Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.C[N:31](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][N:2]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=[O:22])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:31])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a mixture of 2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (64 mg) obtained in Example 335, 1H-1,2,3-benzotriazol-1-ol-ammonia complex (35 mg) and N,N-dimethylformamide (3 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (45 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (54 mg, yield: 85%) as pale-yellow prism crystals. MS: 430 (MH+). melting point 149-150° C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](F)[CH:13]=1.[CH:19]1([C:22]#[N:23])[CH2:21][CH2:20]1.C1(C)C=CC=CC=1>O>[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)[CH:13]=1
Reactant: Fc1cc(Br)ccn1
Reactant: N#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2cc(Br)ccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
LiHMDS (1M in toluene, 17.6 mL, 17.6 mmol, 3.1 eq) is added dropwise to a cold (−5° C.) mixture of 4-bromo-2-fluoro-pyridine [Marsais, F. et al, Journal of Organic Chemistry, (1992), 57, 565-573] (1 g, 5.7 mmol), cyclopropanecarbonitrile (1.25 mL, 17 mmol, 3 eq), 4 Å molecular sieves and toluene (20 mL). The reaction mixture is allowed to warm to rt, stirred for 16 h, poured into H2O and filtered. The filtrate is diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 9:1), to afford 620 mg of the title compound as a white solid: ESI-MS: 223.1/225.1 [M+H]+; tR=4.22 min (System 1); TLC: Rf=0.25 (Hex/EtOAc, 9:1).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[N:14]=[C:13]([CH:19]3[S:24][CH2:23][CH2:22][CH2:21][S:20]3)[C:12]=2[CH:25]=1>O.CO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([CH3:17])([CH3:18])[N:14]=[C:13]([CH:19]3[S:20][CH2:21][CH2:22][CH2:23][S:24]3=[O:2])[C:12]=2[CH:25]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)N=C(C2SCCCS2)c2cc(Br)ccc2O1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)N=C(C2SCCCS2=O)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
A solution of sodium periodate (430 mg) in water (6 ml) was added to a solution of Compound 105 (600 mg) in methanol (18 ml) and the mixture was stirred at room temperature for 18 hours. The methanol was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by chromatography on silica gel to obtain a solid. The solid was recrystallized from ethyl acetate to obtain 2-(6-bromo-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)-1,3-dithian-1-oxide (331 mg) (Compound 111).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:16]([O:18][C:19]([C:21]1[CH:25]=[CH:24][NH:23][C:22]=1[NH2:26])=[O:20])[CH3:17].N1C(C)=CC=CC=1C>C(Cl)Cl>[Br-:15].[NH2:26][C:22]1[NH:23][C:24]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N+:9]=2[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:25][C:21]=1[C:19]([O:18][CH2:16][CH3:17])=[O:20]
Reactant: Brc1cccc[n+]1Cc1ccccc1
Reactant: CCOC(=O)c1cc[nH]c1N
Agent: [Br-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1cc(-c2cccc[n+]2Cc2ccccc2)[nH]c1N
Reaction time: 48 h

Procedure:
Under an argon atmosphere, 658 mg (2.0 mmol) of N-benzyl-2-bromo-pyridinium bromide (for preparation see: J. Heterocyclic Chem. 28, 1083 (1991)) are introduced into 20 ml of abs. methylene chloride, and 308 mg (2.0 mmol) of 2-amino-pyrrole-3-carboxylic acid ethyl ester [for preparation see: J. Heterocyclic Chem. 23, 1555 (1986)] are added thereto. The reaction mixture is stirred for 2 days with the exclusion of light. Since the reaction is not complete, 232 μl (2 mmol) of 2,6-lutidine and a further 0.20 mmol of 2-amino-pyrrole-3-carboxylic acid ethyl ester are added. After a further 12 hours' stirring, the reaction mixture is concentrated by evaporation and the residue is digested in isopropanol. Filtering, washing with hexane and drying yield the title compound which, according to its 1H-NMR spectrum, still contains approximately 10% N-benzyl-2-bromo-pyridinium bromide; 1H-NMR (300 MHz, DMSO-d6): 11.45 (1H), 8.70 (d, J=7, 1H), 8.38 (t, J=7, 1H), 8.00 (d, J=7, 1H), 7.67 (t, J=7, 1H), 7.42 (m, 3H), 7.14 (d, J=7, 2H), 6.85 (d, J=3, 1H), 6.45 (sb, 2H), 5.91 (s, 2H), 4.13 (q, J=7, 2H), 1.19 (t, J=7, 3H); FAB-MS: (M+H)+ =322.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH2:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1>C(Cl)(Cl)Cl>[C:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH:7][S:26]([C:21]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)CN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)CNS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 82.9 %

