Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.C([Li])CCC.[CH:33]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)([CH3:35])[CH3:34].O1CCNC1=O>C1COCC1.O>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[CH2:3][C:4]([N:37]1[C@@H:36]([CH:33]([CH3:35])[CH3:34])[CH2:40][O:39][C:38]1=[O:41])=[O:6]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1C(=O)CC(C)(C)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
3-Methyl-3-phenylbutanoic acid (2, 1.00 g, 5.61 mmol) was dissolved in 70 mL of THF and cooled to −78° C. Triethylamine (1.17 mL, 8.42 mmol) and trimethylacetyl chloride (0.760 mL, 6.17 mmol) were added to the reaction flask producing a white solid. The resulting mixture was warmed to 0° C. for 1 h and then cooled back down to −78° C. In a second flask butyllithium (6.84 mL, 1.6 M in hexanes, 10.9 mmol) was added dropwise with vigorous stirring to a solution of (4S)-(−)-4-isopropyl-2-oxazolidinone (1.45 g, 11.2 mmol) at −78° C. in THF (60 mL) producing a white precipitate. The resulting suspension of the lithiated oxazolidinone was added via cannula to the reaction flask. Stirring was continued for 2 h, water was added and the reaction mixture was warmed to room temperature, whereupon it was extracted three times with diethyl ether. The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo. The product was purified by radial chromatography (4 mm plate, 3:7 diethyl ether-pet. ether) affording compound 3 as a clear, colourless oil in 84% yield (1.37 g, 4.74 mmol). 1H-NMR (400 MHz, CDCl3) 7.38 (d, 2H, J=7.3 Hz, H-19 and H-15) 7.28 (t, 2H, J=7.3 Hz, H-18 and H-16), 7.16 (t, 1H, J=7.3 Hz, H-17), 4.22-4.18 (m, 1H, H-4), 4.05 (dd, 1H, J=9.0 and 2.8 Hz, 1H-5), 4.00 (t, 1H, J=9.0 Hz, 1H-5), 3.38-3.30 (m, 2H, H-10), 2.16-2.12 (m, 1H, H-6), 1.48 (s, 3H, H-13 or H-12), 1.47 (s, 3H, H-13 or H-12), 0.79 (d, 3H, J=7.1 Hz, H-8 or H-7), 0.71 (d, 3H, J=6.9 Hz, H-8 or H-7); Mass spectrum (EI) 289 (8, M.+), 119 (100, [C9H11]+). Optical rotation obtained was [α]D25 +69.5 (c 1.16, CHCl3). Compound 3 was prepared according to D. A. Evans et al. (1988) Tetrahedron 44:5525.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])#[N:2].[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>CC(C)=O>[C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6])#[N:2].[CH:12]([NH2+:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]
Reactant: N#Cc1ncccc1C(=O)O
Reactant: CC(C)NC(C)C
Solvent: CC(C)=O
Product: CC(C)[NH2+]C(C)C
Product: N#Cc1ncccc1C(=O)[O-]
Yield: 99.5 %

Procedure:
2-Cyanonicotinic acid (0.74 g; 0.005 mol) suspended in acetone (40 cc) is treated with diisopropylamine (0.56 g; 0.0056 mol). The solvent is then evaporated off and the residue is crystallized in hexane: diisopropylammonium 2-cyanonicotinate (1.24 g; m.p. 156.7° C.) is obtained (yield=99%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[CH3:17][C:18]1[S:22][C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:20][C:19]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:26]2[CH2:27][CH2:28][N:23]([C:21]3[S:22][C:18]([CH3:17])=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)[CH2:24][CH2:25]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1sc(N2CCNCC2)nc1-c1ccccc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)c(C)s3)CC2)c1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 60.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (244 mg, 0.848 mmol), 1-(5-methyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.148 ml, 0.848 mmol) in dimethylsulfoxide (2.6 ml) was stirred at 70° C. for 5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 186 mg (60.8%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[CH3:30][N:31]([CH3:43])[CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:31]([CH3:30])[CH3:43])=[CH:42][CH:41]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)CCOc1ccc(C=O)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: CN(C)CCOc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.050 g, 0.13 mmol, 1 eq), EtOH (2.2 mL) and DMF (0.29 mL), 4-(2-dimethylaminoethoxy)benzaldehyde (0.027 g, 0.14 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 mL, 0.38 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained after trituration with diethyl ether as a pale yellow solid (0.010 g, 15%); 1H-NMR (500 Mz, DMSO-d6): 2.24 (s, 6H, NMe2), 2.66 (t, J=5.5 Hz, 2H, CH2NMe2), 2.75-2.80 (m, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CO), 3.70-3.76 (m, 4H), 4.13 (t, J=5.8 Hz, 2H, CH2O), 7.10 (d, J=8.5 Hz, 2H, ArH C6H4), 7.23 (d, J=4.0 Hz, 1H) and 7.49 (d, J=3.50 Hz, 1H) (thiazole H-4, H-5), 8.04-8.11 (m, 3H, imidazo[4,5-b]pyridine 5-H and ArH C6H4), 11.88 (br s, 1H, NHCO), 13.24 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.63 min—587/589 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:12]=[C:13]([OH:19])[C:14]([OH:18])=[CH:15][C:16]=1[CH3:17])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:27](Br)[C:28]([OH:30])=[O:29]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]2[O:18][CH:27]([C:28]([OH:30])=[O:29])[O:19][C:13]=2[CH:12]=1)(=[O:10])=[O:9]
Reactant: O=C(O)C(Br)Br
Reactant: Cc1ccccc1S(=O)(=O)c1cc(O)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)c1cc2c(cc1C)OC(C(=O)O)O2

