Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[N:15]([CH2:19][CH2:20][CH2:21][OH:22])[CH:16]=[CH:17][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:42][C:43]1[CH:62]=[CH:61][C:46]([NH:47][C:48]2[C:57]3[C:52](=[CH:53][C:54](O)=[C:55]([O:58][CH3:59])[CH:56]=3)[N:51]=[CH:50][N:49]=2)=[C:45]([F:63])[CH:44]=1>C(Cl)Cl>[ClH:42].[Cl:42][C:43]1[CH:62]=[CH:61][C:46]([NH:47][C:48]2[C:57]3[C:52](=[CH:53][C:54]([O:22][CH2:21][CH2:20][CH2:19][N:15]4[CH:16]=[CH:17][N:18]=[C:14]4[CH3:13])=[C:55]([O:58][CH3:59])[CH:56]=3)[N:51]=[CH:50][N:49]=2)=[C:45]([F:63])[CH:44]=1
Reactant: Cc1nccn1CCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCn1ccnc1C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to a solution of 2-methyl-1-(3-hydroxypropyl)imidazole (131 mg, 0.93 mmol), (EP 0060696 A1), triphenylphosphine (492 mg, 1.8 mmol) and 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 24), in methylene chloride (4 ml) and the mixture stirred for 2 hours at ambient temperature. Further 2-methyl-1-(3-hydroxypropyl)imidazole (43 mg, 0.31 mmol), triphenylphosphine (82 mg, 0.31 mmol) and diethyl azodicarboxylate (50 μl, 0.31 mmol) were added and the mixture stirred for a further 3 hours. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (93/7). The purified solid was dissolved in methylene chloride and 3M ethereal hydrogen chloride (2 ml) was added. The volatiles were removed by evaporation and the solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-methylimidazol-1-yl)propoxy)quinazoline hydrochloride (104 mg, 32%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=O)(C)(C)C.[ClH:24].CCOCC>ClCCl.O1CCOCC1>[ClH:24].[NH2:8][CH2:9][CH2:10][S:11]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: COC(=O)c1ccc(S(=O)(=O)CCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc(S(=O)(=O)CCN)cc1

Procedure:
A solution of methyl 4-(2-tert-butoxycarbonylaminoethanesulfonyl)benzoate (2.86 g, 8.33 mmol) in dichloromethane (20 ml) was treated with 4M HCl in dioxane (20 ml) for 2 h. Ether (200 ml) was added and the suspension was filtered, washed with ether (2×50 hexane (50 ml) and pumped dry to give methyl 4-(2-aminoethylsulfonyl)benzoate hydrochloride (2.23 g) which was coupled with benzofuran 2-carboxylic acid as described above to afford the title compound. MS (M+1): 388.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C(N(CC)CC)C.[NH2:18][C@H:19]([CH3:22])[CH2:20][OH:21]>C(O)(C)C>[NH2:8][C:7]1[C:2]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:3][C:4]([CH3:10])=[N:5][C:6]=1[Cl:9]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: C[C@@H](N)CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c(N)c(N[C@H](C)CO)n1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Charge 4,6-dichloro-2-methyl-pyrimidin-5-ylamine (307 g, 1.72 moles) into a 10 L flange flask mounted on an isomantle equipped with an overhead stirrer, reflux coil condenser, thermometer, and addition funnel. Then add isopropyl alcohol (3.45 L) to the flask and stir to give a clear pale yellow solution. Add triethylamine (456.7 mL, 3.28 mol) to the flask in one portion while stirring and warm to 50° C. Slowly add (R)-(−)-2-amino-1-propanol (194.30 g, 202.10 mL, 2.59 mol) from the addition funnel over 30 min. After the final addition heat the reaction mixture at reflux for 36 h. Allow the reaction mixture to cool. Add additional (R)-(−)-2-amino-1-propanol (64.77 g, 67.37 mL, 862.26 mmol, 0.5 eq) and triethylamine (174.51 g, 240.37 mL, 1.72 moles, 1.0 eq) to the reaction mixture and reflux for 18 h. Allow the reaction mixture to cool. Add additional (R)-(−)-2-amino-1-propanol (32.38 g, 33.68 mL, 431.13 mmol, 0.25 eq) and triethylamine (87.25 g, 120.18 mL, 862.26 mmol, 0.5 eq) to the reaction mixture and heat to reflux for 6 h. Allow to cool while stirring at ambient temperature for 48 h.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH:24][C:25](=[O:27])[CH3:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][CH:38]([F:41])[CH2:39]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH:24][C:25](=[O:27])[CH3:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:39][CH:38]([F:41])[F:37])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]2([CH3:36])[CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cccc(OCC(F)F)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
