Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1>COCCO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:8][CH2:9][O:12][CH3:13])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Solvent: COCCO
Product: COCCOc1cc2ncnc(Cl)c2cc1OC
Yield: 100 %

Procedure:
Using analogous procedures to those described in the portion of Note [1] above that is concerned with the preparation of starting materials, 4-chloro-7-hydroxy-6-methoxyquinazoline was reacted with 2-methoxyethanol to give 4-chloro-6-methoxy-7-(2-methoxyethoxy) quinazoline in 100% yield; 1H NMR: (CDCl3) 3.49 (s, 3H), 3.89 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 7.26 (s, 1H), 7.35 (s, 1H), 8.86 (s, 1H); Mass Spectrum: M+H+ 269; which in turn was reacted with 2-(4-hydroxyphenyl)acetic acid to give the required starting material in 99% yield; 1H NMR: (DMSOd6) 3.35 (s, 3H), 3.63 (s, 2H), 3.76 (m, 2H), 3.98 (s, 3H), 4.33 (m, 2H), 7.25 (d, 2H), 7.36 (d, 2H), 7.4 (s, 1H), 7.56 (s, 1H), 8.54 (s, 1H); Mass Spectrum: M+H+ 385.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:41])[N:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:28]([CH2:31][C@H:32]([OH:34])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:42].[C:43]([NH:53][C@H:54]([C:56](O)=[O:57])[CH3:55])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:41])[N:27]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:28]([CH2:31][C@H:32]([O:34][C:56](=[O:57])[C@@H:54]([NH:53][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[CH3:55])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:42]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)O)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)c2cc1OC

Procedure:
The title compound was prepared according to the procedure described in Example of 73 Step 6 by using (R)—N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (4.1 g, 7.2 mmol), (S)—N-Cbz-alanine (3.2 g, 14.4 mmol). The title compound was obtained as a white powder (4.2 g, 75.1%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][O:13][CH2:12][CH2:11][N:10]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][N:30](C)C(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.O.O.O.[K+].[K+].[K+].[K+].[Fe+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:17]1([C@H:15]([N:10]2[CH2:9][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]#[N:30])=[CH:3][CH:4]=3)[CH2:14][O:13][CH2:12][CH2:11]2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)N(C)C
Reactant: C[C@H](c1ccccc1)N1CCOC[C@@H](c2ccc(Br)cc2)C1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Product: C[C@H](c1ccccc1)N1CCOC[C@@H](c2ccc(C#N)cc2)C1
Temperature: 120 °C
Yield: 53 %

Procedure:
To a solution of (S)-6-(4-bromophenyl)-4-((R)-1-phenylethyl)-[1,4]oxazepane (1.48 g, 4.11 mmol) in N,N-dimethylacetamide (6.9 ml) was added sodium carbonate (0.436 g, 4.11 mmol), palladium acetate (18.4 mg, 0.082 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (78.4 mg, 0.164 mmol), potassium hexacyanoferrate(II) trihydrate (0.521 g, 1.23 mmol) at room temperature under nitrogen atmosphere. The mixture was heated to 120° C. Additional palladium acetate (18.4 mg, 0.082 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (78.4 mg, 0.164 mmol) was added twice to the reaction mixture every one hour. After one hour from last addition of the catalyst, the mixture was filtered through a pad of Celite to remove solid materials and partitioned between water and ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=7/3) to afford (S)-4-(4-((R)-1-phenylethyl)-[1,4]oxazepan-6-yl)benzonitrile as pale yellow solid (662 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1>>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:16][CH:17]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(Br)nc1
Product: COC(=O)c1ccc(-c2ccc(C)cn2)cc1