Procedure:
27.5 g (0.097 mol) of 4-(2-methylphenylsulphonyl)-5-methyl-1,2-benzenediol, 62.1 g (0.45 mol) of potassium carbonate and 32.7 g (0.145 mol) of dibromoacetic acid (97% strength) are reacted in 300 ml of dimethylformamide under an inert gas atmosphere in a manner analogous to that described in Example 27. After working up, purification by way of the ethyl ester and hydrolysis, in a manner entirely analogous to that described in Example 27, 5-(2-methylphenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained in the form of colourless crystals having a melting point of 178°-180° (from toluene).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[C:19]([C:20]3[N:21]=[CH:22][N:23]([C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28](O)=[O:29])[CH:24]=3)=[C:18]([CH3:34])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1>>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[C:19]([C:20]3[N:21]=[CH:22][N:23]([C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([NH:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:29])[CH:24]=3)=[C:18]([CH3:34])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)NC3CCOCC3)c2)cn1
Yield: 49 %

Procedure:
As described for Example 71c, tetrahydro-pyran-4-ylamine was converted, using 3-{4-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (100 mg, 0.28 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (56 mg, 49%) which was obtained as an off-white solid. MS: m/e=447.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](ON3C(=O)CCC3=O)=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C.O>[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (“soln.”) of 6-aminohexanoic acid (1; 144 mg, 1.1 mmol) in 9% aq. Na2CO3 soln. (2.4 ml) was added a soln. of (9H-fluoren-9-yl)methyl succinimidyl carbonate (2; 337 mg, 1 mmol) in DMF (2.5 ml). After stirring for 1 h at room temperature (“r.t.”), the mixture was diluted with H2O (50 ml) and extracted twice with Et2O (2×20 ml). Then, the H2O phase was acified with conc. HCl soln. to pH 2 and extracted with AcOEt (5×30 ml). The organic (“org.”) layer was dried (MgSO4) and evaporated. The residue was crystallized in CHCl3/petroleum ether: 306 mg (86%) of 3. Colorless crystals. M.p. 116°. 1H-NMR (CDCl3): 7.80-7.55 (2m, H—C(1)(fmoc), H—C(4)(fmoc), H—C(5)fmoc, H—C(8)(fmoc); 7.45-7.25 (m, H—C(2)(fmoc), H—C(3)(fmoc), H—C(6)(fmoc), H—C(7)(fmoc); 4.45 (m, CH2O)(fmoc)); 4.2(m, H—C(9)(fmoc)); 3.25-3.0, 2.4, 1.8-1.3 (3m, NH(CH2)5CO). Anal. calc. for C21H23NO4 (353.42): C 71.37, H 6.56, N 3.96; found: C 71.35, H 6.65, N 3.93.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.CCCCCC.[CH3:20][C:21](N(C)C)=[O:22].[NH4+].[Cl-]>CCOCC.O>[C:21]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:22])[CH3:20]
Reactant: CC(=O)N(C)C
Reactant: Brc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cccc(Br)n1
Temperature: -80 °C
Reaction time: 0.25 h
Yield: 106 %

