Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:12]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O.O1CCCC1.CO>[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Lithium hydroxide (3.38 g, 0.14 mol, 3 eq) in water (50 mL) was added to a stirred solution of benzyl 2-benzyloxy-5-formylbenzoate (16.13 g, 0.046 mol, 1 eq) in a mixture of tetrahydrofuran (200 mL) and methanol (50 mL). The solution was stirred overnight, acidified to pH 1 with 10% HCl, and the organic solvents removed in vacuo. The aqueous solution was extracted with ethyl acetate (200 mL), and the organic solution washed with brine (200 mL), then extracted with saturated aqueous sodium bicarbonate (3×200 mL). The basic solution was washed with ethyl acetate (200 mL), then acidified to pH 1 with 10% HCl and back extracted with ethyl acetate (3×200 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a pale yellow powder (10.83 g, 89%). 1H NMR (CDCl3) δ9.94 (s, 1H, O═C—H), 5.37 (s, 2H, CH2Ph).
Reaction SMILES: [H-].[Na+].[C:3]([O:12]C)(=[O:11])[CH2:4][O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[N:23]([CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[CH3:24].C(O)(=O)C>C1C=CC=CC=1.O>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[N:23]([CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31](/[CH:32]=[C:6](\[O:5][CH2:4][C:3]([OH:12])=[O:11])/[C:7]([O:9][CH3:10])=[O:8])=[CH:30][CH:29]=1)[CH3:24]
Reactant: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Reactant: COC(=O)COCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)/C(=C/c1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of sodium hydride (60% dispersion in mineral oil. 0.30 g), dimethyl diglycolate (0.81 g) and 4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]benzaldehyde (2.22 g) in dry benzene (50 mL)was stirred at room temperature overnight. Acetic acid (1 mL) was added, the mixture was poured onto iced water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (MgSO4) and evaporated. The resulting oil was chromatographed on silica gel using 2% methanol in dichloromethane, and the product crystallised from ethyl acetate, mp 111°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1ccccn1
Reactant: COc1cccc(C2CCCN2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2Cc2ccccn2)c1
Reaction time: 65 h
Yield: 90.3 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (3.0 g) in dry acetonitrile (70 ml) was added milled potassium carbonate (6.1 g) followed by 2-picolyl chloride hydrochloride (3.1 g) at ambient temperature, under nitrogen, with stirring for 65 hrs. The reaction mixture was filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated and the residue was purified by flash column chromatography (silica gel, 5% methanol/ether). The appropriate fractions were collected and concentrated to give 4.1 g (91%) of 2-(3-methoxyphenyl)-1-(2-pyridinylmethyl)pyrrolidine. 2-(3-Methoxyphenyl)-1-(2-pyridinylmethyl)pyrrolidine and 48% hydrobromic acid (40 ml) were warmed to 100° C. for 7 hrs, cooled to ambient temperature, and neutralized with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 ethyl acetate/dichloromethane). The appropriate fractions were collected and concentrated to give 2.7 g (69%) of product, mp 96°-98° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6]([CH3:15])=[CH:5][C:3]=1[NH2:4].Cl>CO.O=[Pt]=O>[CH3:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[C:6]([CH3:15])=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1cc(-c2cccnc2)c(C)cc1N
