Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]2=[O:25])([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:7]2=[O:25]
Reactant: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Yield: 94.5 %

Procedure:
To a suspension of benzyl 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetate (1.2 g, 3.528 mmol) in a mixture of ethanol (23 ml) and water (11.5 ml), iron powder (1.182 g, 21.16 mmol) and ammonium chloride (0.132 g, 2.468 mmol) were added, and the mixture was heated to reflux for 1 hour. The insoluble was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water and brine (×3). The organic phase was dried over Na2SO4 and the solvent was removed to give benzyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (1.035 g, 3.335 mmol, 94.5% yield, MS/ESI+ 310.9 [MH]+). This product was used in the following step without further purification.
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]1([CH2:11][C:12]([NH:14][C@@H:15]2[C:44](=[O:45])[N:17]3[C:18]([C:28]([O:30][CH:31]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])=[C:19]([C@@H:23]4[CH2:27][CH2:26][CH2:25][O:24]4)[CH2:20][S:21](=O)[C@H:16]23)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C)C=O>ClCCl.C(OCC)(=O)C>[C:5]1([CH2:11][C:12]([NH:14][C@@H:15]2[C:44](=[O:45])[N:17]3[C:18]([C:28]([O:30][CH:31]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:29])=[C:19]([C@@H:23]4[CH2:27][CH2:26][CH2:25][O:24]4)[CH2:20][S:21][C@H:16]23)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C([C@@H]3CCCO3)CS(=O)[C@H]12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C([C@@H]3CCCO3)CS[C@H]12
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
Phosphorus trichloride (0.1 ml of a solution containing 0.17 ml/ml in dry dichloromethane) was added to a stirred, ice bath cooled, mixture of the sulphoxide from Example 5 (55 mg) and dry dimethylformamide (0.05 ml) in dry dichloromethane (2 ml). After stirring for 15 minutes at ice bath temperature the mixture was diluted with ethyl acetate (10 ml) and was washed with satd NaHCO3 (2 ml), and brine (3×2 ml). The dried (MgSO4) organic layer was evaporated and the residue was chromatographed on silica gel eluting with ethylacetate/hexane mixtures to give the title compound as an amorphous solid (45 mg), d ppm (CDCl3) 1.42-1.58 (1H, m), 1.79-1.95 (2H, m), 2.21-2.33 (1H, m), 3.24 (1H, d, J 18.7 Hz), 3.56-3.66 (3H, m), 3.71-3.92 (2H, m), 4.84 (1H, dd, J 9.2 and 6.6 Hz), 4.95 (1H, d, J 4.8 Hz), 5.85 (1H, dd, J 9.1 and 4.8 Hz), 6.04 (1H, d, J 9.1 Hz), 6.86 (1H, s), 7.25-7.42 (15H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)/[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CCCC/C(=C/C=C/C(=O)O)c1cccc(OC)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.7 %