Procedure:
To a solution of 2,6-dibromopyridine (0.75 mol) in 2000 ml of anhydrous ether, which was cooled to -60° C. under N2, was added a solution of n-butyllithium in hexane (0.75 mol) over 15 min. The reaction mixture was cooled to -80° C. and a solution of dimethylacetamide (0.86 mol) in 70 ml anhydrous ether was added slowly over 1 hour. After stirring the mixture for 15 min, a solution of NH4Cl (0.93 mol) in 150 ml of water was added slowly over 8 min. After stirring an additional 45 min at room temperature, the aqueous layer was separated and extracted with 500 ml of ether. The combined organic layer was washed with water (2×800 ml), dried (MgSO4), filtered, and stripped on a rotary evaporator to yield 159 g of the desired product. This material was distilled at 80° C./0.1 mm Hg to give a near colorless oil that crystallized readily on cooling.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:22].N1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[Cl:12][C:8]1[C:7]2[S:22][C:4]([C:3]3[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:2]=3[Cl:1])=[N:5][C:6]=2[CH:11]=[CH:10][N:9]=1
Reactant: NC(N)=S
Reactant: Fc1cccc(Cl)c1C(Cl)=Nc1ccnc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Fc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A mixture of 2-chloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-6-fluorobenzimidoyl chloride (80 mg, 0.25 mmol), thiourea (76 mg, 1.0 mmol) and pyridine (82 μL, 1.0 mmol) in anhydrous isopropanol (1.5 mL) was heated under reflux, under nitrogen, for 3.5 hours. The reaction mixture was allowed to cool to ambient temperature and then triethylamine (1 mL) was added. The resultant mixture was heated under reflux for a further 1 hour then cooled to ambient temperature. The mixture was concentrated to dryness under reduced pressure and the residue was triturated with DCM, filtered and left to air dry. The crude product was purified by silica gel flash chromatography (0-10% EtOAc in cyclohexane) to give the desired compound as a white solid (65 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J=5.6 Hz, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.50 (td, J=8.3, 5.8 Hz, 1H), 7.41 (dt, J=8.2, 1.1 Hz, 1H), 7.21 (ddd, J=9.0, 8.4, 1.1 Hz, 1H). LCMS (Method C): RT=3.90 min, m/z: 299 [M+H+].
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[C:28]([CH3:31])[C:29]=2[CH3:30])[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[OH-].[NH4+].C(OCC)(=O)C>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[C:28]([CH3:31])[C:29]=2[CH3:30])[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3
Reactant: Cc1c[nH]c(-c2cc(SCCNC(=O)OC(C)(C)C)c3c(F)ccc4c3c2C(=O)N4)c1C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c(-c2cc(SCCN)c3c(F)ccc4c3c2C(=O)N4)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of [2-[6-fluoro-2-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester (from Example 49 above) (66 mg, 0.145 mmol) in CH2Cl2 (5 mL) was added TFA (Aldrich, 2.5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Aqueous ammonium hydroxide (4 mL) and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by RP-HPLC (C-18, eluted with 1% acetonitrile/0.05% TFA in H2O) to give 5-(2-amino-ethylsulfanyl)-6-fluoro-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one trifluoroacetic acid salt as a yellow-green solid. (Yield 20 mg, 29.4%).
Reaction SMILES: NC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=O)[CH:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27].ClC1C=CN=C(C#N)C=1>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:14])[CH:7]=2)=[CH:21][C:20]=1[C:26]([F:27])([F:28])[F:29]
Reactant: Nc1ccc(O)cc1C(F)(F)F
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Agent: N#Cc1cc(Cl)ccn1
Product: N#Cc1cc(Oc2ccc(N)c(C(F)(F)F)c2)ccn1

