Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1.CN1CCOCC1.[CH2:46]([O:48][C:49]([NH:51][C@H:52]([C:56](O)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH3:47].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:52]([CH:53]([CH3:55])[CH3:54])[NH:51][C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an argon atmosphere, 321 mg (0.60 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 21b) and 182 mg (1.8 mmol) of NMM in 5.8 ml of DMF are added to 136 mg (0.72 mmol) of N-ethoxycarbonyl-(L)-valine and 178 mg (0.60 mmol) of TPTU in 3 ml of DMF and the mixture is stirred at room temperature for 15 hours. The reaction mixture is poured into ice-water, stirred for 30 min and filtered. Crystallisation from THF with DIPE and hexane yields the title compound: m.p.: 209-211° C.; HPLC20-100 : tRet =15.2; FAB MS (M+H)+ =711.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[C:9]([CH2:13][C:14](O)=[O:15])[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[O:15]=[C:14]1[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH:9]([C:10]([OH:12])=[O:11])[CH2:13]1
Reactant: Nc1ccccc1
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccccc2)C1
Temperature: 110 °C
Yield: 97.2 %

Procedure:
A mixture of aniline (3.26 g; 34.68 mmol) and 2-methylenesuccinic acid (5.47 g; 41.62 mmol) in water (10 mL) was heated in a sealed tube at 110° C. for 30 hours. After cooling to room temperature, 6N NaOH (13 mL) was added and the resulting precipitate was filtered off. The filtrate was acidified with 6N hydrochloric acid to pH 1 and the resulting precipitate was filtered, washed with water, and dried to yield 6.92 g (97%) of 5-oxo-1-phenypyrrolidine-3-carboxylic acid as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:27])[C:16]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:18]([C:19](OC)=[O:20])[CH:17]=1>C(Cl)(Cl)Cl>[O:20]=[C:19]1[C:18]2[CH:17]=[C:16]([C:15]([O:14][CH3:13])=[O:27])[CH:25]=[CH:24][C:23]=2[N:26]=[C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:7]12
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Reactant: CCOC(=O)c1ccc(Cl)nn1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2nc3ccc(C(=O)OC)cc3c(=O)n2n1