Procedure:
In 50 ml of chloroform were dissolved 2.0 g of 2-acetamidopropylamine and 2.6 g of triethylamine, and to the solution was added dropwise 50 ml of a chloroform solution containing 3.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. Then the mixed solution was stirred at a temperature of 15° C. to 25° C. for two hours, and the reaction solution was washed with water, dried with anhydrous magnesium sulfate and the chloroform was distilled therefrom under reduced pressure to give 3.67 g of N-(2-acetamidopropyl)-5-isoquinolinesulfonamide in a yield of 83%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[C:32]([CH3:39])[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:8]2[C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=3)[N:9]=2)=[C:32]([CH3:39])[CH:31]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3C)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (150 mg, 0.41 mmol) in dioxane (5.0 mL) and water (3 drops) was added (4-fluoro-2-methylphenyl)boronic acid (101 mg, 0.66 mmol), Pd(PPh3)4 (19.0 mg, 0.02 mmol), and K3PO4 (138.3 mg, 0.65 mmol). The reaction was stirred for 1 hour at 90° C. under a nitrogen atmosphere. The resulting solution was concentrated in vacuo, and then purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to provide (S)-methyl 2-(4-fluoro-2-methylphenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (120 mg, 78%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C[N:14](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:14])=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of substituted indole-2-carboxylic acid (1e: 1 mmol) in dry DMF (4 mL) were added HATU (1.5 eq.) and the desired amine (R6—NH2: 1.2 eq.) followed by DIPEA (5.0 eq.) at 0° C. The resulting mixture was stirred at room temperature for 12 h to 24 h. To the reaction mixture water (10 mL) was added and stirred for 10 minutes. The resultant solid was collected by filtration, washed with water, hexane and dried. In some instances reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compounds were purified by column chromatography over silica gel (100-200 mesh) or CombiFlash® purification system (Teledyne Isco) using appropriate mixtures of ethyl acetate and hexanes/petroleum ether or preparative HPLC to obtain the desired product indole-2-carboxamide (I).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1/[N:13]=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccccc1N
Solvent: Cc1ccccc1
Product: COc1ccccc1/N=C/c1ccccc1

Procedure:
A mixture of 31.8 g (0.30 mol) of benzaldehyde, 36.9 g (0.30 g) of 2-methoxyaniline and 450 mL of toluene was refluxed using a Dean-Stark head for 1 hr. 15 granules of 4A molecular sieves were added. This mixture was refluxed for 4 hr, then filtered off, and the filtrate was evaporated to dryness. The residue was dried in vacuum at 70° C. This crude product was further used without an additional purification, since it is unstable on silica gel 60 and decomposes when dried under vacuum. Yield 52.0 g (82%) of the title material.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.CCCCCC>[C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH:12]([O:14][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])[CH2:11]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC1CC(O)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CC(ON2C(=O)c3ccccc3C2=O)C1

Procedure:
Analogously to Example 1 b, but using ethyl acetate/hexane mixtures (1:3 and 1:1) in the flash chromatography, starting from 15.24 g (0.0757 mol) of 3-(N-BOC-aminomethyl)-cyclobutanol, 12.35 g (0.0757 mol) of N-hydroxyphthalimide, 19.85 g (0.0757 mol) of triphenylphosphine and 13.3 ml (0.0795 mol) of diethyl azodicarboxylate (93%), the title compound, which melts at 161°-162° C. after recrystallization from ethyl acetate, is obtained. Evaporation of the mother liquor and recrystallization of the residue from ethyl acetate/hexane gives a further batch of the title compound, m.p. 145°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[CH:16]1(O)[CH2:20]C[CH2:18][CH2:17]1>>[CH:1]1([O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=2)[CH2:18][CH2:17][CH2:16][CH2:20]1
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Reactant: OC1CCCC1
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)OC1CCCC1