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: Cc1cc(C2CCCNC2)c(C)cc1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2,5-Dimethyl-4-(pyridin-3-yl)aniline (403 mg, 2.03 mmol) was dissolved in MeOH (5 mL) and conc. aqueous HCl (1 mL), followed by addition of PtO2 (40 mg). The flask was purged with H2 and the reaction was vigorously stirred at rt under H2 (1 atm). After two days, LCMS shows the completion of the reaction. The catalyst was removed by filtration and the remaining solution was concentrated in vacuo to give 2,5-Dimethyl-4-(piperidin-3-yl)aniline as a white solid, which can be used in subsequent reactions without further purification; ESMS m/z 205.2 (MAI).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([O:13][C:14]1[C:15]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[O:20][C:16]=2[N:17]=[CH:18][N:19]=1)[CH3:12])(C)(C)C>Cl.O1CCOCC1>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:21]1[O:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([O:13][C@H:11]([CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:38])=[O:5])[C:15]=2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@H](C)CCCCC(=O)OC(C)(C)C)c23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@H](C)CCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 373 mg (0.72 mmol) (6R)-6-{[6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]oxy}heptanoic acid tert.-butyl ester in 4 ml 4 N hydrogen chloride in dioxan and stir for 16 h at RT. After concentrating the reaction solution by evaporation under vacuum, purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 171 mg (51% of theor.) of the desired product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([O-:9])=O.[Li+].Cl.[NH2:29][C@H:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)[CH3:31]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:29][C@H:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)[CH3:31])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C([O-])c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2N2CCC(Oc3ccc(C(F)(F)F)cc3)C2)cc1
Yield: 27.6 %

Procedure:
The title compound (D191) (50 mg) was prepared according to the experimental procedure described in Description 148 starting from lithium 5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinate (D136) (130 mg, 0.331 mmol) and (S)-methyl 4-(1-aminoethyl)benzoate (D3) (71.19 mg, 0.331 mmol)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:28][OH:29])[CH2:19][CH2:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])C>C1COCC1.C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH:18]([N:28]([OH:29])[CH:30]=[O:32])[CH2:19][CH2:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(Br)cc2)CC1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a stirred solution of N-[1-([4-(4-bromophenyl)piperazino]sulfonylmethyl)-4-pyrimidin-2-ylbutyl]hydroxylamine (497 mg, 1.0 mmol) in THF (5.0 ml) and formic acid (2.5 ml), cooled to 0° C., was added a preformed mixture of acetic anhydride (566 μl, 6.0 mmol) and formic acid (2.0 ml). The mixture was stirred at 0° C. for 1 hour and allowed to come to room temperature. The solvents were removed by rotary evaporation and the residue purified by chromatography (50 g Silica Bond Elute, eluent 0→15% Methanol/Dichloromethane), pure fractions evaporated, and crystallised from hot ethyl acetate to give N-[1-([4-(4-bromophenyl)piperazino]sulfonylmethyl)-4-pyrimidin-2-ylbutyl]-N-hydroxyformamide as a white crystalline powder (262 mg, 51%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:16][C:15]3[CH:17]=[C:18]([CH:20]4[CH2:22][CH2:21]4)[S:19][C:14]=3[C:13]2=[O:23])=[CH:10][CH:9]=[CH:8][C:7]=1Br)(=O)C.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][N:45]=[CH:44][N:43]=2)[C:27]1=[O:48].C(=O)([O-])[O-].[Na+].[Na+].O.[OH-].[Li+]>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.O.CO.O1CCOCC1.CN(C=O)C>[CH:20]1([C:18]2[S:19][C:14]3[C:13](=[O:23])[N:12]([C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:47]=[CH:46][N:45]=[CH:44][N:43]=6)[C:27](=[O:48])[N:26]([CH3:25])[CH:31]=5)[C:6]=4[CH2:5][OH:4])[CH2:16][C:15]=3[CH:17]=2)[CH2:22][CH2:21]1
Reactant: CC(=O)OCc1c(Br)cccc1N1Cc2cc(C3CC3)sc2C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccncn2)c1=O
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: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(N3Cc4cc(C5CC5)sc4C3=O)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
