N,N-diisopropylethylamine (5.7 uL, 0.033 mmol) and mixed for 1 hour until dissolution. The reaction was stirred overnight, then 4-{1-[1-(piperazin-1-ylmethyl)propyl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.010 g, 0.022 mmol from step 4 in example 115 and 0.5 mL THF were added. After 0.5 hour, the reaction was purified by LCMS (pH 10) to give 14 mg white solid which was stirred in 1 mL MeOH and 50 microL EDA for 2 hours. The reaction was purified by LCMS (pH 10) to give 2.2 mg white solid. 1H NMR (400 MHz, DMSO): δ 8.64 (1H, s); 8.6 (1H, s); 8.22 (1H, s); 7.55 (1H, d); 7.35 (1H, m); 6.99 (1H, m); 6.93 (1H, m); 688 (1H, m); 6.75 (1H, m); 4.39 (1H, m); 3.5-2.2 (10H, br); 1.78 (2H, m); 0.65 (3H, t). LCMS (M+1); 446.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:50]>C(O)C>[Na+:50].[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)[O-])cn1

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (78 mg) is dissolved in ethanol (1 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (162 μl) and the mixture is stirred at room temperature for 3 hours. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (66 mg). The resulting carboxylic acid is dissolved in ethanol (0.5 ml), and thereto is added 2N-aqueous sodium hydroxide solution (47 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (68 mg). MS (m/z): 693 [M−Na]−
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].C(OCC)(=O)C.CCN(CC)CC>CO.O.[Fe]>[O:10]1[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=[C:9]1[C:7]1[S:8][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cnccc3o2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2nc3cnccc3o2)s1
Yield: 70.3 %

Procedure:
2-(5-nitrothiophen-2-yl)oxazolo[4,5-c]pyridine (1.775 g, 7.2 mmol), iron powder (2.108 g, 36.0 mmol) and NH4Cl (3.081 g, 57.6 mmol) were refluxed in CH3OH/H2O (4:1, 360 mL) for 6 h. The mixture was filtered and the filtration was evaporated in vacuo. The residue was purified by chromatography on silica gel eluted with petroleum ether:ethyl acetate:Et3N=160:40:1 to afford 5-(oxazolo[4,5-c]pyridin-2-yl)thiophen-2-amine as a yellow solid (1.1 g, yield: 70%). 1HNMR (400 MHz, DMSO-d6) δ: 8.83 (1H, s), 8.41 (1H, d, J=4.8 Hz), 7.67 (1H, d, J=4.8 Hz), 7.57 (1H, d, J=4.4 Hz), 6.91 (2H, s), 6.03 (1H, d, J=4.4 Hz); MS (ESI) calcd. for C10H7N3OS (m/z): 217, found: 218 [M+1]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([O-:10])=[O:9])[CH:6]=1.[Na+].O.C(=O)(O)[O-].[Na+].S(Cl)(O[CH2:31][Cl:32])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][C:8]([O:10][CH2:31][Cl:32])=[O:9]
Reactant: O=S(=O)(Cl)OCCl
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)OCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Diclofenac sodium [331] (0.1 g, 0.33 mmol, 1.0 eq) DCM (2 ml), water (2 ml), sodium bicarbonate (0.105 g, 0.125 mmol, 3.81 eq) and tetrabutylammonium hydrogen sulfate (0.011 g, 0.033 mmol, 0.1 eq) were stirred at 25° C. for 2 min. A solution of chloromethyl chlorosulfate [323] (0.06 g, 0.363 mmol, 1.1 eq) in DCM (1 ml) was added dropwise. This biphasic system was stirred at RT for 1 h. The organic layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent under vacuum gave the product as a white solid, chloromethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate [332] (0.11 g, 95%)
Reaction SMILES: C(OC([C:6]1[N:7]([CH:26]([CH3:36])[CH2:27][NH:28][C:29]([O:31]C(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1)=[C:10]([Br:25])[CH:9]=2)=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Br:25][C:10]1[C:11]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:20][CH2:21]2)=[CH:12][C:13]2[CH:14]=[C:6]3[C:29](=[O:31])[NH:28][CH2:27][C@@H:26]([CH3:36])[N:7]3[C:8]=2[CH:9]=1
Reactant: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2n1C(C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)N1CCC(Oc2cc3cc4n(c3cc2Br)[C@H](C)CNC4=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.5 %

