Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[CH:23]1(O)[CH2:28][CH2:27]C[CH2:25][CH2:24]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C1C=CN=CC=1)C>[CH:1]1([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:8][N:7]=2)[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OC1CCCCC1
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A mixture of [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid methyl ester (prepared above, 50 mg, 0.17 mmol) and cyclohexanol (51 mg, 0.51 mmol) were slurried in dichloromethane. DMAP (17 mg, 0.14 mmol) was added, and the slurry became homogeneous and colorless. The solution was then treated with 1 M dicyclohexylcarbodiimide (190 μL, 0.19 mmol), which initiated formation of a white slurry within 5 min. After 1 h, thin layer chromatography indicated complete conversion. The reaction was quenched with 10 mL 1 M HCl(aq) and 25 mL dichloromethane. The phases were partitioned, and the aqueous phase extracted with 5 mL dichloromethane. The organic phases were combined and sequentially washed with 10 mL portions of 0.1 M HCl(aq), saturated. NaHCO3(aq) and brine. The organic layer was dried using Na2SO4, filtered and concentrated. The 101 mg of crude product was chromatographed over SiO2 (1:1 ethyl acetate:hexane) to yield 50 mg (79%) of the titled compound. ESI-MS m/z 374 (MH+), 372 (M−H−).
Reaction SMILES: [C:1]1([S:15]([OH:18])(=[O:17])=[O:16])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([OH:14])(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:19]([C:21]1[CH:22]=[C:23]([CH:62]=[CH:63][C:64]=1[CH2:65][CH3:66])[CH2:24][C@@H:25]([NH:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([N:50]2[CH2:56][CH2:55][C:54]3[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=3[NH:52][C:51]2=[O:61])[CH2:46][CH2:45]1)=[O:43])[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[CH2:30][CH2:29]1)=[O:27])[CH3:20]>C(O)(C)C>[CH2:19]([C:21]1[CH:22]=[C:23]([CH:62]=[CH:63][C:64]=1[CH2:65][CH3:66])[CH2:24][C@@H:25]([NH:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([N:50]2[CH2:56][CH2:55][C:54]3[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=3[NH:52][C:51]2=[O:61])[CH2:46][CH2:45]1)=[O:43])[C:26]([N:28]1[CH2:29][CH2:30][N:31]([CH:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)[CH2:32][CH2:33]1)=[O:27])[CH3:20].[C:1]1([S:15]([O-:18])(=[O:17])=[O:16])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([O-:14])(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Solvent: CC(C)O
Product: O=S(=O)([O-])c1cccc2c(S(=O)(=O)[O-])cccc12
Temperature: 80 °C

Procedure:
A solution of 1.427 g naphthalene-1,5-disulphonic acid (4.95 mmol) in 70 ml isopropanol is added to 3.25 g (4.94 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide and heated to 80° C. The now clear solution is cooled to ambient temperature, by lowering the temperature of the heating bath by 5° C. every 6 hours. The resultant suspension is filtered, the isolated solid is dried for 12 hours at 40° C.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClC[CH2:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)C>[C:20]([CH2:21][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)(=[O:22])[CH3:19]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of benzyl 1-piperazinecarboxylate (4.1 ml), chloromethyl acetone (1.8 ml) and potassium carbonate (8.8 g) in acetonitrile (40 ml) was stirred overnight at ambient temperature. The reaction mixture was diluted in diethyl ether and the solution was partitioned between diethyl ether and water. The water phase was extracted with diethyl ether, the organic phases were combined and washed with water, brine, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography using dichloromethane/methanol saturated with ammonia (3.5 M) (98/2). Evaporation of the solvent gave benzyl 4-(acetylmethyl)-1-piperazinecarboxylate (3.7 g, 63%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[C:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[CH:27][CH:26]=1)(=[O:23])[CH3:22].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[N+:15]([C:11]1[CH:10]=[C:9]([CH:7]([C:6]2[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:33][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][C:21](=[O:23])[CH3:22])=[CH:26][CH:27]=2)[CH3:32])[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: CC(=O)Oc1ccc(C(C)N)cc1
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(C)c2ccc(OC(C)=O)cc2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 26.3 %