Procedure:
Following transesterification General Procedure B above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example 9 above) and cyclopentanol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.66 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: C[C:2](C)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C(C)(C)C.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[O:45]1CC[NH:47][C:46]1=O>O1CCCC1.C(N(CC)CC)C>[CH2:2]([C@H:3]1[CH2:4][O:5][C:46](=[O:45])[NH:47]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: O=C1NCCO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@@H](Cc2ccccc2)CO1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,3-dimethyl-3-phenyl propionic acid (10 g, 57 mmol, from Reference Example 22) in anhydrous tetrahydrofuran (120 mL) is added under inert atmosphere triethylamine (10 mL) and the mixture is cooled to −78° C. in a dry-ice acetone bath. Pivaloyl chloride (7.4 mL, 60 mmol) is added dropwise, causing the immediate formation of a white precipitate. The reaction mixture is allowed to sit for 15 minutes at −78° C. and is then stirred at 0° C. in an ice-water bath. In a separate flask, a solution of (S)-4-benzyl-2-oxazolidinone (9.9 g, 56 mmol) in anhydrous tetrahydrofuran (130 mL) is prepared under inert atmosphere and cooled to −35° C. in a dry-ice/acetone bath. A small amount of triphenylmethane (<5 mg) is added as an indicator of deprotonation. n-Butyllithium (1.6 M solution in hexanes, 40 mL, 64 mmol) is added dropwise via syringe. After 30 minutes of stirring at 0° C., the flask containing the mixed anhydride is re-cooled to −78° C. in a dry-ice/acetone bath. The solution of the lithium anion of the oxazolidinone is added to the mixed anhydride solution via cannula. The source flask is washed twice with tetrahydrofuran (4 mL×2) and these washings are also transferred via cannula to the mixed anhydride solution. The reaction mixture is stirred at −78° C. for 1 hour and at 0° C. for 1 hour. Water (100 mL) is added and stirring is continued for 15 minutes. The aqueous phase is extracted thrice with diethyl ether. The combined extracts are washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and concentrated under reduced pressure to afford 20 g of a white paste. The crude material is purified by flash chromatography (ethyl acetate/hexanes) to afford 11 g (56%) of a flocculent white solid. MS (ES+): (M+H)=338.1
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]2[N:12]([CH:13]=[N:14][N:15]=2)[C:11]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].CO>C(Cl)Cl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:22][C:19]1[CH:20]=[CH:21][C:10]2[CH2:9][NH:8][CH2:17][C:16]3[N:12]([CH:13]=[N:14][N:15]=3)[C:11]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(F)cc2-n2cnnc2C1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2c(c1)-n1cnnc1CNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 9-fluoro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester, (1.45 g, 4.76 mmol) in dry DCM (15 mL) was added trifluoroacetic acid (14.30 mL, 3 mL/mmol) at 0° C. The reaction mixture was stirred at r.t. for 2 h under argon. After completion of the reaction as confirmed by TLC, MeOH (2×10 mL) was added and the reaction mixture was evaporated under vacuo to remove excess of solvent and trifluoroacetic acid. The remaining solvents were removed under vacuo and 9-fluoro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene trifluoroacetate (1.50 g, 4.71 mmol, 99%) was obtained as thick brown jelly. The crude compound was used as such without any further purification for the next step.
Reaction SMILES: N[C@@H:2]([CH:11](C)C)[C@@H:3]([C:5]1C=CC=CC=1)O.[NH2:14][C@@H:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].CCCCCC>CCOC(C)=O>[C:18]1([C@@H:16]([OH:17])[C@H:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]2[CH2:5][CH2:3][CH2:2][CH2:11]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)[C@H](N)[C@H](O)c1ccccc1
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O[C@H](c1ccccc1)[C@H](c1ccccc1)N1CCCC1
Yield: 93 %

Procedure:
Repeat Step (a) of EXAMPLE 6, but replace (1R,2S)-2-amino-1-phenyl-3-methyl-butanol with (1R,2S)-2-amino-1,2-diphenyl-ethanol. Column chromatography (Silica gel, eluent is n-Hexane:EtOAc=5:1) is used to purify the coarse product and a white solid (1.24 g) is obtained. The yield is 93% and the other analysis includes:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])=[CH:18][CH:17]=1.O>CS(C)=O>[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[CH2:2][C@H:23]2[N+:24]([O-:26])=[O:25])=[CH:18][CH:17]=1
Reactant: COCCOCOc1ccc(/C=C/[N+](=O)[O-])cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCCOCOc1ccc([C@@H]2C[C@H]2[N+](=O)[O-])cc1
Yield: 57.6 %