Procedure:
Repeating the operations of Production Example 14 using 4-(methoxycarbonyl)phenylboronic acid and 2-bromo-5-methylpyridine, methyl 4-(5-methyl-2-pyridyl)benzoate was obtained. Hydrolyzing the same with 5N aqueous sodium hydroxide solution, the title compound was obtained as white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:11][C:12]1[CH:13]=[N:14][N:15]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=2)[CH:16]=1
Reactant: Clc1cn[nH]c1
Reactant: OCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCc1ccc(Cn2cc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A mixture of 4-(chloromethyl)benzyl alcohol (0.500 g, 3.19 mmol), 4-chloro-1H-pyrazole (0.753 g, 7.34 mmol), and potassium carbonate (0.908 g, 7.02 mmol) in acetonitrile (40 mL) was stirred at rt overnight. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.375 g, 75%) as a white solid. MW=222.67. 1H NMR (CDCl3, 500 MHz) δ 7.45 (s, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 7.22 (s, 1H), 5.24 (s, 2H), 4.70 (d, J=5.9 Hz, 2H), 1.68 (t, J=5.9 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=3)[CH:16]=[CH:15][C:14]=2[Cl:26])[N:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]=1)=[O:5])[CH3:2].[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>N1C=CC=CC=1>[Cl:26][C:14]1[CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=2)=[CH:18][C:13]=1[C:12]([NH:11][C:9]1[N:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:10]=1)=[O:27]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3cccc(N)n3)ccc2Cl)n(-c2ccccc2)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3cccc(NC(=O)C(C)(C)C)n3)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a solution of 5-(5-(6-aminopyridin-2-yl)-2-chlorobenzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (Preparation 2, 4.61 g, 10 mmol) in anhydrous pyridine (50 mL) was added pivaloyl chloride (1.32 g, 11 mmol) over 10 minutes with stirring at room temperature. The reaction was stirred for 90 minutes before concentrating in vacuo to low volume. The solution was partitioned between EtOAc (250 mL) and water (100 mL). The organic layer was separated, washed with brine (10 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 50% EtOAc in heptanes to afford the title compound (5 g, 92%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:4].C(O)(=O)C.CCOCC>C(O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[NH:5][C:3](=[O:4])[CH2:2][N:1]=1
Reactant: NCC(=O)Nc1sccc1C(=O)c1ccccc1Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CN=C(c2ccccc2Cl)c2ccsc2N1

Procedure:
150 g (0.51 mol) of 2-aminoacetylamino-3-(o-chlorobenzoyl)-thiophene are dissolved in 2.5 liters of absolute ethanol and 250 ml of glacial acetic acid are added. The solution is heated to reflux with stirring until the reaction has ended (about 5 hours) as indicated by thin-layer chromatography (eluant: ether). The solvent is removed under a vacuum and the product taken up in 2 liters of methylene chloride. The methylene chloride solution is shaken out with dilute aqueous sodium bicarbonate solution, washed with water and evaporated. The product is brought to crystallization, treated with 150 ml of methylene chloride, refluxed and left to crystallize in a refrigerator. After filtration under a vacuum and treatment with ice-cold methylene chloride, pure 5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one is obtained in the form of bright-yellow crystals, melting point 221°-223° C.
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:6]=[C:5]1[NH:18][C:19](=[O:22])[O:20][CH3:21].[OH-].[NH4+:26].C1(S(Cl)(=O)=O)C=CC=CC=1>CO>[NH2:26][C:8]1[C:7]2[N:6]=[C:5]([NH:18][C:19](=[O:22])[O:20][CH3:21])[N:4]([CH2:3][C:2]([OH:1])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c[n+]([O-])c3ccccc3c2n1CC(C)(C)O
Reactant: [NH4+]
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: CO
Product: COC(=O)Nc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 0 °C
Yield: 45.5 %

Procedure:
A suspension of methyl [1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-2-yl]carbamate (0.80 g, 2.4 mmol) in methanol (10 mL) was stirred vigorously and cooled to 0° C. Concentrated ammonium hydroxide (0.8 mL, 25 mmol) was added followed by benzenesulfonyl chloride (0.9 g, 5 mmol), which was added dropwise. The mixture was stirred for two hours at 0° C. to 5° C. An analysis by LC/MS indicated the reaction was incomplete. Additional benzenesulfonyl chloride (0.9 g) was added, and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 0% to 25% CMA in chloroform) followed by recrystallization from ethyl acetate to provide 0.36 g of methyl [4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]carbamate as a white solid, mp 255-258° C. (decomposition).
Reaction SMILES: [OH-].[Na+].[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH2:18][C:19]([NH:21][C@@H:22]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]([O:25]C)=[O:24])=[O:20])[C:8](=[O:34])[CH:7]1[CH:35]([CH3:37])[CH3:36])(=[O:5])[CH3:4]>C(O)C>[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]([CH2:18][C:19]([NH:21][C@@H:22]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:23]([OH:25])=[O:24])=[O:20])[C:8](=[O:34])[CH:7]1[CH:35]([CH3:37])[CH3:36])(=[O:5])[CH3:4]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)C(=O)C1C(C)C
Reaction time: 4.5 h
Yield: 99.9 %

