Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([CH:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[N:7][CH:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc(C2CCN(C(=O)OC(C)(C)C)C2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(C2CCNC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of tert-butyl 3-(5-methoxypyrimidin-2-yl)pyrrolidine-1-carboxylate (13 mg, 0.047 mmol) in dry CH2Cl2 (0.5 mL) was added TFA (20% in CH2Cl2, 2 mL) at 0° C. The formed solution was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to give the crude product (8 mg), which was used for next step without purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.Cl[C:10]1[CH:15]=[C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:13]([N+:29]([O-:31])=[O:30])=[CH:12][N:11]=1>>[CH:26]([NH:25][C:23]([C@H:20]1[CH2:19][CH2:18][C@@H:17]([NH:16][C:14]2[C:13]([N+:29]([O-:31])=[O:30])=[CH:12][N:11]=[C:10]([O:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:15]=2)[CH2:22][CH2:21]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: CN1CCC(O)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OC3CCN(C)CC3)ncc2[N+](=O)[O-])CC1

Procedure:
Intermediate cis-N-isopropyl-4-(2-(1-methylpiperidin-4-yloxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide was prepared from 1-methylpiperidin-4-ol using a procedure analogous to that used for cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (95 mg).
Reaction SMILES: [Na+].[N:2]1[CH:7]=[CH:6][C:5]([C:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([O-:13])=[O:12].[Na+].[CH3:15][C:16]1[O:20][C:19](=[O:21])[O:18][C:17]=1[CH2:22]Br.[C:24](=[O:27])([O-:26])[O-:25].[K+].[K+]>CC(C)=O>[N:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:15][C:16]2[O:20][C:19](=[O:21])[O:18][C:17]=2[CH3:22])=[O:9])=[CH:4][C:3]=1[C:11]([O:13][CH2:11][C:3]1[O:27][C:24](=[O:26])[O:25][C:4]=1[CH3:5])=[O:12]
Reactant: Cc1oc(=O)oc1CBr
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])c1ccnc(C(=O)[O-])c1
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1oc(=O)oc1COC(=O)c1ccnc(C(=O)OCc2oc(=O)oc2C)c1

Procedure:
6.3 g of-pyridine-2,4-dicarboxylic acid sodium salt are boiled under reflux with 14.3 g of 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl bromide and 4.5 g of potassium carbonate in 125 ml of dry acetone for 40 hours. The carbonate is filtered off and the solution is chromatographed over silica gel with a 4:1 mixture of toluene and ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH:11]([S:14][CH3:15])[CH2:12][CH3:13])=[CH:7][C:6]=2[C:5]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:4]([F:28])[CH:3]=1.[OH2:29].OOS([O-])=O.[K+].C[OH:37]>>[Cl:1][C:2]1[C:10]2[O:9][C:8]([CH:11]([S:14]([CH3:15])(=[O:37])=[O:29])[CH2:12][CH3:13])=[CH:7][C:6]=2[C:5]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=2)=[C:4]([F:28])[CH:3]=1
Reactant: O
Reactant: CCC(SC)c1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Product: CCC(c1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
0.20 g (0.461 mmol) of 3-[7-chloro-5-fluoro-2-(1-methylthiopropyl)benzofuran-4-yl]-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 15 ml of methanol, and 5 ml of water and 0.57 g (0.922 mmol) of Oxone were added thereto, followed by stirring at room temperature for 2 hours. Insoluble substances were removed by filtration. Then, methanol was distilled off under reduced pressure, and the obtained residue was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.18 g (yield: 85%) of the desired product. Melting point: 146-148° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][N:14]3C(OC(C)(C)C)=O)[CH2:11]2)=[N:7][CH:8]=1.Cl>CCOC(C)=O.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][NH:14]3)[CH2:11]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H](Oc3ccc(C(F)(F)F)cn3)[C@@H]1C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(O[C@@H]2C[C@@H]3CN[C@H]2C3)nc1
Reaction time: 2 h
Yield: 112.8 %

Procedure:
To the title compound of step A (622 mg, 1.74 mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (10 mL). After 2 h, the reaction was concentrated to give the title compound of step B (507 mg) which was used without further purification. MS (ESI) mass calcd. for C12H13F3N2O, 258.1. m/z found 259.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[C:4]([CH3:6])=[O:5].[C:16]([O:22][CH2:23]Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[C:16]([O:22][CH2:23][O:12][C:11]([C:10]1[CH:14]=[CH:15][C:7]([CH2:3][C:4](=[O:5])[CH3:6])=[CH:8][CH:9]=1)=[O:13])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Cc1ccc(C(=O)OCOC(=O)C(C)(C)C)cc1