Procedure:
Trimethylsulfoxonium iodide (0.76 g, 3.44 mmol) was added in small portions to a suspension of NaH 0.14 g (60% in mineral oil), 3.44 mmol] in dry DMSO (5 mL). The mixture was stirred until gas evolution ceased and a clear solution was formed (45 min). Then, a solution of (E)-1-((2-methoxyethoxy)methoxy)-4-(2-nitrovinyl)benzene (Intermediate J, 0.73 g, 2.86 mmol) in DMSO (5 mL) was transferred via cannula and the reaction was stirred for additional 20 h. The mixture was poured into water (20 mL) and extracted with Et2O (3×15 mL). The organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered; after removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (10-20% EtOAc/Hexanes) affording 0.44 g of 1-((2-methoxyethoxy)methoxy)-4-((trans)-2-nitrocyclopropyl)benzene [Rf=0.4 (50% AcOEt/Hexanes), colorless oil, 36% yield].
Reaction SMILES: FC(F)(F)C([N:5]([C:22]1[CH:23]=[C:24]([C:27](Cl)=[O:28])[S:25][CH:26]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=O.C(N(CC)CC)C.[C:39]([O:50][CH2:51][CH3:52])(=[O:49])[CH:40]([CH:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[OH:43])[OH:41]>CCOCC>[CH2:6]([NH:5][C:22]1[CH:23]=[C:24]([C:27]([O:41][CH:40]([CH:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[OH:43])[C:39]([O:50][CH2:51][CH3:52])=[O:49])=[O:28])[S:25][CH:26]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1csc(C(=O)Cl)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OC(C(=O)OCC)C(O)C(=O)OCC)c1

Procedure:
A mixture of 4-[N-(trifluoroacetyl)-N-(hexadecyl)amino]-2-thiophenecarbonyl chloride and 1.2 g. of triethylamine in 100 ml. of warm ether is treated with 2.5 g. of diethyl tartarate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[NH2:11][C:12]1[NH:13][C:14](=O)[C:15]2[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=2[N:17]=1>C(#N)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH2:11])[N:13]=[C:14]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:15]=2[N:21]=1
Reactant: Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
A solution of 1,2,4-triazole (1.4 g, 20 mmol) and phosphorus oxychloride (1.4 mL, 15 mmol) in dry acetonitrile (40 mL) was adder to a stirred suspension of 2-amino-6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (1 g, 5 mmol) and N-N-di-isopropyl-ethyl-amine (DIEA; 4.4 ml, 25 mmol) in dry acetonitrile (30 ml). The mixture was stirred at room temperature for 24 hours. 2 molar equivalents of 1,2,4-triazole (0.7 g, 10 mmol), 1.5 equivalent of phosphorus oxychloride (0.7 ml, 7.5 mmol) and 2.5 equivalents of DIEA (2.2 ml, 12.5 mmol) were added to the mixture. After stirring at room temperature for 48 hours, the same amount of the above reagents was added again. The reaction mixture was stirred for 7 full days and the yellow precipitate was filtered off, washed successively with acetonitrile, DCM and ether. The solid was dried under vacuum, providing the pure title compound as a yellow solid (667 mg, yield 53%) which was characterised as follows: MS (m/z) 248.8 [M+H]+.
Reaction SMILES: FC1C=CC(Br)=C[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(OCC(F)=C[C:24]1(C2C=CC(F)=CC=2F)[CH2:26][CH2:25]1)(=O)C.[O:36]1CCCC1>>[CH2:3]1[O:9][C:10]2[CH:11]=[CH:12][C:13]([CH:24]3[CH2:26][CH2:25]3)=[CH:14][C:15]=2[O:36]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(F)cc2F)CC1
Reactant: C1CCOC1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Agent: [Mg]
Product: c1cc2c(cc1C1CC1)OCO2
Yield: 28 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.31 g), tetrahydrofuran (2 ml) and magnesium (22 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(2,4-difluorophenyl)cyclopropane (Example 23) (0.11 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 8 ml/min) to afford 1-(2,4-difluorophenyl)-3-(4-fluoro-3-phenoxyphenyl)prop-1-enyl)-1-(3,4-methylenedioxyphenyl)-cyclopropane (40 mg, 28%).