Procedure:
In a similar manner to that described in Example (1a), 4-methoxy-3′-nitrobenzophenone (500 mg), 4-(1-aminoethyl)phenyl acetate hydrochloride (1.0 g), triethylamine (1.63 ml), titanium tetrachloride (0.26 ml), sodium cyanoborohydride (543 mg) and acetic acid (0.17 ml) were reacted, to afford the title compound (215 mg) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][O:10][NH:11][C:12]([C@@H:14]1[CH2:20][CH2:19][C@@H:18]2[CH2:21][N:15]1[C:16](=[O:30])[N:17]2[O:22]CC1C=CC=CC=1)=[O:13])([CH3:4])([CH3:3])[CH3:2].O>O1CCCC1.[Pd]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][O:10][NH:11][C:12]([C@@H:14]1[CH2:20][CH2:19][C@@H:18]2[CH2:21][N:15]1[C:16](=[O:30])[N:17]2[OH:22])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 100.2 %

Procedure:
tert-Butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (43.4 g, 100 mmol) was dissolved in tetrahydrofuran (475 mL). After the dissolution was confirmed, water (25 mL) was added, and set under an argon atmosphere. 10% Pd/C (8.68 g, 50% wet) was added, and stirred vigorously under hydrogen atmosphere for 3 h. The end point was confirmed by TLC, and then catalyst was filtered through Celite. The solvent of filtrate was concentrated under reduced pressure. The concentrated residue was subjected to workup of substitution and concentration with ethyl acetate (100 mL) twice, and with methylene chloride (100 mL) once to afford 34.5 g of the title compound (quantitative). Instrumental data were consistent with those of Example 59.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.Br[C:26]1[C:27]([C:32]#[N:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:26]3[C:27](=[C:32]([NH2:33])[N:8]=[C:6]2[CH:7]=1)[N:28]=[CH:29][CH:30]=[CH:31]3
Reactant: N#Cc1ncccc1Br
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)nc(N)c1ncccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from step 2) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give a pure solid. 1H NMR (acetone d-6): δ 8.98 (d, 1H), 8.87 (d, 1H), 8.32 (d, 1H), 7.79-7.82 (dd, 1H), 7.42 (s, 1H), 7.18 (d, 1H), 6.6 (br, 2H), 2.45 (s, 3H). LRMS [M+H]=210.1
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[O:17][N:16]=[C:15]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:9][CH2:8]1)(=O)=O.Cl.[F:22][C:23]1[CH:28]=[C:27]([S:29][CH3:30])[CH:26]=[CH:25][C:24]=1[C:31]1[N:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:22][C:23]1[CH:28]=[C:27]([S:29][CH3:30])[CH:26]=[CH:25][C:24]=1[C:31]1[CH:32]=[CH:33][C:34]([O:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[O:17][N:16]=[C:15]([CH:18]([CH3:19])[CH3:20])[N:14]=3)[CH2:11][CH2:12]2)=[CH:35][N:36]=1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Reactant: CSc1ccc(-c2ccc(O)cn2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
A mixture of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, 50.4 g, 166 mmol), 6-[2-fluoro-4-(methylthio)phenyl]-3-pyridinol hydrochloride (47.6 g, 175 mmol), powdered potassium carbonate (72.6 g, 525 mmol) and N,N-dimethylformamide (450 mL) was mechanically stirred and heated at 80° C. under nitrogen for 48 h. The reaction was cooled to ambient temperature, poured onto ice water (2.5 L) and allowed to stand for 30 min. The resulting solid was filtered, rinsed with water (500 mL), heptane (500 mL) and air-dried to afford 2-[2-fluoro-4-(methylthio)phenyl]-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (67.5 g, 92%) as a light tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:19]=1)[NH:7][C:8](=[O:18])[CH2:9][N:10]=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>CN(C=O)C.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]>[O:18]=[C:8]1[NH:7][C:6]2[CH:19]=[C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])[CH:3]=[CH:4][C:5]=2[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH2:9]1