Procedure:
Sodium hydride (0.48 g) was added to 4-acetonylbenzoic acid (3.56 g) in acetonitrile and the solution refluxed for 1/2 hour. Chloromethyl pivalate (3.02 g) was then added and the mixture refluxed for 22 hours. Acetonitrile was removed, the residue partitioned between ether and water and the organic layer separated and washed with sodium bicarbonate solution (×2). The ether layer was dried (MgSO4) and evaporated to give the title compound which was crystallised and recrystallised from hexane. τ(CDCl3) 8.77 (9H, s), 7.82 (3H, s), 6.25 (2H, s), 4.02 (2H, s), 2.73 (2H, d, J=9 Hz), 1.96 (2H, d, J=9 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>N1C=CC=CC=1>[NH:11]([C:2]1[C:7]([I:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1)[NH2:12]
Reactant: NN
Reactant: Cc1ccnc(Cl)c1I
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccnc(NN)c1I
Reaction time: 24 h
Yield: 86.9 %

Procedure:
A mixture of 2-chloro-3-iodo-4-methylpyridine (preparation 28a, 2.0 g, 7.9 mmol) and hydrazine hydrate (1.2 mL, 24.2 mmol) in pyridine (12 mL) under an argon atmosphere was stirred and heated to reflux. After 24 hours, the mixture was cooled and evaporated to dryness. The crude mixture was triturated with water and the solid was filtered and washed with water to give the title compound (1.71 g, 87%) which was used without further purification in the next reaction.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>>[C:1]1([C:7]2[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=2[OH:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CC(=O)C(c2ccccc2)=C1
Reactant: [H][H]
Product: Oc1ccc(O)c(-c2ccccc2)c1

Procedure:
The oxidation of biphenyl using a solution containing ceric ammonium nitrate to produce 2-phenylbenzoquinone, i.e. ##STR3## is disclosed in U.S. Pat. No. 3,873,580 to Rennie. 2-phenylbenzoquinone can be reduced with hydrogen to produce phenylhydroquinone, i.e. ##STR4##
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:23][CH2:22][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:2]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCC(c1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved .in methanol (10 ml), and 2,2-diphenylethylamine (0.58 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide (0.61 g, 1.9 mmol, yield: 71%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride solution in methanol (2.5 ml). The solution was crystallized from methanol diethyl ether to give N-cyano-N'-(2,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(I)cc1F
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4nnsc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (50 mg, 0.12 mmol) in DCM (5 mL) was added triethylamine (24 mg, 0.23 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (32 mg, 0.17 mmol) and DMAP (10 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (60 mg, 89.9% yield). 1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 7.76-7.74 (m, 2H), 7.35 (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.11 (m, 2H).
Reaction SMILES: [OH:1][C:2](C)([CH3:12])[CH2:3]OC1C=CC=CC=1O.C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.[C:25]1([CH3:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:3][C:2]1([CH3:12])[O:1][C:26]2[C:27]([OH:21])=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:31]1
Reactant: CC(C)(O)COc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1
Product: CC1(C)Cc2cccc(O)c2O1
Temperature: 111 °C

Procedure:
Preferably, in this step, the intermediate 2-(2-hydroxy-2-methylpropoxy)phenol is combined with para-toluensulfonic acid and toluene and heated to reflux (approximately 111° C.) to produce carbofuran phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:16]([CH3:18])[CH3:17])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=1.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:16]([CH3:18])[CH3:17])=[C:11]([CH2:13][CH2:14][O:15][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[N:12]=1
Reactant: CC(C)c1oc(-c2ccccc2Cl)nc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3Cl)oc2C(C)C)cc1
Reaction time: 5 h
Yield: 49 %

Procedure:
In a mixture of methylene chloride (1 mL) and pyridine (2 mL) was dissolved 2-[2-(2-chlorophenyl)-5-isopropyloxazol-4-yl]ethanol (159 mg, 0.598 mmol). Under cooling with water, to the solution was added p-toluenesulfonyl chloride (125 mg, 0.658 mmol). The mixture was stirred for 5 hours. The reaction mixture was poured into 1N HCl and extracted with chloroform. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate=2/1), to obtain the desired compound (123 mg, 49%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:12][C:13]([F:18])([F:17])[CH2:14][Mg]Br>>[CH3:3][C:1]([CH3:4])([O:5][C:6]([NH:7][CH2:8][CH:9]([OH:10])[CH2:14][C:13]([F:18])([F:17])[F:12])=[O:11])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: FC(F)(F)C[Mg]Br
Product: CC(C)(C)OC(=O)NCC(O)CC(F)(F)F