A 50-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 116h (124 mg, 0.300 mmol), 116a (100 mg, 0.300 mmol), sodium carbonate (95 mg, 0.900 mmol), DMF (2.5 mL), water (1.2 mL) and 1,4-dioxane (4 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.003 mmol) was added, and the reaction mixture was heated at reflux for 14 h. After this time, the mixture was cooled to room temperature, and methanol (2 mL), water (2 mL) and lithium hydroxide monohydrate (42 mg, 1.00 mmol) were added. The mixture was stirred for 4 h at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride) to afford a 22% yield (32 mg) of 116 as an off-white solid: mp 140-141° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.70 (d, 1H, J=1.1 Hz), 8.64 (s, 1H), 8.29 (d, 1H, J=5.8 Hz), 7.52 (d, 1H, J=2.5 Hz), 7.48 (m, 1H), 7.43 (m, 1H), 7.38 (m, 1H), 7.31 (dd, 1H, J=5.9, 1.1 Hz), 7.04 (s, 1H), 4.91 (t, 1H, J=5.0 Hz), 4.83 (s, 2H), 4.34 (d, 2H, J=5.0 Hz), 3.60 (s, 3H), 2.29 (m, 1H), 1.12 (m, 2H), 0.82 (m, 2H); MS (ESI+) m/z 486.2 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:33])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and (4-phenoxy-phenyl)-acetic acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.82 (m, 2 H), 1.98 (m, 2 H), 3.03 (m, 2 H), 3.52 (m, 2 H), 3.69 (m, 4 H), 4.67 (t, J=6.24 Hz, 2 H), 6.99 (m, 4 H), 7.13 (m, 2 H), 7.38 (m, 4 H), 7.72 (m, 1 H), 8.08 (m, 1 H), 8.29 (s, 1 H), 10.42 (s, 1 H); MS (DCI/NH3) m/z 441 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CS(C)=O>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCO)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred solution of (2-hydroxyethyl)carbamic acid benzyl ester (1.0 g, 5.1 mmol) and DIPEA (1.78 mL, 10.2 mmol) in DCM (15 mL) was added a solution of sulfur trioxide-pyridine complex (1.63 g, 10.2 mmol) in DMSO (15 mL) at −20° C. After 1 h, the reaction was warmed to room temperature, diluted with dichloromethane (50 mL) and washed with 1.0 N HCl (50 mL) and brine. The organics were separated, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give the title intermediate (810 mg, 82%). 1H NMR (CDCl3, 300 MHz) δ (ppm): 9.5 (s, 1H) 7.4-7.2 (m, 5H), 5.1 (s, 2H), 3.9 (d, J=5.8 Hz, 2H), 2.9-3.3 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:20][C:21]1[C:33]([O:34][CH3:35])=[CH:32][C:24]2[CH2:25][CH2:26][O:27][C:28](=[O:31])[N:29]([CH3:30])[C:23]=2[CH:22]=1>>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([NH:20][C:21]2[C:33]([O:34][CH3:35])=[CH:32][C:24]3[CH2:25][CH2:26][O:27][C:28](=[O:31])[N:29]([CH3:30])[C:23]=3[CH:22]=2)=[N:6][CH:7]=1
Reactant: COc1cc2c(cc1N)N(C)C(=O)OCC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCOC(=O)N3C)ncc1Br
Yield: 30 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 3-Amino-2-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product triturated from Et2O to obtain a white solid (28 mg, 30%). mp: 251-253° C., MS (ESI+): 527 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 10.86 (s, 1H), 8.45 (s, J=8 Hz, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 7.57 (s, 1H), 7.51 (d, J=7 Hz, 1H), 7.41 (t, J=7 Hz, 1H), 7.16 (t, J=7 Hz, 1H), 6.73 (s, 1H), 6.24 (br s, 1H), 4.53 (t, 7 Hz, 2H), 3.93 (s, 1H), 3.06 (d, J=5 Hz, 3H), 2.97 (s, 3H), 2.93 (t, J=7, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[O:4][C:5]2[C:6](=[C:8]([C:20]#[N:21])[C:9]([CH3:19])=[C:10]([C:13]3[N:14]=[C:15]([CH3:18])[S:16][CH:17]=3)[C:11]=2F)[N:7]=1.C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>CS(C)=O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:22])[C:3]1[O:4][C:5]2[C:6](=[C:8]([C:20]#[N:21])[C:9]([CH3:19])=[C:10]([C:13]3[N:14]=[C:15]([CH3:18])[S:16][CH:17]=3)[C:11]=2[N:34]2[CH2:35][CH2:36][C@H:32]([N:31]([CH3:37])[CH3:30])[CH2:33]2)[N:7]=1
Reactant: Cc1nc(-c2c(C)c(C#N)c3nc(N(C)C)oc3c2F)cs1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(-c2c(C)c(C#N)c3nc(N(C)C)oc3c2N2CC[C@H](N(C)C)C2)cs1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