Reactant: O=C1CN=C(c2ccccc2)c2ccc(Br)cc2N1
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2c(c1)NC(=O)CN=C2c1ccccc1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
Title compound 354 (400 mg, 1.28 mmol), methyl acrylate (132 mg, 1.54 mmol), Pd2(dba)3 (16 mg, 0.038 mmol), POT (24 mg, 0.07 mmol) and triethylamine (0.446 mL, 3.2 mmol) were mixed in DMF (15 mL). The mixture was degassed with nitrogen for 5 minutes and the reaction mixture was heated to 100° C. for 2 hours. The DMF was removed and the residue was partitioned between ethyl acetate and water. The 2 layers were split and the aqueous layer was extracted with 2 other portions of ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (50% to 65% ethyl acetate in hexanes) to afford title compound 355 (135 mg, 33%) as a light yellow solid. 1H NMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.68 (d, J=16.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.24 (d, J=6.4 Hz, 2H), 7.16 (td, J=7.5, 1.0 Hz, 1H), 6.70 (d, J=16.2 Hz, 1H), 4.12 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:13]=1[CH2:14][N:15]1[CH2:19][C@H:18]([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[C@@H:17]([CH2:25][OH:26])[CH2:16]1.CCOCC>C(Cl)Cl>[Cl:11][C:12]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:13]=1[CH2:14][N:15]1[CH2:19][C@H:18]([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[C@@H:17]([CH:25]=[O:26])[CH2:16]1
Reactant: OC[C@H]1CN(Cc2ccc(Cl)cc2Cl)C[C@@H]1c1ccsc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C[C@H]1CN(Cc2ccc(Cl)cc2Cl)C[C@@H]1c1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a solution of 0.31 mL (3.6 mmol) of oxalyl chloride in 20 mL of CH2Cl2 at −78° C. was added 0.51 mL (7.2 mmol) of DMSO and the reaction mixture was stirred. After 10 min., a solution of 0.49 g (1.8 mmol) of 1-(2,4-dichlorobenzyl)-3-(R)-hydroxymethyl-4-(S)-(3-thienyl)pyrrolidine in 20 mL of CH2Cl2 was then added. After stirring for 10 min. at −78° C., the reaction was allowed to warm to rt. The reaction mixture was poured into ether and extracted twice with sat'd NaHCO3 solution and once with sat'd NaCl solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give 0.49 g of the title compound. Mass Spectrum (ESI) m/e=340 (M+1 35Cl, 35Cl), 342 (M+1 35Cl, 37Cl), and 344 (M+1 37Cl, 37Cl).
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH:36]1(B(O)O)[CH2:38][CH2:37]1>>[CH:36]1([C:2]2[CH:31]=[CH:30][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][C:12]([CH:16]=[C:17]5[S:21][C:20]([N:22]6[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]6)=[N:19][C:18]5=[O:29])=[CH:13][CH:14]=4)[CH:9]=[N:8]3)=[C:4]([C:32]([F:34])([F:33])[F:35])[CH:3]=2)[CH2:38][CH2:37]1
Reactant: OB(O)C1CC1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Br)cc4C(F)(F)F)c3)S2)CC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C5CC5)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one and cyclopropyl boronic acid following General Procedure F.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[NH:7][C:6](=[O:11])[CH:5]([CH3:12])[S:4]1)[OH:2].[CH3:13][N:14]=[C:15]=[O:16].CN(C)C>>[CH3:13][NH:14][C:15]([O:2][N:1]=[C:3]1[C:8]([CH3:9])([CH3:10])[NH:7][C:6](=[O:11])[CH:5]([CH3:12])[S:4]1)=[O:16]
Reactant: CC1SC(=NO)C(C)(C)NC1=O
Reactant: CN=C=O
Agent: CN(C)C
Product: CNC(=O)ON=C1SC(C)C(=O)NC1(C)C