Procedure:
As in Example 115, (2E,4Z)-5-(3-methoxyphenyl)-2,4-nonadienoic acid (7.37 g) and 4-nitrophenol (4.89 g) in 30 mL of dichloromethane was reacted with 1,3-dicyclohexylcarbodiimide (5.91 g). The mixture was stirred at room temperature for 3 days and the usual work up furnished 9.69 g of (2E,4Z)-5-(3-methoxyphenyl)-2,4-nonadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.C([Cu])#N.[CH3:29][CH2:30][Mg+].[Br-]>C1COCC1>[CH2:29]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1)[CH3:30]
Reactant: Cc1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Reactant: CC[Mg+]
Agent: N#C[Cu]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCc1cc(Oc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)ncn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-p-tolyl-urea (Example 97; 106 mg, 0.3 mmol) is dissolved in THF (10 mL) under an argon atmosphere and CuCN (215 mg, 2.4 mmol) is added. The mixture is then cooled to −78° C. and EtMgBr (1.8 ml of a 3 M solution in THF) is added via a canula. The reaction mixture is allowed to stir for 30 min at −78° C. and then warmed to rt resulting in a brown suspension. It Is stirred for additional 30 min at rt and then the solvent is removed in vacuo. The residual crude product is re-dissloved in CH2Cl2/MeOH 1:1 and purified by flash chromatography (SiO2, gradient hexanes/ethyl acetate 1:1 to 3:7) to give the title compound which is further purified by preparative TLC (SiO2, hexanes/AcOEt 3:7): m.p.=160-162° C.; C20H20N4O2: M+=349.1; 1H-NMR (DMSO-d6): 9.55 (s, 1H, HN), 9.45 (s, 1H, HN), 8.64 (s, 1H), 7.55 (d, 2H); 7.40 (d, 2H), 7.10-7.06 (m, 4H), 6.92 (s, 1H), 2.70 (q, 2H), 2.24 (s, 3H), 1.22 (t, 3H).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[C:8]([F:24])=[CH:7][C:6]=1[Cl:25])C>C(Cl)Cl>[Cl:25][C:6]1[CH:7]=[C:8]([F:24])[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:10][C:5]=1[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
2-Chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid ethyl ester (5.2 g) was dissolved in methylenechloride (100 ml) and borontribromide (10 g) was added dropwise at ambient temperature. The reaction mixture was stirred for three hours at this temperature and poured into ice-water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine (×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the titled compound (4.3 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:25]=[CH:24][C:12]([CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]4)=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: O=C(O)C1CCN(CCc2ccc(Nc3ncc(Br)cn3)cc2)CC1
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: C1COCCO1
Product: O=C(O)C1CCN(CCc2ccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)cc2)CC1
Temperature: 150 °C

Procedure:
To a solution of 1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic acid 21 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.05 mmol), 3M Na2CO3 (0.15 mmol) and Pd(PPh3)4 (0.0025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated in a microwave oven at 150° C. for 10 min. Purification by preparative HPLC (ACN gradient 10-70%) affords 1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic acid A6. MS (m/z) (M+1)+: 469.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=O)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][C:48]1[N:49]([C:53]2[CH:54]=[C:55]([CH:57]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=2)[NH2:56])[CH:50]=[CH:51][N:52]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([NH:56][C:55]2[CH:57]=[C:58]([C:60]([F:61])([F:62])[F:63])[CH:59]=[C:53]([N:49]3[CH:50]=[CH:51][N:52]=[C:48]3[CH3:47])[CH:54]=2)=[O:9])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 123 %

Procedure:
3-Nitro-4-methyl benzoic acid (14.8 g, 81.5 mmol) was dissolved in DMF (150 mL), and HATU (62 g, 163 mmol) and DIPEA (57 mL, 326 mmol) were added thereto at room temperature. The reaction mixture was stirred for 15 minutes, 3-(2-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline (13.1 g, 54.3 mmol) was added thereto and stirred at 45° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with sat. NaHCO3 solution. The organic layer was dried with anhydrous MgSO4, filtered with Celite and concentrated. The residue was crystallized with ethyl acetate and hexane to obtain the title compound (27 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1.O.CN(C1C=CC=CN=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@@H:13]([O:18][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)[C@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 112.1 %