Dissolve (2R,5R)-5-[(1S,2S)-2-acetylamino-1-hydroxy-3-(3-hydroxyphenyl)-propyl]-2-(1-methylcyclopentylmethoxy)-morpholine-4-carboxylic acid tert-butyl ester (204 mg) and 2,2-difluoro-1-bromoethane (0.065 mL) and cesium carbonate (391 mg) in N,N-dimethylformamide (5 mL) and heat to 60° C. for 18 hours. Dilute with ethyl acetate, wash with saturated aqueous sodium chloride, dry and purify (silica gel chromatography, eluting with 1:1 ethyl acetate:dichloromethane), to give the desired compound (223 mg).
Reaction SMILES: Cl.[CH:2]1([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)(=O)C(C)(C)C.CN1CCOCC1.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl.O>[C:32]([O:36][C:37](=[O:38])[NH:39][CH2:40][C:41]([N:9]1[CH2:10][CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]1[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:42])([CH3:35])([CH3:33])[CH3:34]
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCc2ccccc2C1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g) was dissolved in methylene chloride (20 mL), and pivaloyl chloride (0.98 mL) and 4-methylmorpholine (2.2 mL) were added thereto under ice-cooling. The reaction liquid was stirred at room temperature for 30 minutes and then ice-cooled, and [(tert-butoxycarbonyl)amino]acetic acid (1.54 g) was added thereto. The reaction liquid was stirred at room temperature for 14 hours and then water was added thereto, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain tert-butyl[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]carbamate (1.49 g).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:23]([NH:26][C@@H:27]1[C@H:32]([O:33][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=[C:30]([C:51]([O:53]C)=[O:52])[O:29][C@H:28]1[C:55]([O-:57])=O)(=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C.[CH2:67]([CH2:75][CH2:76][CH2:77][NH2:78])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C)C=O>[C:23]([NH:26][C@H:27]1[C@H:28]([C:55](=[O:57])[NH:78][CH2:77][CH2:76][CH2:75][CH2:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[O:29][C:30]([C:51]([OH:53])=[O:52])=[CH:31][C@H:32]1[OH:33])(=[O:25])[CH3:24]
Reactant: COC(=O)C1=C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](NC(C)=O)[C@H](C(=O)[O-])O1
Reactant: NCCCCCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1[C@H](O)C=C(C(=O)O)O[C@H]1C(=O)NCCCCCc1ccccc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.42 g) was added to a solution of (2R,3S,4R)-3-acetylamino-4-(tert-butyldiphenylsilanyloxy)-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid, 6-methyl ester (2 g) and N,N-diisopropylethylamine (1.4 ml) in dimethylformamide (5 ml), under nitrogen. To this was added N-phenethylpropylamine (722 mg) and the reaction was stirred at 23° C. for 16 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic extracts were dried over anhydrous sodium sulphate and the solvent was removed in vacuo to give a fawn foam. The foam was chromatographed over silica (Merck 9385, 45 g) using medium pressure (ca 4 psi) and ethyl acetate/cyclohexane (1:2 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white foam (1.1 g). 1H NMR (250 MHz, CDCl3, rotamers) 7.6--7.1 (15H, m), 6.0+5.95 (1H, 2×m), 5.9--5.8 (1H, 2×d, J=6Hz), 5.2 (1H, 2×d, J=5Hz), 4.6 (1H, 2×d, J=3Hz), 4.0--3.7 (1H, m), 3.8 (3H, 2×s), 3.5--2.9 (4H, m), 2.8+2.5 (2H, 2×m), 2.0 (3H, 2×s), 1.5 --1.2 (2H, m), 1.1 (9H, s), 0.9+0.7 (3H, 2×t, J=7Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:11]>C(Cl)Cl>[CH3:8][NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH2:13]1)=[O:11]
Reactant: CNC(=O)C1CN(C(=O)OC(C)(C)C)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C1CNc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3 ml of a 25% solution of trifluoroacetic acid in methylene chloride are added to a solution of 216 mg of 1-(tert-butoxycarbonyl)indoline-3(R,S)-carboxylic acid (N-methyl)amide in 1 ml of methylene chloride at 0° C., while stirring. After 90 min, the mixture is allowed to warm to room temperature and stirring is continued for 2 h. Concentration of the mixture and purification of the crude product over 50 g of silica gel (mobile phase K) gives the title compound: Rf (P)=0.52.