Procedure:
Utilizing the procedure of Example V, 2-oximino-3,3,6-trimethyltetrahydro-1,4-thiazin-5-one was reacted with methyl isocyanate in the presence of trimethylamine to yield 3 g of 2-[O-(methylcarbamoyl)oximino]-3,3,6-trimethyltetrahydro-1,4-thiazin-5-one, m.p. 190°-191° C. IR spectrum supported the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[NH:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][N:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@@H]1CCCN1Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (101.1 mg, 0.270 mmol) and L-(−)-proline (93.3 mg, 0.810 mμmol) according to Reference R and the general procedure for reductive amination to give (S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)pyrrolidine-2-carboxylic acid as a light yellow solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.2 (M++1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)/[C:6](=[C:16](/[NH:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])=[CH:26][CH:25]=2)\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:5]1=[O:41])(=O)C.[CH3:42][N:43]([CH3:48])[C:44](=[O:47])[CH2:45]Br.CC(C)([O-])C.[K+].[OH-].[Na+]>CS(C)=O.CO>[CH3:42][N:43]([CH3:48])[C:44]([CH2:45][N:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23]/[C:16](=[C:6]2\[C:5](=[O:41])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:25][CH:26]=1)[S:31]([C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1)(=[O:33])=[O:32])=[O:47]
Reactant: CN(C)C(=O)CBr
Reactant: CC(=O)N1C(=O)/C(=C(\Nc2ccc(NS(=O)(=O)c3ccc(C)cc3)cc2)c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(CC(=O)N(C)C)c2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)cc1

Procedure:
Prepared analogously to Examples 82 and 187 from (Z)-1-acetyl-3-{1-[4-(p-tolylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone, bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSO and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[CH:26][C:23]=1[CH:24]=[O:25]>>[C:6]1([C:8]#[C:9][CH:24]([C:23]2[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])[OH:25])[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1cc(OC)c(C(O)C#Cc2ccccc2)cc1OC
Yield: 90 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,4,5-trimethoxybenzaldehyde was reacted to give the title compound as an off-white solid (535 mg, 90%). LCMS (Method B): RT=3.99 min, [M+Na]+=321.
Reaction SMILES: Cl[Sn]Cl.Cl.[N+:5]([C:8]1[C:9]([C:26]#[C:27][C:28]2[C:33]([F:34])=[C:32]([F:35])[N:31]=[C:30]([F:36])[C:29]=2[F:37])=[C:10]([C:14]#[C:15][C:16]2[C:21]([F:22])=[C:20]([F:23])[N:19]=[C:18]([F:24])[C:17]=2[F:25])[CH:11]=[CH:12][CH:13]=1)([O-])=O>C1COCC1>[F:36][C:30]1[C:29]([F:37])=[C:28]([C:27]#[C:26][C:9]2[C:10]([C:14]#[C:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[N:19]=[C:18]([F:24])[C:17]=3[F:25])=[CH:11][CH:12]=[CH:13][C:8]=2[NH2:5])[C:33]([F:34])=[C:32]([F:35])[N:31]=1
Reactant: O=[N+]([O-])c1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1C#Cc1c(F)c(F)nc(F)c1F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1C#Cc1c(F)c(F)nc(F)c1F
Reaction time: 24 h

Procedure:
SnCl2 (5.8 g, 31 mmol) and 1.5 mL of conc. HCl (aq) were added to the solution of 4,4′-((3-Nitro-1,2-phenylene)bis (ethyne-2, 1-diyl))bis (2,3,5,6-tetrafluoropyridine), (18) (1.45 g, 3.1 mmol) in 30 mL of THF. The reaction mixture was stired for 1 day. After basification till pH>9 with NaOH (1.0 N solution), the product was extracted with dichloromethane. Solvent was evaporated and 0.4 g (31%) of the product aniline was purified by recrystallization: 1H-NMR (300 MHz, CDCl3) δ 7.29 (m, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 4.58 (s, 2H)
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH2:7][CH2:6]1)=[O:4].O[Li].O>CO.O>[O:16]=[C:14]1[NH:13][C:12]2[CH:17]=[C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)[CH:9]=[CH:10][C:11]=2[O:15]1
Reactant: COC(=O)C1(c2ccc3oc(=O)[nH]c3c2)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2ccc3oc(=O)[nH]c3c2)CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 84.5 %