Procedure:
A mixture of ethyl 6-chloro-3-pyridazinecarboxylate (0.29 g, 1.55 mmol, Example 1, Step A) and dimethyl 4-aminoisophthalate (0.36 g, 1.72 mmol, Example 1, Step B) was heated as a melt at 165°-170° C. for 30 min. The oil was dissolved into chloroform, washed with 10% ammonium hydroxide solution, dried (MgSO4) , filtered and concentrated. Medium pressure chromatography (silica gel, chloroform to 1% methanol in chloroform) of the crude oily-solid afforded 2-ethyl 8-methyl 10-oxo-10H-pyridazino[6,1-b]quinazoline-2,8-dicarboxylate as a yellow solid, mp 218°-221° C. dec.
Reaction SMILES: C(O[C:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:7][C:6](=[O:23])[CH:5]=1)C.[CH2:24]([Li])[CH3:25].O>C1C=CC=CC=1>[CH2:24]([C:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:7][C:6](=[O:23])[CH:5]=1)[CH3:25]
Reactant: [Li]CC
Reactant: CCOC1=CC(=O)CC(c2ccccc2OCOCCOC)C1
Solvent: O
Solvent: c1ccccc1
Product: CCC1=CC(=O)CC(c2ccccc2OCOCCOC)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 3-ethoxy-5-(2-methoxyethoxymethoxyphenyl)-2-cyclohexenone (2.0 g) in benzene (60 ml) was added dropwise with stirring in an atmosphere of dry nitrogen to an ice-cooled 1.5 M solution of ethyllithium in benzene (20.8 ml). When the addition was complete, water was added and the mixture was allowed to stand overnight at room temperature. The benzene layer was separated and the aqueous layer was extracted with ether. The organic solutions were combined, dried and the solvents were evaporated under reduced pressure. The residue was purified by preparative-layer chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (b.p. 60°-80°) for elution to afford the title compound (0.65 g) as a pale yellow oil. (Found: C, 70.9; H, 7.7. C18H24O4 requires C, 71.0; H, 7.9%.)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:24][C:25]1[N:26]=[C:27]([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([C:40]([F:43])([F:42])[F:41])=[O:39])=[CH:34][CH:33]=2)[O:28][CH:29]=1.[I-].[K+]>CC(=O)CC.ClCCl.CO>[F:43][C:40]([F:41])([F:42])[S:38]([C:35]1[CH:36]=[CH:37][C:32](/[CH:31]=[CH:30]/[C:27]2[O:28][CH:29]=[C:25]([CH2:24][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:26]=2)=[CH:33][CH:34]=1)=[O:39]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CO
Solvent: CCC(C)=O
Solvent: ClCCl
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A mixture of 0.815 g (3.75 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol and 0.815 g (2.50 mmol) cesium carbonate in 15 ml butanone was stirred at 60° C. for 30 min, then 1.40 g (4.17 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole and 0.692 g (4.17 mmol) potassium iodide were added and stirring at 60° C. continued for 40 hours. After evaporation, 50 ml water was added and the mixture extracted with two portions of 50 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give 2.20 g raw product. After chromatography on silica, eluent dichloromethane/methanol 20:1, resulted 1.40 g (72%) pure title compound as tan crystals melting at 122-123° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[CH3:15][CH:16]([C:29](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:30])[C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:18].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:29]([OH:30])=[C:16]([CH3:15])[C:17](=[O:18])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1nnc(SCc2ccccc2)s1
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: Cc1c(O)nc2sc(SCc3ccccc3)nn2c1=O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A mixture of 19.3 g of 2-amino-5-benzylthio-1,3,4-thiadiazole, 41.3 g of bis(2,4,6-trichlorophenyl) 2-methylmalonate and 60 ml of chlorobenzene was stirred at 135°-140° C. for 1 hour. After cooling, n-hexane was added to the reaction mixture and the formed precipitate was separated by filtration. The separated precipitate was washed with n-hexane and thus 23.9 g of 2-benzylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 247°-250° C. Yield 91%.
Reaction SMILES: COC1C=CC=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH3:35])=[S:47])=[C:29]([F:34])[CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: COc1ccccc1C(=O)Cl
Agent: COc1ccccc1C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4OC)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
2-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (56 mg, yield 70%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2.Br[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:16][CH2:17][CH3:18])[CH2:8][CH2:7]2
Reactant: CCCBr
Reactant: O=C1NCCc2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCc2cc(Br)ccc2C1=O
Temperature: 25 °C
Yield: 71.1 %

Procedure:
Sodium hydride (60% w/w suspension in oil) (1.17 mmol, 46.7 mg) was suspended in DMF (0.5 ml) under argon. The mixture was cooled to 0° C. before dropwise addition of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (1K2) (1.06 mmol, 240 mg) in DMF (1.5 ml) The reaction was stirred at 0° C. for 30 min before addition of 3-bromopropane (1K3) (1.592 mmol, 196 mg) in DMF (1 ml). Once addition was complete the reaction was allowed to warm to room temperature then heated at 60° C. for 4hrs. The reaction mixture was cooled, quenched with water and extracted three times with diethyl ether. The combined organics were washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified on silica eluting with 30-100% EtOAc/heptane to give 6-bromo-2-propyl-3,4-dihydroisoquinolin-1(2H)-one (1K4) 202 mg (70.9%); 1H NMR (400 MHz, CDCl3) δ 7.94 (d, 1H) 7.47 (d, 1H) 7.33 (s, 1H) 3.54 (m, 4H) 2.96 (t, 2H) 1.65 (m, 2H) 0.96 (t, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-])=O)=[CH:10][C:11]=3[F:13])[CH2:6][C:5]2=[O:17])[CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:14][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([F:13])[CH:10]=1)[N:4]([CH:1]1[CH2:2][CH2:3]1)[C:5](=[O:17])[CH2:6]2
Reactant: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1C1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Nc1cc(F)c2c(c1)CC(=O)N2C1CC1
Temperature: 25 °C