Procedure:
The solution of 0.21 g (0.37 mmol) 6-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid ethyl ester in 4 mL dichloromethane was cooled to 0° C. and 2 mL (2.98 g, 26.1 mmol) trifluoroacetic acid were added dropwise within 5 min. The cooling bath was removed and after 1 h the volatile components were removed at a rotary evaporator. The residue was dissolved in 4 mL methanol and 0.2 g (1.48 mmol) potassium carbonate was added under cooling. The suspension was stirred for 72 hours at room temperature and then diluted with water. The solution was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) to give 49 mg (31%) of the product as a white solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][C:31](O)=[O:32]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:31](=[O:32])[CH2:30][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc2ccccc2c1
Product: O=C(Cc1ccc2ccccc2c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 2-(2-naphthyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.96-8.04 (m, 2H), 7.86-7.94 (m, 4H), 7.72-7.75 (m, 1H), 7.61-7.66 (m, 4H), 7.50-7.57 (m, 3H), 3.88 (s, 2H); MS (APCI+) M/Z 440 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:17][C:18](=[O:27])[C:19]3[C:24]([F:25])=[CH:23][C:22](Cl)=[CH:21][N:20]=3)[CH:12]=[C:13]([F:16])[C:14]=2[F:15])([CH3:8])[N:7]=1.C[C:33]([N:35](C)C)=O>O.CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:17][C:18](=[O:27])[C:19]3[C:24]([F:25])=[CH:23][C:22]([C:33]#[N:35])=[CH:21][N:20]=3)[CH:12]=[C:13]([F:16])[C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: C[C@@]1(c2cc(NC(=O)c3ncc(Cl)cc3F)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@]1(c2cc(NC(=O)c3ncc(C#N)cc3F)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 120 °C
Yield: 50.7 %

Procedure:
A microwave vial was charged with N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-chloro-3-fluoropicolinamide (0.182 g, 0.390 mmol), zinc cyanide (0.056 g, 0.468 mmol, Sigma Aldrich), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1′1′-biphenyl (0.032 g, 0.078 mmol, Strem), and tris(dibenzylideneacetone)dipalladium (0) (0.036 g, 0.039 mmol, Strem). The vial was sealed and evacuated/backfilled with nitrogen three times. 1 ml of a premixed 99:1 DMA:water solution was added and the reaction was heated to 120° C. in the microwave for 20 minutes. Upon cooling, the reaction was diluted with water and EtOAc. The organic layer was separated, washed with brine and dried over magnesium sulfate. The crude residue was purified via silica gel flash chromatography using a gradient of 20-100% EtOAc in hexanes) to afford the title compound (0.0904 g, 0.198 mmol, 50.7% yield) as a yellow solid. MS m/z=458.0 [M+H]+. Calculated for C19H13F6N5O2: 457.329.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[CH3:38][N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([CH2:48][NH2:49])=[N:40]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:49][CH2:48][C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:39]([CH3:38])[N:40]=1)=[O:24]
Reactant: Cn1nc(CN)c2ccccc21
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2nn(C)c3ccccc23)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-(1-methyl-1H-indazol-3-yl)-methylamine hydrochloride.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH:11]([CH2:14][NH2:15])[CH2:10][C:9]=2[CH:8]=[C:7]([Cl:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27](=[O:28])[NH:15][CH2:14][CH:11]1[CH2:10][C:9]2[CH:8]=[C:7]([Cl:16])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:13]=2[O:12]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)c1cc(Cl)cc2c1OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(Cl)cc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 95.6 %

Procedure:
Treatment of (±)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine (1.80 g, 6.52 mmol) with diisopropylethylamine (2.11 g, 16.29 mmol) and benzyl chloroformate (1.28 g, 7.49 mmol) generally according to the procedure described for Intermediate 12 gave 2.33 g (95%) of (±)-benzyl(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C21H24ClNO3 C, 67.46; H, 6.47; N, 3.75. Found C, 67.27; H, 6.62; N, 3.66. Chiral HPLC separation of (±)-benzyl(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=5.642 min, Chiralpak AD, hexane:isopropanol 9:1); Fraction 2 (Rt=6.494 min, Chiralpak AD, hexane:isopropanol 9:1).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10](Cl)=[O:11].[CH2:13]([C:16]#[N:17])[C:14]#[N:15].[NH4+]=[S:19]>O.CN(C)C=O>[NH2:15][C:14]1[S:19][CH:9]=[C:10]([OH:11])[C:13]=1[C:16]#[N:17]
Reactant: N#CCC#N
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(O)csc1N
Temperature: 25 °C
Yield: 62 %