2-(Dimethylamino)-7-fluoro-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1,3-benzoxazole-4-carbonitrile (I-171) (0.44 g, 1.39 mmol) was suspended in dimethyl sulfoxide (10 ml), then triethylamine (0.42 ml 3.03 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.38 ml, 3.00 mmol) were added, followed by stirring at an external temperature of about 110° C. for 4 hours. This was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain a brown amorphous substance (0.51 g, 83%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:18]
Reactant: CNCc1ccccc1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Product: CN(Cc1ccccc1)C(=O)C1CCNCC1

Procedure:
This compound was prepared similarly to Preparation C starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and N-methylbenzylamine, and was used directly in Example 10. This intermediate was characterised as the hydrochloride salt, m.p. 175°-176°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N,N-diethylamine (3.60 ml, 34.7 mmol) in DMSO (20 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.78 g, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:29])=[C:6]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])[CH:7]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C(O)=CC4N(C)C(=O)COC=4C=3)(O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:29])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])[CH:7]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc(Br)ccc1O
Agent: CN1C(=O)COc2cc(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Product: O=C1C(c2cc(Br)ccc2O)c2ccccc2N1Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 17B, and making non-critical variations using 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one to replace 7-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one, 3-(5-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one was obtained (89%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.78 (br s, 1H), 7.44-7.36 (m, 1H), 7.36-7.19 (m, 3H), 7.08 (d, J=7.9 Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.73-6.68 (m, 1H), 6.37-6.32 (m, 1H), 5.10 (s, 1H), 5.00-4.85 (m, 2H); MS (ES+) m/z 452.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:15]([CH:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[NH2:14])[CH:6]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH:34]=O)[CH:27]=1.C(#N)C.FC(F)(F)C(O)=O>O>[CH3:1][C:2]([CH3:24])([CH3:25])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:15]([CH:17]2[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]2)=[O:16])[NH:14][CH2:34][CH2:33][O:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[CH:6]=1
Reactant: O=CCOc1cccnc1
Reactant: CC1CCC(C(=O)N(N)c2cc(C#CC(C)(C)C)sc2C(=O)O)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC1CCC(C(=O)N(NCCOc2cccnc2)c2cc(C#CC(C)(C)C)sc2C(=O)O)CC1

Procedure:
The title compound was synthesized from 5-(3,3-dimethyl-but-1-ynyl)-3-[N-(4-methyl-cyclohexanecarbonyl)-hydrazino]-thiophene-2-carboxylic acid and (pyridin-3-yloxy)-acetaldehyde in a manner similar to that of Example 131. MS (m/z): 484.0 [M−H]+; HPLC retention time: 3.44 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[NH4+].[OH-].[CH3:21]O>C1COCC1.O.ClCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccc(N)cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
A 250-mL round bottom flask was charged with 4-(4-aminophenyl)butyric acid (2.00 g, 11.2 mmol) in methanol (50 mL) and treated with conc. sulfuric acid (1 mL). The resultant mixture was heated to reflux for 1.5 h. After this time, methanol (˜25 mL) was distilled off. The reaction was cooled to 60° C. and methyl tert-butyl ether was added. The mixture was allowed to slowly cool to room temperature, then diluted with hexanes (50 mL) to afford a white solid. The solid was dissolved in THF (6 mL)/water (4 mL) and treated with conc. NH4OH (6 mL). The mixture was diluted with dichloromethane (50 mL) and the layers separated. The organic layer was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (2.07 g, 96%) as a brown solid. MW=193.24. 1H NMR (DMSO-d6, 500 MHz) δ 6.83-6.79 (m, 2H), 6.50-6.46 (m, 2H), 4.81 (s, 2H), 3.57 (s, 3H), 2.39 (t, J=7.5 Hz, 2H), 2.25 (t, J=7.5 Hz, 2H), 1.73 (quin, J=7.5 Hz, 2H).