Procedure:
t-Butyl-N-(2-oxoethyl)carbamate is treated with 1,1,1-trifluoroethyl magnesium bromide to give (R/S)-1-[(1,1-dimethylethoxycarbonyl)]amino4,4,4-trifluoro-2-butanol. The procedures and methods used in this synthesis are the same as those listed in Example 3, except that (R/S)-1-[(1,1-dimethylethoxy)carbonyl]amino-4,4,4-trifluoro-2-butanol is used instead of (S)-1-[(benzyloxycarbonyl)amino]-2-propanol, to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:25][Cr](O[Cr]([O-])(=O)=O)(=O)=O.O>CN(C=O)C>[C:11]([C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][C:2]([OH:25])=[O:1])[CH:10]=[CH:9][N:8]=1)#[N:12]
Reactant: N#Cc1cc(CCCO)ccn1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(CCC(=O)O)ccn1
Reaction time: 16 h

Procedure:
A solution of K2CO3 (1.67 g, 12.1 mmol) in H2O (30 ml) was added to a stirred solution of 3-(2-cyanopyridin-4-yl)propyl acetate (4.94 g, 24.2 mmol) in MeOH (130 ml). After 25 min, the MeOH was removed under reduced pressure, then the aqueous phase was extracted three times with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a residue that was purified by column chromatography (IH-EtOAc, 1:3) to furnish 4-(3-hydroxypropyl)pyridine-2-carbonitrile: m/z (ES+)=163.1 [M+H]+. A solution of this alcohol (500 mg, 3.1 mmol) in DMF (20 ml) was treated with PDC (7 g, 18.6 mmol) and H2O (0.5 ml). The reaction was stirred for 16 h, before being partitioned between H2O and EtOAc. The aqueous phase was extracted twice with EtOAc, then the combined organic extracts were washed with brine, before being dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES−)=177.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[CH:3]=1)[NH:11][CH:10]=[C:9]([C:14]#[N:15])[C:8]3=O.P(Cl)(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][C:8]1[C:7]2[C:12](=[CH:13][C:4]3[CH:3]=[C:2]([OH:1])[C:18]([O:19][CH3:20])=[CH:17][C:5]=3[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:14]#[N:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1O
Solvent: Cc1ccccc1
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1O
Temperature: 25 °C

Procedure:
A mixture of 3.0 g (11.3mmol) of 8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 20.0 mL of phosphorus oxychloride is heated under reflux for 0.5 hour, then cooled to room temperature. Excess phosphorus oxychloride is evaporated to yield a residue, to which toluene is added and the resulting solution is reduced in vacuo. Toluene is added and evaporated twice more. The resulting residue is cooled with ice bath, neutralized with cold saturated solution of sodium bicarbonate and stirred. The solid is collected by filtration, washed with cold water and dried to yield 2.83 g of 4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid. A sample of the material is purified by silica gel chromatography, eluting with 97:3 methylene chloride/methanol to yield a yellow solid, mp. >300° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](O)=[CH:5][C:4](=[O:9])[CH2:3]1.[C:10]1([CH3:18])[C:11]([CH:16]=O)=[CH:12][CH:13]=[CH:14][CH:15]=1.[CH3:19][O:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:25])/[CH3:24].C(O)C>C(O)(=O)C>[CH3:19][O:20][C:21]([C:22]1[CH:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:18])[C:5]2[C:4](=[O:9])[CH2:3][N:2]([CH3:1])[CH2:7][C:6]=2[NH:25][C:23]=1[CH3:24])=[O:26]
Reactant: CN1CC(=O)C=C(O)C1
Reactant: Cc1ccccc1C=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(C)C2)C1c1ccccc1C

Procedure:
A mixture of 7.65 g. of 1-methyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine, 7.2 g. of o-tolualdehyde, 6.9 g. of methyl-3-aminocrotonate (97%), 110 ml. of ethanol and 35 ml. of acetic acid was refluxed for 3 hours. The mixture was evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and extracted with saturated sodium carbonate solution. The dichloromethane solution was evaporated to dryness. The residue was slurried with diethyl ether and the solid was separated by filtration. Recrystallization from ethanol afforded the title compound, m.p. 249°-252° C. dec.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16]>C1COCC1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Fc1ccc(CCl)c(F)c1
Solvent: C1CCOC1
Product: Fc1ccc(CN2CCNCC2)c(F)c1
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A mixture of piperazine (26.5 g, 308 mmol) in THF (350 mL) was heated to 70° C. and 1-(chloromethyl)-2,4-difluorobenzene (5 g, 30.8 mmol) was added. The suspension was heated at 70° C. overnight. The solid (piperazine) was filtered off, and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was dried and concentrated to give the title compound (6 g, 92%). ESI-MS m/z [M+H]+ 213.04.
Reaction SMILES: Br[C:2]1[C:22]([NH2:23])=[CH:21][C:5]2[O:6][CH2:7][CH2:8][CH:9]3[CH2:18][C:13]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:12][CH2:11][C:10]3([CH2:19][CH3:20])[C:4]=2[CH:3]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].COCCOC.CB1OB(C)OB(C)O1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:19]([C:10]12[CH2:11][CH2:12][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:18][CH:9]1[CH2:8][CH2:7][O:6][C:5]1[CH:21]=[C:22]([NH2:23])[C:2]([CH3:24])=[CH:3][C:4]2=1)[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: CCC12CCC3(CC1CCOc1cc(N)c(Br)cc12)OCCO3
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCC12CCC3(CC1CCOc1cc(N)c(C)cc12)OCCO3
Temperature: 90 °C
Yield: 74.9 %