Procedure:
20 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyrate was dissolved in 100 ml of pyridine and 13.3 g of p-toluenesulfonyl chloride was added thereto while maintaining the reaction temperature at 10° to 20° C. Next, 0.03 g of dimethylaminopyridine (DMAP) was added thereto as a catalyst and the mixture was stirred at 20° to 25° C. for 5 hours. Then the reaction mixture was diluted with 500 ml of water and extracted with 150 ml portions of ethyl acetate twice. The extract was washed successively with 50 ml of 2 N hydrochloric acid and 50 ml of a saturated aqueous solution of sodium chloride, dehydrated over anhydrous sodium sulfate and filtered. After distilling off the solvent, 32.5 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-p-toluenesulfonyloxy-4-phenylbutyrate was obtained as a pale yellow, oily substance.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:10]1[CH2:14][CH2:13][CH:12]([O:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:30]=[C:29]([N:31]4[C:39]5[C:34](=[CH:35][C:36]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=5)[CH2:33][CH2:32]4)[N:28]=[CH:27][N:26]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:10]1[CH2:14][CH2:13][CH:12]([O:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:30]=[C:29]([N:31]4[C:39]5[C:34](=[CH:35][C:36]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=5)[CH2:33][CH2:32]4)[N:28]=[CH:27][N:26]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:11]1
Reactant: O=Cc1ccccc1F
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCNC3)CC2)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCN(Cc4ccccc4F)C3)CC2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluoro-benzaldehyde (11 μL, 0.1 mmol) was dissolved in 1 mL of DCE with 21b (49 mg, 0.1 mmol) and NaBH(OAc)3 (30 mg, 0.14 mmol). The mixture was stirred for 8 h at room temperature then was diluted with DCM and quenched with saturated NaHCO3. The organic layer was washed with saturated NaHCO3 followed by brine. The organic layer was dried, filtered and evaporated. The residue was purified by preparative HPLC to afford 21-1, LCMS 596.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:50]3[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:48][CH2:49]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(S(C)(=O)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(S(C)(=O)=O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methanesulfonyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C35H43N4O6S2Cl2 [(M+H)+] 749.1996, observed 749.1995.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH3:30])=[C:13]([C:15]2[N:16]=[C:17]([CH3:28])[S:18][C:19]=2[NH:20]C(=O)OC(C)(C)C)[CH:14]=1>C(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH3:30])=[C:13]([C:15]2[N:16]=[C:17]([CH3:28])[S:18][C:19]=2[NH2:20])[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1nc(C)sc1NC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nc(C)sc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
TFA (4.0 mL) was added to a solution of tert-butyl 4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-ylcarbamate (315 mg, 0.89 mmol) in DCM (10 mL) and water (3 drops). The reaction mixture was stirred for 1.5 hours at room temperature, then evaporated to dryness to give 215 mg (95%) of 4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-amine as a yellow solid. LCMS (ESI) m+H=255.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([NH2:16])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([NH:16][C:25](=[O:26])[CH2:24][Cl:23])[CH2:13][O:12][C:11]([CH3:14])([CH3:15])[O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OCC(N)(c2ccnc(Br)c2)CO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OCC(NC(=O)CCl)(c2ccnc(Br)c2)CO1
Reaction time: 0.08 h

Procedure:
To a solution of 5-(2-bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxan-5-ylamine (9.5 g, 33.1 mmol) in DCM (100 ml) was added aq. Na2CO3 (8.7 g in 50 ml) at 0° C. and stirring continued for 5 min. Chloroacetyl chloride (2.9 ml, 36.41 mmol) was added to the resultant reaction mixture drop wise and stirred for 30 min at 0° C. Reaction mass was diluted with DCM (200 ml) and organic layer was washed successively washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain brown solid. The product was directly used in the next step with further purification. Yield=10.2 g (85%). TLC (50% ethyl acetate in hexane) Rf=0.15; LCMS: RtH8=0.55 [M+1]+=363.0 and 364.9.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][N:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N1CCC[C@@H](CN(C2C=CC=CC=2)S(C)(=O)=O)C1)CC1C=CC=CC=1>>[CH2:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][N:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)N(C[C@H]1CCCN(CCc2ccccc2)C1)c1ccccc1
Agent: CS(=O)(=O)N(C[C@@H]1CCCN(CCc2ccccc2)C1)c1ccccc1
Product: CS(=O)(=O)N(CC1CCCN(CCc2ccccc2)C1)c1ccccc1

Procedure:
The two homogeneous enantiomers (12 and 16) were also obtained by chiral HPLC separation of the racemate 6 (ChiralPak AD column, 10% i-PrOH, 0.1% Et2NH in hexane, 4.7 mL/min, 254 nm): Rt1=13.92 min (16), Rt2=17.02 min (12).
Reaction SMILES: C([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C:10]([NH:21][CH2:22][C:23](=[O:41])[NH:24][CH:25]2[CH2:28][N:27]([CH:29]3[CH2:34][CH2:33][C:32]([OH:40])([C:35]4[S:36][CH:37]=[CH:38][N:39]=4)[CH2:31][CH2:30]3)[CH2:26]2)=[N:9]1)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[OH:40][C:32]1([C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[CH2:31][CH2:30][CH:29]([N:27]2[CH2:26][CH:25]([NH:24][C:23]([CH2:22][NH:21][C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=4)[N:8]([C:6]([NH2:5])=[O:7])[N:9]=3)=[O:41])[CH2:28]2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)(F)F)ccc21
Yield: 26.8 %