Reaction SMILES: O[CH:2]1O[C:5](=[O:7])[CH2:4][CH:3]1[CH2:8][CH2:9][CH3:10].CCN(C(C)C)C(C)C.Cl.[O:21]1[CH:25]=[C:24]([CH2:26][NH2:27])[CH:23]=[N:22]1>ClCCCl.CC(O)=O>[O:21]1[CH:25]=[C:24]([CH2:26][N:27]2[CH2:2][CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][C:5]2=[O:7])[CH:23]=[N:22]1
Reactant: NCc1cnoc1
Reactant: CCCC1CC(=O)OC1O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCC1CC(=O)N(Cc2cnoc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.3 %

Procedure:
A solution of 5-hydroxy-4-propyldihydrofuran-2(3H)-one x252 (0.44 g, 3.0 mmol) in dry DCE (8 ml), DIEA (0.364 g, 2.8 mmol), and several drops AcOH is added to a suspension of 1-isoxazol-4-ylmethanamine hydrochloride x251 (0.46 g, 3.0 mmol) in dry DCE, and NaHB(OAc)3 (0.976 g, 2.3 mmol) is added in 50 min. The reaction mixture is stirred at room temperature for 72 h and washed with 20% K2CO3 (2×25 ml). The aqueous layer is subjected to extraction with dichloromethane (3×30 ml). The combined organic layers are washed with brine (40 ml), dried over Na2SO4, and evaporated. The residue (0.55 g) is purified by chromatography on silicagel (chloroform/ethyl acetate 1/1) to afford 0.202 g of 1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one 157 (yield 0.202 g, 32%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH2:1][C:33]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])=[O:34])=[CH:3][C:4](=[O:14])[O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(=O)Nc3ccccc3Cl)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (670 mg, 3.6 mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (5.4 mL). After 30 minutes 2-chloro-1-isocyanato-benzene (221 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-100% ethyl acetate in hexanes to yield 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2-chloro-phenyl)-acetamide as a foam.
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:32]1[CH2:36][C:35]([OH:43])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][N:33]1C(OC(C)(C)C)=O)[C@@H:10](NC(=O)C1C=CC=C(C(=O)N)C=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H]([NH:70][C:71](=[O:88])[C:72]1[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([N:80]2[CH2:84][CH2:83][CH2:82][C@@H:81]2COC)=[O:79])[CH:73]=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[C:105]1([Mg]Br)C=CC=CC=1.O>C1COCC1>[CH2:84]([N:80]([CH3:105])[C:78](=[O:79])[C:74]1[CH:75]=[CH:76][CH:77]=[C:72]([C:71]([NH:70][C@@H:10]([CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)[C@H:9]([OH:8])[C@H:32]2[CH2:36][C:35]([OH:43])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:34][NH:33]2)=[O:88])[CH:73]=1)[CH2:83][CH2:82][CH3:81]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cc(F)cc(F)c1)NC(=O)c1cccc(C(N)=O)c1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N3CCC[C@@H]3COC)c2)N(C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CC(O)(c3ccccc3)CN2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