Procedure:
A 500 mL round-bottom flask equipped with air cooled reflux condenser outfitted with a nitrogen inlet adapter was charged with rac-(7aR,11aS)-2-bromo-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (87, R2=Ethyl) (9.14 g, 23.9 mmol), bis(triphenylphosphine)palladium(II) chloride (0.839 g, 1.20 mmol) and Cs2CO3 (23.4 g, 71.7 mmol), and then DME (180 mL), water (60 mL) and trimethylboroxine (6.67 mL, 47.8 mmol) were added. The reaction mixture was heated to about 90° C. for about 15 h. The reaction was allowed to cool to rt and then it was partitioned between EtOAc (350 mL) and water (200 mL). After separating the layers, the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were then washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on silica gel (330 g, eluted with 0% to 50% EtOAc in heptane). Collection and concentration of the appropriate fractions gave rac-(7aR,11aS)-11a-ethyl-2-methyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (88, R2=Ethyl) (5.68 g, 74.8%) containing about 20% of a minor regioisomer. The material was used directly in Step #5 without further purification. LC/MS, method 3, 2.26 min, MS m/z 318 (M+H)+.
Reaction SMILES: NC(=NO)C1C=CC(COCC(OC(C)(C)C)=O)=CC=1.[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][OH:27])#[N:22].Br[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:27][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])#[N:22]
Reactant: N#Cc1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)CCBr
Agent: CC(C)(C)OC(=O)COCc1ccc(C(N)=NO)cc1
Product: CC(C)(C)OC(=O)CCOCc1cccc(C#N)c1

Procedure:
The title compound was prepared according the procedure described for Intermediate 15 Step 1, but starting from 3-cyanobenzyl alcohol and tert-butyl 3-bromopropionate. It was isolated as a colorless oil (630 mg, 32%). 1H NMR (DMSO-d6, 300 MHz) δ 7.76 (m, 2H), 7.65 (m, 1H), 7.57 (m, 1H), 4.53 (brs, 2H), 3.64 (t, J=6.3 Hz, 2H), 2.49 (t, J=6.3 Hz, 2H), 1.40 (s, 9H). LC/MS (Method B) 262.2 (M+H)+. HPLC (Method A) Rt 4.75 min (Purity: 99.9%).
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH2:6]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(NCc2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
10% Sodium hydroxide aqueous solution 0.82 mL was added to a suspension of ethanol 3.0 mL of methyl 4-(benzylamino)-2-(4-fluoroanilino)benzoate 0.24 g at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 10% sodium hydroxide aqueous solution 0.82 mL was added, and it was heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, acetic acid 2.0 mL, saturated sodium chloride aqueous solution and ethyl acetate were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and solid matter was filtrated to give 4-(benzylamino)-2-(4-fluoroanilino)benzoic acid 0.17 g of white solid.
Reaction SMILES: NC(N)=[S:3].[Cl:5][C:6]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:7]=1[CH2:8]Cl.[OH-].[Na+].Cl[CH2:18][C:19]([O-:21])=O.[Na+]>O>[Cl:5][C:6]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:7]=1[CH2:8][CH2:18][C:19]([OH:21])=[S:3]
Reactant: O=C([O-])CCl
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(=S)CCc1ccc(Cl)cc1Cl
Yield: 88.7 %

Procedure:
15.2 g (0.2 mol) of thiourea in 100 ml of water are introduced into a 1 liter 3-necked flask. The mixture is heated to 50°-60° C. and 39.1 g (0.2 mol) of 2,4-dichlorobenzylchloride are introduced in a single operation. The mixture is heated under reflux and boiling is maintained for 15 minutes; the solution becomes limpid. The mixture is cooled and a solution of 32 g (0.8 mol) of NaOH in 50 ml of water is introduced dropwise at about 60° C. The mixture is again heated under reflux for 30 minutes, cooled and a solution of about 0.28 mol of sodium chloroacetate (obtained by neutralising 26.46 g of chloroacetic acid in 200 ml of water with 23.52 g of NaHCO3) is introduced, dropwise, at 60°-70° C. The whole is then heated under reflux for 30 minutes, cooled, filtered and acidified with 3 N HCl; the precipitate obtained is filtered off the redissolved cold in dilute sodium bicarbonate solution, and this solution is washed with methylene chloride, filtered and again acidified. 41.7 g (yield: 83 %) of product are thus collected. Instantaneous melting point: 72°-73° C.