Procedure:
To a solution of 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid methyl ester (1.9 g, 8.1 mmol) in MeOH (20 mL) and water (2 mL) was added LiOH.H2O (1.7 g, 41 mmol) in portions at room temperature. The reaction mixture was stirred for 20 hours at 50° C. MeOH was removed by evaporation under vacuum before water (100 mL) and EtOAc (50 mL) were added. The aqueous layer was separated, acidified with HCl (3 mol/L) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (1.5 g, 84%). 1H NMR (DMSO, 400 MHz) δ 12.32 (brs, 1H), 11.59 (brs, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 1.44-1.41 (m, 2H), 1.13-1.10 (m, 2H). MS (ESI) m/e (M+H+) 218.1.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1>>[CH3:7][N:6]1[C:2]([O:11][C@@H:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: O[C@@H]1CCOC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1O[C@@H]1CCOC1
Yield: 34 %

Procedure:
Following the procedure for Example 230 starting with 5-chloro-1-methyl-4-nitro-1H-pyrazole and (R)-(−)-3-hydroxy tetrahydrofuran gave (R)-1-methyl-4-nitro-5-(tetrahydrofuran-3-yloxy)-1H-pyrazole as a clear oil (90 mg, 34%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.65 (q, J=3.4 Hz, 1H), 4.10 (q, J=8.0 Hz, 1H), 4.02-3.87 (m, 2H), 3.81 (dd, J=11.3, 3.4 Hz, 1H), 3.71 (s, 3H), 2.26 (td, J=7.3, 3.4 Hz, 2H)
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.I[C:34]1SC2C=CC(C)=CC=2N=1>>[CH3:34][C:4]1[CH:3]=[CH:2][C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: Cc1ccc2sc(I)nc2c1
Product: Cc1ccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc2c1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-5-methyl-1,3-benzothiazole and conducting the Suzuki coupling at 80° C. for 3 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=8.96-8.87 (brm, 1H), 8.75-8.65 (brm, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 8.37 (brs, 1H), 8.35 (very brs, 1H), 8.06 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 7.36 (dd, J=8.0, 1.0 Hz, 1H), 4.56-4.48 (mc, 1H), 3.11 (brq, J=11.0 Hz, 2H), 2.30-2.10 (m, 4H); CH3 and additional 2H hidden under water peak. MS(ES+): m/z=391.14 (72) [MH+], 308.09 (100) [MH+-piperidine]. HPLC: tR=2.10 min (polar—5 min, ZQ2).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].I[C:8]1[C:9]([CH:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[N:10][N:11](COCC[Si](C)(C)C)[CH:12]=1.CCO.CCO.C(N(CC)CC)C>CCO.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:6][C:8]1[C:9]([CH:21]2[CH:26]3[CH2:25][CH2:24][N:23]([CH2:28][CH2:27]3)[CH2:22]2)=[N:10][NH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCO
Reactant: C[Si](C)(C)CCOCn1cc(I)c(C2CN3CCC2CC3)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCOc1c[nH]nc1C1CN2CCC1CC2

Procedure:
Compound 52C was prepared following the procedure as described for the synthesis of compound 52A (see Scheme 10) using pentanol (25 ml) and 3-[4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane (50), (2 g, 4.61 mmol). Work-up and flash chromatography (gradient EtOH to EtOH/triethylamine 300/1) followed by a second flash chromatography (EtOH/ethyl acetate/triethylamine 25/75/1) afforded compound 51C as an oil (0.46 g, 15%). LCMS (method B); Rt: 3.30 min, ([M+H]+=394).