Procedure:
3-({[1-(4-Hydroxy-4-thiazol-2-yl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-amino)-5-trifluoromethyl-indazole-1-carboxylic acid tert-butylamide (as prepared in Example 80, 150 mg, 0.25 mmol) in TFA (2 mL) in a sealed tube was heated at 80° C. for 6 hours. The TFA was removed, and the residue was partitioned between DCM and saturated NaHCO3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, purified by silica gel column (DCM: 7 N NH3 in MeOH 9:1) to afford the title compound as white solid (36 mg, 27%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH2:13]([O:15][CH2:16][CH2:17]O)[CH3:14]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:14][CH2:13][O:15][CH2:16][CH3:17])=[O:8])=[CH:3][C:2]=1[C:10]([O:12][CH2:17][CH2:16][O:15][CH2:13][CH3:14])=[O:11]
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Reactant: CCOCCO
Product: CCOCCOC(=O)c1ccnc(C(=O)OCCOCC)c1

Procedure:
As described in Example 26, 10 g of pyridine-2,4-dicarboxylic acid are reacted with ethylene glycol monoethyl ether via the acid chloride. The reaction mixture is worked up analogously to Example 26. The product is obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH3:11]
Reactant: Cc1cncc(C=O)c1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cncc(C)c1

Procedure:
prepared by reaction of 5-methyl-pyridin-3-carbaldehyde (Kemnitzer W. et al J. Med. Chem. 2004, 47, 25, 6299-6310) with 2M ethylamine in THF.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([O:68][C:69]([N:71]1[CH2:76][CH2:75][N:74]([C:77](=[O:82])[C@@H:78]([NH2:81])[CH2:79][F:80])[CH2:73][CH2:72]1)=[O:70])[CH2:65][CH2:66][CH3:67].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:64]([O:68][C:69]([N:71]1[CH2:72][CH2:73][N:74]([C:77](=[O:82])[C@@H:78]([NH:81][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:30])[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=2)=[O:28])[CH2:79][F:80])[CH2:75][CH2:76]1)=[O:70])[CH2:65][CH2:66][CH3:67]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Reactant: Cc1ccc2c(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1

Procedure:
To a solution of 108 mg 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 2.5 ml DMF were added 134 μl DIPEA and 97 mg HATU. After 5 minutes 102 mg 4-((R)-2-Amino-3-fluoro-propionyl)piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate were added and the mixture stirred for 3 h before 2 ml of saturated aqueous NaHCO3 were added. The mixture was loaded on a chem Elute® cartridge and the crude product eluted with DCM. Further purification was performed by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 76 mg MS(ES+): m/e=669.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][N:26]=[C:21]3[CH:20]=2)=[CH:11]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N:26]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:27][C:19]([C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]([CH2:9][CH2:8][CH2:7][OH:6])[CH:11]=3)=[CH:20][C:21]=12
Reactant: CC(C)(C)[Si](C)(C)OCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A solution of 6-{1-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-1H-indol-3-yl}-5H-pyrrolo[2,3-b]pyrazine [29 g, Reference Example 3(a)] in tetrahydrofuran (500 mL) under nitrogen was treated with a solution of tetrabutylammonium fluoride in tetrahydrofuran (144 mL, 1.0M). After stirring at ambient temperature for 4 hours the reaction mixture was concentrated in vacuo. The residue was treated with water to give a solid which was filtered then washed with water and then dried to give the title compound (17.5 g) as a yellow-brown solid, m.p. 220-221° C. MS: 293 (MH+).