Step 6 (E): Preparation of (2R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate. To a solution of (R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-oxopyrrolidine-1-carboxylate (Step 6 (D), 25 mg, 0.036 mmol) in THF (1 mL) was added phenylmagnesium bromide (3.0 M in diethyl ether, 0.0144 mL, 0.0432 mmol) at −20° C. After stirring for 20 min, the reaction mixture was warmed up to 0° C. and stirred for 30 min and another portion of phenylmagnesium bromide (3.0 M in diethyl ether, 0.0144 mL, 0.0432 mmol) was added and the reaction mixture was stirred at rt for 2 h. Another portion of phenylmagnesium bromide (3.0 M in diethyl ether, 0.024 mL, 0.072 mmol) was added and the reaction mixture was stirred at rt for 2 days. H2O (50 mL) was added and the mixture was extracted with ethyl acetate, dried (Na2SO4) and concentrated. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% EtOAc/Hexane step gradient) to give 12 mg of the title compound (42% yield): 1H NMR (CDCl3, 500 MHz) δ 0.15 (3H, s), 0.20 (3H, s), 0.72-0.79 (1H, m), 0.86 (1H, m), 0.96 (9H, s), 1.08-1.11 (1H, m), 1.45 (9H, s), 1.58-1.62 (1H, m), 1.77 (3H, s), 2.52 (2H, d, J=5 Hz), 2.63 (1H, m), 2.87-3.04 (3H, m), 3.16 (1H, brd s), 3.28 (1H, d, J=10 Hz), 3.51 (1H, brd s), 3.66 (1H, d, J=15 Hz), 3.78 (1H, d, J=10H), 3.95 (1H, m), 4.30 (1H, s), 4.56 (2H, s), 6.59 (1H, t, J=10 Hz), 6.78 (2H, d, J=5 Hz), 7.14 (1H, m), 7.24-7.27 (1H, m), 7.34 (2H, m), 7.39 (1H, m), 7.46-7.50 (3H, m), 7.68 (2H, m). MS (ESI) (M+H)+ 780.49.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([OH:17])[CH2:15][CH3:16])[N:11]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][CH2:29]N(CC)CC.S1C=CC=C1>C1COCC1.[Pd]>[F:26][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[N:9]=[C:8]([C:6]3[CH:7]=[CH:2][N:3]=[C:4]([CH3:27])[CH:5]=3)[N:12]([CH2:13][CH:14]([OH:17])[CH2:15][CH2:16][CH2:28][CH3:29])[N:11]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CC[C@H](O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1cc(C)nc(Cl)c1
Reactant: CCN(CC)CC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccsc1
Product: CCCCC(O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1ccnc(C)c1

Procedure:
A mixture of intermediate, 1-[5-(2-chloro-6-methyl-pyridin-4-yl)-3-(3,4-difluoro-phenylamino)-[1,2,4]triazol-1-yl]-hexan-2-ol (prepared according to D4) (1.5 g; 3.5 mmol) and Et3N (2 ml) in THF (40 ml) was hydrogenated with Pd/C 10% (0.020 g) as a catalyst in the presence of thiophene solution (0.1 ml; 4% in DIPE). After uptake of H2 (1 equiv) had ceased, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was suspended in DIPE and filtrated. The crystals were dried in a vacuum oven at 70° C. overnight.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]2[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]12.[Cl:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Cl:32][C:11]1[N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=3)=[CH:15][CH:14]=2)[CH:9]=[C:6]2[C:5]=1[N:4]1[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]1[N:2]([CH3:1])[C:7]2=[O:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)cc2N2C1=N[C@@H]1CCC[C@@H]12
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Cl)c2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 0 °C
Yield: 44.7 %

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (38 mg, 0.082 mmol) is dissolved in a mixture of CCl4 and DMF (8/1, v/v). The solution is cooled to 0° C., and then a solution of N-chlorosuccinimide (10.9 mg, 0.082 mmol) in CCl4 and DMF (8/1, v/v) is added dropwise. The reaction mixture is stirred at room temperature for half an hour. Solvents are removed under vacuum, and the residue is purified by a semi-preparative HPLC to give pure product as off white solids (16.5 mg, yield 45%). MS (ESI) m/z 450.1 [M+H]+.