Procedure:
Iron powder (0.994 g, 17.8 mmol) is added in small portions to 1-cyclopropyl-7-fluoro-5-nitro-1,3-dihydro-indol-2-one (1.05 g, 4.44 mmol) and ammonium chloride (2.32 g, 44.5 mmol) in ethanol (50 ml) and water (25 ml) at 90° C. The reaction mixture is stirred vigorously and heated for 60 min, cooled to room temperature, and diluted with dichloromethane (250 ml). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a yellowish-brown solid. HPLC r.t. 2.62 min; MS for C11H11FN2O m/z 207.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8](=[O:12])[CH2:7]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].CC#N>[Na+].[I-].CO.C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[CH2:9][S:8](=[O:12])[CH2:7]2)[CH2:23][CH2:22]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1CS(=O)CN1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCN2CS(=O)CC2=O)CC1
Temperature: 95 °C
Yield: 99.7 %

Procedure:
A mixture of 3-(4-bromobutyl)-1,4-dioxothiazolidine (3.37 g), 1-(2-methoxyphenyl)piperazine (2.80 g), K2CO3 (4.60 g), NaI (190 mg) and CH3CN (150 ml) was heated at reflux (bath temperature 95° C.) for 24 h. TLC analysis (silica gel, 20% MeOH/CH2Cl2) showed the consumption of the starting sulfoxide and the presence of one major product with Rf =0.43. The mixture was cooled to room temperature, EtOAc (100 m) was added and the mixture was filtered. The filtrate was concentrated in vacuo to an oil which was filtered through silica gel using 20% MeOH/CH2Cl2 as the eluent. The fractions containing the material with Rf =0.43 were concentrated in vacuo to yield 4.83 g of a foam, which was dissolved in MeOH/CH2Cl2 and flash chromatographed (silica gel) to yield 3.28 g of a crude product. Rechromatography over silica gel using 50% MeOH/toluene as eluent yielded 2.98 g of an oil which solidified on standing. The solid was dissolved in 50% MeOH/EtOAc and filtered through silica gel. The filtrate containing the product was concentrated to approximately 5 ml and the oily liquid was seeded and left standing, yielding 0.91 g of a white solid, mp, 111°-113° C. The mother liquor was concentrated in vacuo to a solid which was recrystallized from CH2Cl2 /Et2O, yielding an additional 0.79 g of fine needles, mp, 111°-113° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.[NH2:14][C@@H:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:19]=[CH:20][CH:21]=2)[CH2:16]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl.C(OCC)(=O)C>[CH3:31][N:28]1[CH2:29][CH2:30][CH:25]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH2:16][C@H:15]([NH:14][C:9](=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:8][CH:7]=2)[CH2:24][CH2:23]3)[CH2:26][CH2:27]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCC(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
α,α,α-Trifluoro-p-toluic acid (0.15 g, 0.8 mmol) was suspended in thionyl chloride (3 mL) and refluxed for 30 minutes (everything dissolved after a few minutes). The excess of thionyl chloride was removed in vacuo with toluene. The residue was dissolved in methylene chloride (5 mL) and added dropwise to an ice cold solution of (R)-2-amino-8-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydronaphthalene (0.15 g, 0.6 mmol) and triethylamine (92 mg, 0.9 mmol) in methylene chloride (5 mL). The mixture was stirred for 15 minutes and was then diluted with ethyl acetate, washed with ammonia (2 M) and dried (MgSO4). The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel using methylene chloride/ethanol 5:1, containing 0.5% of ammonia, as the eluent. The title compound was obtained as off-white crystals. Yield 140 mg (55%): mp 163-166° C.; [α]21D +36° (c 0.5, CHCl3); EIMS (70 eV) m/z (relative intensity) 416 (48, M+).
Reaction SMILES: [OH:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].O.NN>CCO.CC(O)=O.O.CCOC(C)=O>[NH2:13][C:12]1[C:2]([OH:1])=[C:3]([CH:9]=[CH:10][CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)c1cccc([N+](=O)[O-])c1O
Agent: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cccc(N)c1O
Temperature: 25 °C