Procedure:
350 parts of triethylamine are added dropwise to a mixture of 178 parts of chloroacetyl chloride, 104 parts of malonodinitrile and 900 parts of dimethylformamide, while cooling with ice. The solution is stirred for a further hour at room temperature, after which it is introduced into a mixture of 294.5 parts of a 40% strength aqueous ammonium sulfide solution, 1000 parts of ice and 1000 parts of water, and the reaction mixture is stirred for a further 3 hours at room temperature. The precipitate formed is filtered off under suction, washed with water and dried. 137 parts (62% of theory) of 2-amino-3-cyano-4-hydroxythiophene are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:25])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:12]=1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:25])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[N:12]=1
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Reduced iron (10.6 g) was added portionwise mixture of 4-{2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy}nitrobenzene (22.9 g), acetic acid (150 ml) and water (50 ml) at 70° C. After stirring at 80° C. for 2 hours, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the filtrate, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to give 4-{2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy}aniline as a crude oily material (20.5 g, 97.6%). NMR δppm in CDCl3 : 2.35(3H, s), 2.93(2H, t, J=7 Hz), 3.77(2H, s), 4.15(2H, t, J=7 Hz), 6.56(2H, d, J=9 Hz), 6.75(2H, d, J= 9 Hz), 7.2 to 7.5(3H, m), 7.9 (1H, m).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:44])[NH:33][C:34]4[C:39]([CH2:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:42][CH3:43])=[CH:28][C:27]=3[CH3:45])[N:20]=2)[N:16]([CH3:46])[CH:15]=1)=[O:13])[CH3:2].C1C(=O)N([Br:54])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[C:24]([Br:54])=[CH:23][N:22]=[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:44])[NH:33][C:34]4[C:39]([CH2:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:42][CH3:43])=[CH:28][C:27]=3[CH3:45])[N:20]=2)[N:16]([CH3:46])[CH:15]=1)=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc(CC)c1NC(=O)c1ccc(Nc2nccc(-c3cc(C(=O)Nc4c(CC)cccc4CC)cn3C)n2)c(C)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1NC(=O)c1ccc(Nc2ncc(Br)c(-c3cc(C(=O)Nc4c(CC)cccc4CC)cn3C)n2)c(C)c1

Procedure:
A solution of 5-{2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide (100 mg, 0.1626 mmol) and NBS (29 mg, 0.1626 mmol) in 7.5 mL of DMF was stirred at room temperature for 1 h. The mixture was then diluted with AcOEt and washed with water. The organic layer was dried over Na2SO4 and the solvent removed under reduced pressure. The target product was purified by preparative HPLC (39.8 mg, 35%, Exact Mass: calculated 693.2547, found 693.2548) as well as 2-bromo-5-{2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide (24.7 mg, 22%, Exact Mass: calculated 693.2547, found 693.2556.) and 2-bromo-5-{5-bromo-2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide (8.1 mg, 6.5%, Exact Mass: calculated 771.1652, found 771.1653).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([OH:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:31][CH:32]([CH3:39])[CH2:33][O:34][CH2:35][C:36](Cl)=[O:37].O>ClCCCl.CN(C)C1C=CN=CC=1>[CH3:31][CH:32]([CH3:39])[CH2:33][O:34][CH2:35][C:36]([O:23][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[N:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)=[O:37]
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(C)COCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)COCC(C)C)nc2n1
Yield: 62.6 %

Procedure:
To a solution, maintained at a temperature in the region of 20° C., of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (9.2 g) and triethylamine (20 cc) in 1,2-dichloroethane (150 cc), there is added, in the course of 20 minutes, a solution of 2-methylpropoxyacetyl chloride (9 g) in 1,2-dichloroethane (20 cc) followed by 4-dimethylaminopyridine (50 mg), and the mixture is heated to reflux for 16 hours. The reaction mixture is poured into water (250 cc) and then extracted with methylene chloride (100 cc.) After the extract is washed with water, dried and concentrated to dryness under reduced pressure (3kPa), the residue obtained is purified by two successive recrystallizations in ethanol. 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 2-methylpropoxyacetate (7.9 g), m.p. 114° C., is thereby obtained.
Reaction SMILES: [H-].[Na+].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][C:19](OCC)=O)=[CH:13][C:12]=1[CH3:25])C1C=CC=CC=1.ClC[C:28]1[S:29][C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]=1[CH3:33]>C1COCC1>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:28]2[S:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32]=2[CH3:33])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1c(CCl)sc2ccccc12
Reactant: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CCc2sc3ccccc3c2C)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
Then, to a suspension of 55% sodium hydride (123 mg, 3.07 mmol) in THF (18 mL) was added dropwise over 10 minutes under N2 atmosphere, a solution of ethyl 3-(4-benzyloxy-3-methylphenyl)-3-oxopropionate (870 mg, 2.79 mmol) in THF (5 mL). After 20 minutes, to the resultant mixture was added dropwise over 10 minutes a solution of 2-chloromethyl-3-methylbenzothiophene (548 mg, 2.79 mmol) in THF (5 mL). The mixture was heated under reflux for 25 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was heated in acetic acid (18 mL) and concentrated hydrochloric acid (4 mL) at 110° C. for 20 hours. The reaction mixture was cooled at room temperature, extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine, successively. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), to give the titled compound as a yellow crystal (790 mg, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:20])=O.S(Cl)([Cl:30])=O>>[Cl:16][C:4]1[CH:5]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([Cl:30])=[O:20]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Product: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 2 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetic acid and 48 parts of thionyl chloride was stirred for 1 hour at reflux temperature. The reaction mixture was evaporated, yielding 2.28 parts (100%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetyl chloride as a residue (intermediate 32).