Procedure:
A 4 N aqueous sodium hydroxide solution (7.2 ml) is added to a solution of methyl (2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionate (4.60 g, Compound No. 1-48) in ethanol (30 ml), and the mixture is stirred for 4.5 hours. The reaction mixture is washed with ether, then 2 N hydrochloric acid is added to the reaction mixture to acidify the system, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled compound (4.46 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.[H-].[Na+].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[C:6]=2[CH:11]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OCc4ccccc4)cc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.4 %

Procedure:
To a suspension of 6-bromo-2-methyl-4-[(phenylmethyl)oxy]-1H-benzimidazole (79.2 g, 250 mmol, STEP 1) in N,N-dimethylformamide (500 mL) was added sodium hydride (60% in mineral oil, 12.0 g, 300 mmol) at 0° C. After stirring at room temperature for 20 minutes, the reaction mixture was cooled to 0° C. To the mixture was added 4-methylbenzenesulfonyl chloride (47.6 g, 250 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water (800 mL), and the white precipitates were collected by filtration, washed with diisopropyl ether (500 mL), and dried in vacuum at 70° C. for 7 hours to afford the title compound as a white solid (116 g, 98%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[NH:42][CH2:41][CH2:40]3)O1>>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[C:39]4[C:44](=[CH:45][CH:46]=3)[C:43](=[O:47])[NH:42][CH2:41][CH2:40]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CCNC5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, Step 1). LCMS (M+H)+=437.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CO[CH:10]=[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].CC(N(C)C)=O.Cl>C(OCC)C>[C:21]1([C:11]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccccn1
Reactant: COC=C(c1ccccc1)S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: O=S(=O)(C(=CNc1ccccn1)c1ccccc1)c1ccccc1
Yield: 12.2 %

Procedure:
A solution of 2-aminopyridine (1.05 g) and 2-methoxy-1-phenyl-1-phenylsulphonylethene (2.0 g) in a mixture of anhydrous dimethylacetamide (50 ml) and a solution of hydrogen chloride in diethyl ether (6N; 0.5 ml) was heated at reflux for 25 hours, and then it was cooled and poured onto ice (150 g). The yellow precipitate was filtered off, subjected twice to medium pressure chromatography on silica gel, eluting with chloroform, triturated with light petroleum ether (b.p. 60°-80° C.) and recrystallised from a mixture of diethyl ether and light petroleum ether (b.p. 60°-80° C.), to give 1-phenyl-1-phenylsulphonyl-2-(pyrid-2-ylamino)ethene (0.3 g), m.p. 159°-160° C.
Reaction SMILES: [Cl:1]C1C=C(NC(NC)=O)C=CC=1Cl.O=CC(Cl)(Cl)Cl.[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([N:31]([CH:33](O)[C:34]([Cl:37])([Cl:36])[Cl:35])[CH3:32])=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].S(Cl)(Cl)=O>S(=O)(=O)(O)O.C(OCC)C>[CH3:32][N:31]([CH:33]([Cl:1])[C:34]([Cl:37])([Cl:36])[Cl:35])[C:29]([NH:28][C:23]1[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=1)=[O:30]
Reactant: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(O)C(Cl)(Cl)Cl
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Agent: O=CC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(Cl)C(Cl)(Cl)Cl
Temperature: 65 °C

Procedure:
1-(3,4-dichlorophenyl)-3-methyl urea (15.2 g, 0.07 mol) was combined with 15.0 g (0.1 mol) of chloral and 5 drops of concentrated sulfuric acid. The mixture was heated for an hour to effect reaction, then stripped under vacuum. To the crude 1-(3,4-dichlorophenyl)-3-(1-hydroxy-2,2,2-trichloroethyl)-3-methyl urea was added an excess of thionyl chloride and the mixture was heated gradually to a maximum of 65° C. Diethyl ether was added to the crude product, and the insoluble product was collected on a filter, washed twice with diethyl ether and dried. The 15.3 g of product, which melted at 132°-140° C., analyzed as follows: %Cl, calculated 55.2, found 46.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[C:7]#[N:8].C(O)C>CO.Cl.[Fe]>[NH2:10][C:5]1[CH:4]=[C:3]([C:13]([F:14])([F:15])[F:16])[C:2]([CH3:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: Cc1cc(C#N)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(C#N)c(N)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Iron powder (37.42 g, 670 mmol) was added in small portions to a stirred suspension of finely grinded 5-methyl-2-nitro-4-trifluoromethyl-benzonitrile from step 3 (34.58 g, 150 mmol) in methanol (75 mL) and 37% HCl (93 mL). The internal temperature was kept between 40 and 60° C. by external water bath cooling. The resulting brown solution was stirred for 1 h at 50° C., giving a green suspension. The mixture was poured into ice cold water (600 mL), the precipitated solid was filtered off and washed with water to give a green solid, which was dissolved in boiling ethanol (700 mL), activated carbon (ca. 10 g) was added and the mixture was refluxed for 1 h. The hot solution was filtered and the solvent was evaporated in vacuum to leave the title compound as a brown-yellow solid (23.55 g, 78%), which was used without further purification. MS (EI) 200.1 [M].
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[N:12])[CH:5]=1.B(OC)(OC)OC>C1COCC1.[Li+].[BH4-]>[NH2:12][CH2:11][CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:2]
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1cccc(CO)c1
Temperature: 72.5 °C
Yield: 66.1 %