Reaction SMILES: F[C:2]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[CH:18][C:3]=1[C:4]([C:6](=[CH:12][NH:13][N:14]=[CH:15][CH2:16]C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-].[Na+].[CH3:27]N(C)C=O>C(Cl)Cl.O>[F:24][C:19]1[CH:18]=[C:3]2[C:2](=[C:21]([F:22])[C:20]=1[F:23])[N:13]([N:14]=[C:15]([CH3:16])[CH3:27])[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CCC=NNC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CN(C)C=O
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn(N=C(C)C)c2c(F)c(F)c(F)cc2c1=O

Procedure:
10.38 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-propylidenehydrazino)-acrylate, 2 g of sodium fluoride and 60 ml of dimethylformamide are heated at 150°-160° C. for 2.5 hours. The dimethylformamide is stripped off in vacuo, the residue is taken up in CH2Cl2 /H2O and the CH2Cl phase is concentrated in vacuo, after drying with Na2SO4. Recrystallization from ethanol gives 6 g of ethyl 6,7,8-trifluoro-1-(2-propylideneamino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 166° C. A suspension of 6 g of the propylideneamino-quinolinecarboxylic acid ester in 72 ml of isopropanol and 0.7 g of water is heated at 70° C. with 0.16 g of p-toluenesulphonic acid for 1 hour. About 50 ml are then distilled off under normal pressure, and 25 ml of water are added to the residue. The solid is filtered off with suction in the cold and rinsed with an isopropanol/water (1:1) mixture. 4.7 g of ethyl 1-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 217° C. are obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][NH:16][C:17]([NH2:19])=[O:18].C(OC(=O)C)(=O)C>CCOCC>[C:1]([CH2:3][C:4]([N:15]([C:9]1[C:8]([CH3:7])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:14])[NH:16][C:17]([NH2:19])=[O:18])=[O:6])#[N:2]
Reactant: Cc1cccc(C)c1NNC(N)=O
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: Cc1cccc(C)c1N(NC(N)=O)C(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1 mole of cyanoacetic acid, 1 mole of 1-(2,6-dimethylphenyl)semicarbazide and 300 ml of acetic anhydride is heated to 80° for 2 hours. The mixture is cooled to RT, 50 ml of ether is added and it is stirred at RT overnight. The reaction mixture is filtered, washed with ether (3X) and dried to give N-(2-cyanoacetyl)-1-(2,6-dimethylphenyl)semicarbazide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([CH3:25])[C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)(=[O:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:37](I)[CH3:38]>C(OCC)(=O)C>[CH2:37]([N:9]([S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])[C:10]1[CH:11]=[C:12]([CH3:25])[C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)[CH3:38]
Reactant: CCI
Reactant: CCOC(=O)c1cc2c(C)c(C)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(C)c(C)cc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a mixture of ethyl 7-[(2-thienylsulfonyl)amino]-4,5-dimethyl-1H-indole-2-carboxylate (0.35 g), potassium carbonate (0.13 g) and N,N-dimethylformamide (8 mL) was added dropwise ethyl iodide (0.074 mL) under ice-cooling. The mixture was stirred at from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-2:8), and the obtained colorless crystals were recrystallized from ethyl acetate-hexane to give the title compound (253 mg, yield 67%) as colorless prism crystals. melting point 134-135° C.
Reaction SMILES: C[O:2][CH:3]1[CH:7]([CH:8]=O)[CH2:6][CH:5](OC)O1.[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:12]1([S:18]([N:21]2[CH:5]=[CH:6][C:7]([CH:3]=[O:2])=[CH:8]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccn(S(=O)(=O)c2ccccc2)c1
Yield: 88.2 %

Procedure:
A solution of 5.91 g (0.037 mol) of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde, 5.80 g (0.037 mol) of phenylsulfonamide and a spatula tip of 4-toluenesulfonic acid in 50 ml of toluene was refluxed with a water trap until water no longer separated out. The reaction mixture was washed three times with water. The organic phase was dried over magnesium sulfate with addition of activated carbon and silica gel and concentrated in vacuo. 7.68 g of a brown resin were obtained.