Procedure:
67.5 g of 2-Hydroxy-N,N-dimethyl-3-nitro-benzamide are dissolved in 1000 ml of EtOH/AcOH 9/1 and degassed 4× by evacuating and purging with argon. 7.5 g of Ru/C are added and the mixture obtained is degassed 4× by evacuating and purging with argon. A reaction mixture obtained is heated to reflux and 25 ml of hydrazine hydrate are added slowly. At 1 hour intervals 3 further portions of 25 ml of hydrazine hydrate are added. A reaction mixture obtained is cooled to rt, filtered and washed with EtOH. Solvent from the filtrate obtained is evaporated. Toluene is added 4× to the residue obtained and solvent is evaporated. A residue obtained is taken up in 1 l of H2O and 1 l of EtOAc. An aqueous layer obtained is extracted 3× with EtOAc. The organic layers obtained are washed 2× with brine, dried, filtered and solvent is evaporated. A residue obtained is purified by column chromatography over 500 g of silica using EtOAc/heptane 1/1 as the eluant to give 3-amino-2-hydroxy-N,N-dimethyl-benzamide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([F:29])[C:15]=1[O:30][CH3:31].P(=O)(O)(O)O.[K]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=2)=[C:16]([F:29])[C:15]=1[O:30][CH3:31]
Reactant: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: COC(=O)c1c(Cl)ccnc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P(O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ccc(Cl)c(OC)c2F)ccnc1C
Temperature: 100 °C
Yield: 31.2 %

Procedure:
A mixture of methyl 4-chloro-2-methylnicotinate (1.5 g, 8.08 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.316 g, 8.08 mmol), phosphoric acid, potassium salt (3.43 g, 16.16 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.660 g, 0.808 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was purged with nitrogen for 5 min. The reaction was then heated to 100° C. for 18 h. After cooling, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using 50% ethyl acetate in hexanes to yield methyl 4-(4-chloro-2-fluoro-3-methoxyphenyl)-2-methylnicotinate (1.2 g, 2.52 mmol, 31% yield) as pale brown oil. LC/MS (ESI) m/e 309.9 [(M+H)+, calcd for C15H14ClFNO3 310.1]; LC/MS retention time (method D): tR=0.84 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8](Cl)[N:7]=1)[CH3:2].[F:15][C:16]([F:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][NH2:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH:18][CH2:17][C:16]([F:15])([F:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)[CH3:2]
Reactant: NCC(F)(F)c1ccccc1
Reactant: CCOC(=O)Cc1nc(Cl)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: CCOC(=O)Cc1nc(NCC(F)(F)c2ccccc2)ccc1Cl
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
A mixture of (3,6-dichloro-pyridin-2-yl)-acetic acid ethyl ester (139 mg, 593 μmol), as prepared in the previous step, 2,2-difluoro-2-phenylethylamine (132.5 mg, 844 μmol) (see Example 8a), K3PO4 (317 mg, 1.50 mmol) (Fluka, Catalog # 04347), Pd(OAc)2 (5.8 mg, 26 μmol), biphenyl-2-yl-dicyclohexyl-phosphane (22 mg, 62 μmol) (Strem) was taken up in dry, argon-sparged dioxane (650 μL), and the mixture was sealed under a blanket of argon. The yellowish heterogeneous mixture was microwaved with stirring (Smith Synthesizer) at 150° C. for 20 min, and the resulting amber-red heterogeneous mixture was diluted with 8 mL ether, filtered, and concentrated. Flash silica chromatography of the residue (6:1 hexanes/EtOAc eluent) afforded the title compound as a light yellow oil (128 mg, 61%).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CI.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>CN(C)C=O.C(Cl)Cl.C(C(C)=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[CH3:31][O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: COC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 2 h
Yield: 147.8 %

Procedure:
A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-3-hydroxy-1-isoindolinone (5.2 g) in anhydrous dimethyl formamide (50 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil, 0.8 g) in anhydrous dimethylformamide (10 cc) at a temperature close to 20° C. in the course of 15 minutes, and agitation is continued for 2 hours. Then, 1 cc of methyl iodide is added in the course of 5 minutes and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (1000 cc) and extracted with methylene chloride (3×1000 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (20 cc) and the solution poured onto silica (300 g) contained in a column of 7 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (98-2 by volume, 1 liter) and the corresponding eluate evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in methyl ethyl ketone (30 cc). A solution of oxalic acid (0.7 g) in methyl ethyl ketone (10 cc) is added and agitation is continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 2.6 g of 3-methoxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 160° C.