Procedure:
To a solution of methyl-3-(cyanomethyl)benzoate (4 grams, 0.023 mol, 1 molequivalent) in 5 ml dry THF, 2M LiBH4 in THF (60 ml, 5 molequivalents) and (MeO)3B (3 ml, 1 molequivalent) were added under nitrogen atmosphere. The reaction mixture was stirred and heated at 70-75° C. for 16-18 hours. After cooling, THF was evaporated, and 2NH2SO4 was added to the residue (to acidify the solution to pH of 1-2). The resulting solution was washed with ether and powdered K2CO3 was added to the aqueous phase until the pH reached 7. NaCl was then added and the solution was extracted with THF. The organic phase was dried over MgSO4 and the solvent was evaporated, to give a 2.3 grams (67%) of a pure product, which was used without purification.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19]>CN(C=O)C>[CH2:16]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[C:2](=[O:3])[O:4][C:5]1=[O:12])[CH2:17][CH2:18][CH3:19]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)oc(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
To a solution of isatoic anhydride (8.16 g, 50.0 mmol) in DMF (100 mL) was added sodium hydride (66% in oil, 2.00 g, 55 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 10 min. 1-Iodobutane (8.5 mL, 75 mmol) was added to the obtained mixture and the mixture was stirred at room temperature for 64 hr. Ice water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure to give the title compound (10.5 g), which was used for the next reaction without purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([CH2:27][C@H:28]([OH:33])[C:29]([F:32])([F:31])[F:30])[C:24]([N:34]=CN(C)C)=[C:23]([F:39])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:40])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+].[Cl-].[Cl-].[Zn+2]>[NH2:34][C:24]1[C:25]([CH2:27][C@H:28]([OH:33])[C:29]([F:31])([F:32])[F:30])=[CH:26][C:21]([CH2:20][C@H:13]2[C@H:12]3[C@@H:17]([N:9]([CH2:8][C:7]4[CH:41]=[CH:42][CH:43]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=4)[C:10](=[O:40])[O:11]3)[CH2:16][S:15](=[O:19])(=[O:18])[CH2:14]2)=[CH:22][C:23]=1[F:39]
Reactant: CN(C)C=Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(C[C@H](O)C(F)(F)F)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
To a solution of N′-[4-[(3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-6-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-phenyl]-N,N-dimethyl-formamidine (0.11 g, 0.17 mmol) in anhydrous EtOH (3 mL) was added ZnCl2 (0.12 g, 0.86 mmol) and the reaction mixture was heated at reflux for 8 h. The reaction mixture was diluted with EtOAc and aq. K2CO3 solution. The product was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (hexane-EtOAc 2:1 to 1:2) to yield the title compound as a colorless foam: TLC (hexane-EtOAc 1:1) Rf=0.39; HPLC RtA=2.21 min; ESIMS [M+H]+=573.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[C:14]([CH3:15])=[C:13]([N+:16]([O-:18])=[O:17])[C:12](F)=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].C(O)(=O)C[C:22](CC(O)=O)(C(O)=O)[OH:23]>C(#N)C>[F:4][C:5]1[C:14]([CH3:15])=[C:13]([N+:16]([O-:18])=[O:17])[C:12]([O:23][CH3:22])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(C(=O)O)c(F)c(C)c1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Sodium methoxide (28% methanol solution; 1.66 g) was added to a solution of methyl 2,5-difluoro-3-methyl-4-nitrobenzoate (1.0 g) in acetonitrile (5 ml) under ice cooling, and the mixture was stirred for 1 hour at 0° C. and for 2 hours at 50° C. The reaction mixture was additionally stirred overnight at room temperature and then poured into ice water. The mixture was acidified with citric acid and then extracted with diethyl ether. An organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (1.1 g).