Procedure:
This material is prepared by a method analogous to that described for preparation of 2C, starting from 4-amino-3-(trifluoromethyl) phenol and 4-chloro-2-cyanopyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:14][NH:15][CH3:16].[CH2:17]=O.Cl.[OH-].[Na+]>CC(O)C.O.C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:16])[CH2:11][CH:10]([CH3:17])[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:12]
Reactant: CNC
Reactant: C=O
Reactant: CCC(=O)c1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: COc1cccc(C(=O)C(C)CN(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(3-methoxyphenyl)-1-propanone (240 g) in 2-propanol (584 ml) is stirred at ambient temperature. Dimethylamine hydrochloride (238.3 g) is added, followed by paraformaldehyde (109.5 g) and an aqueous HCl solution (26.5 ml, 35% w/w). The reaction mixture is heated to reflux temperature and stirred and refluxed for 5 hours. The reaction mixture is allowed to cool to 20° C., and water (730 ml) and toluene (146 ml) are added. The upper organic layer is discarded and an aqueous NaOH solution (50% w/w, 175.2 ml) is added to the water layer while stirring for 10 minutes and keeping the temperature below 25° C. After 10 minutes the layers are allowed to separate, the upper organic layer is isolated and washed with water (219 ml). The organic layer is isolated and concentrated to obtain 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methyl-1-propanone as on oily residue (294.9 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:41]1([SH:47])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.C(OCC)(=O)C>[C:41]1([S:47][CH2:32][CH2:31][C:30]([NH:29][C:25]2[CH:24]=[C:23]([C:9]3[S:10][C:11]([C:12]4[NH:16][CH:15]=[N:14][N:13]=4)=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH:28]=[CH:27][N:26]=2)=[O:33])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C=CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCSc1ccccc1)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a solution of N-(4-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyridin-2-yl)prop-2-enamide (92 mg, 0.2 mmol) prepared in Example 4-B (iii) in tetrahydrofuran (2.0 mL) were added triethylamine (30 mg, 0.3 mmol) and thiophenol (29 mg, 0.26 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate (25 mL), and washed with saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was extracted with ethyl acetate (25 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (8.0 mL), and the mixture was stirred at room temperature for 6 hr. Trifluoroacetic acid was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (40 mL) and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated and extracted with ethyl acetate (40 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (69 mg, 71%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]=C=O)[CH3:2].[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20]([CH2:27][O:28][CH2:29]CO)=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(O)C(N)(CO)C[OH:35].C([O-])(=O)C.[NH4+]>CO.O.C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20]([CH2:27][O:28][C:29](=[O:35])[NH:3][CH2:1][CH3:2])=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: NC(CO)(CO)CO
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reactant: CCN=C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)OCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 140 °C
Yield: 215.4 %

Procedure:
Ethyl isocyanate (22 mL, 0.31 mmol) was added to a mixture of DMAP (0.008 g, 0.063 mmol) (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 15, intermediate b) (0.02 g, 0.063 mmol), 4 Å molecular sieves (0.02 g, crushed) and DCM (2 mL). The reaction vessel was sealed and heated at 140° C. in a CEM Discoverer™ microwave for 15 min. The reaction mixture was cooled to room temperature, DCM (2 mL) and AP-trisamine (2.49 mmol/g, 0.25 g, 0.63 mmol) were added, the reaction vessel was sealed and heated at 130° C. in a CEM Discoverer™ microwave for 5 min. The reaction mixture was filtered and the solid washed with DCM (4 mL) the filtrate was evaporated and the crude product purified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 μm 60 Å 30 mm×300 mm column, UV detection 254 nm, mobile phase 95:5 methanol:water and 10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to afford the title compound (0.053 g, 22% yield) as a pale yellow oil: m/z 391.28 (MH+); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 2.98 min, 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([OH:30])[C:27]([OH:29])=O)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34].C(N(CC)CC)C.[NH3:44]>C(OCC)(=O)C>[CH2:33]([O:32][C:31]([O:30][CH:26]([CH2:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])/[CH:15]=[CH:14]/[C:9]2[CH:10]=[N:11][N:12]([CH3:13])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:24][CH:23]=1)[C:27]([NH2:44])=[O:29])=[O:35])[CH3:34]
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(O)C(=O)O)cc2)c1-c1ccc(F)cc1
Reactant: N
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)OC(Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of 3-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]-2-hydroxypropionic acid (409 mg), ethyl chlorocarbonate (324 mg), triethylamine (405 mg) and ethyl acetate (10 ml) was stirred at 0° C. for 1 hr. Conc. aqueous ammonia (10 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the precipitated solids were collected by filtration, washed with water and dried to give 2-(ethoxycarbonyloxy)-3-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]propionamide (471 mg, 98%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:19]([C:25](=O)[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21].FC1C=NC=C(F)C=1C=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]2[N:6]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:26])[N:8]=2)[CH:7]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncc(Cl)cc1OCc1ncccc1F
Agent: O=Cc1c(F)cncc1F
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(Cl)cn12

Procedure:
3.00 g (11.83 mmol) of 5-chloro-3-[(3-fluoropyridin-2-yl)methoxy]pyridine-2-amine from Example 127A and 9.73 g (59.13 mmol) of ethyl 2-chloro-3-oxobutanoate were dissolved in 72 ml of ethanol and, together with 4.5 g of 3 A molecular sieve, stirred under reflux for 6 days. The mixture was cooled and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient=4/1 to 2/1). This gave 2.0 g (46% of theory) of the target compound.