Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C([Si](C)(C)[O:68][CH2:69][CH2:70][O:71][C:72]1[N:77]=[CH:76][C:75]([NH2:78])=[C:74]([O:79][CH3:80])[CH:73]=1)(C)(C)C>ClCCl>[OH:68][CH2:69][CH2:70][O:71][C:72]1[N:77]=[CH:76][C:75]([NH:78][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:74]([O:79][CH3:80])[CH:73]=1
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ncc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCCO)ncc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 45.7 %

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol) in dichloromethane (9 mL) was added diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (Aldrich) (0.24 g, 1 mmol) respectively. The mixture was stirred at room temperature for 8 min, then 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-methoxy-pyridin-3-ylamine prepared in Example 191 (0.23 g, 0.78 mmol) was added. The reaction mixture was stirred at room temperature for 48 h. The mixture was concentrated. The residue was dissolved into tetrahydrofuran (3 mL), and an aqueous solution (1N) of HCl (1 mL) was added. The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (0-15% MeOH in CH2Cl2) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [6-(2-hydroxy-ethoxy)-4-methoxy-pyridin-3-yl]-amide as a white solid (0.15 g, 46%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:15][CH2:14][C@:13]2([OH:16])[C@:4]34[CH2:19][CH2:18][N:17]([CH2:20][CH:21]5[CH2:23][CH2:22]5)[C@@H:12]2[CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:24][CH2:25][O:26][CH3:27])=[C:6]([O:28][C@@H:3]13)[C:5]4=2.C(N(CC)CC)C.[C:36]1([S:46](Cl)(=[O:48])=[O:47])[C:37]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH:21]1([CH2:20][N:17]2[CH2:18][CH2:19][C@:4]34[C:5]5[C:6]6[O:28][C@H:3]3[C@H:2]([N:1]3[S:46](=[O:48])(=[O:47])[C:36]7[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=7[S:42]3(=[O:44])=[O:43])[CH2:15][CH2:14][C@@:13]4([OH:16])[C@H:12]2[CH2:11][C:10]=5[CH:9]=[CH:8][C:7]=6[O:24][CH2:25][O:26][CH3:27])[CH2:22][CH2:23]1
Reactant: COCOc1ccc2c3c1O[C@H]1[C@H](N)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc2c3c1O[C@H]1[C@H](N4S(=O)(=O)c5ccccc5S4(=O)=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Yield: 108.7 %

Procedure:
In 5 mL of dichloromethane, 117 mg (0.30 mmol) of 6β-amino-17-cyclopropylmethyl-4,5α-epoxy-3-methoxymethoxy-morphinan-14-ol was dissolved, and 0.04 mL (0.29 mmol) of triethylamine and 79 mg (0.31 mmol) of benzene-1,2-disulfonyl dichloride were added, followed by heating the mixture to reflux for 1 hour. After allowing the reaction solution to cool to room temperature, aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain 192 mg of 2-(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl)-benzo[1,3,2]dithiazol-1,1,3,3-tetroxide as a crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][O:31][CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=2)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:43]2[CH:42]=[CH:41][C:40]([CH2:39][N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[CH:45][CH:44]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][O:31][CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: COCCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COCCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
A solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (110 mg, 0.21 mmol), (4-(morpholinomethyl)phenyl)boronic acid (99 mg, 0.33 mmol), sodium carbonate (83 mg, 0.78 mmol) in 4 ml of dioxane was degassed with argon for 20 min, Pd(PPh3) (25 mg, 0.02 mmol) was added to the mixture and heated to 100° C. for overnight. The reaction was cooled to room temperature and diluted with water, compound was extracted in 10% MeOH in DCM, dried over Na2SO4, concentrated and crude product purified by silica gel (100-200) chromatography to obtain the title compound (50 mg 38%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=2)[N:3]=1.[CH:23]([B-](F)(F)F)=[CH2:24].[K+].C(N(CC)CC)C>CC(O)C.C1COCC1>[CH3:22][O:21][C:17]1[N:16]=[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:23]=[CH2:24])=[N:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: C=C[B-](F)(F)F
Reactant: COc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=Cc1nn(Cc2cccc(OC)n2)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To 3-iodo-1-((6-methoxypyridin-2-yl)methyl)-4-nitro-1H-indazole (2.65 g, 6.46 mmol) in IPA/THF (40 mL/10 mL) was added potassium vinyltrifluoroborate (1.30 g, 9.69 mmol), triethylamine (1.31 g, 12.9 mmol) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.264 g, 0.323 mmol). The reaction mixture was heated to reflux and stirred for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated to remove solvent. The residue was dissolved with EtOAc (100 mL) and washed with saturated NH4Cl, H2O and brine. The solution was dried (Na2SO4) and concentrated to provide the desired product (1.89 g).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].[Cl-].[Li+].C(N(CC)CC)C>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.CN(C=O)C>[CH2:32]([O:31][C:27](=[O:30])/[CH:28]=[CH:29]/[C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1)[CH3:33]
Reactant: C=CC(=O)OCC
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Temperature: 180 °C
Yield: 103.1 %

Procedure:
Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester (0.40 g), ethyl acrylate (0.13 g), dichlorobis(triphenylphosphine)palladium (II) (35 mg), lithium chloride (64 mg), and triethylamine (0.19 ml) were added to DMF (4 ml). The mixture was heated at 180° C. (microwave reactor) for 20 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→30:70). The purified product was condensed under reduced pressure to give the title compound (0.36 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][OH:18].O>CN(C)C=O>[OH:18][CH2:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: OCCCCl
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2ncn(CCCO)c2cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.46 g of 5,6-dimethylbenzimidazole dissolved in 50 ml of dry N,N-dimethylformamide was added 0.76 g of NaH, the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise 5 ml of 3-chloro-1-propanol, and the reaction was carried out by stirring at room temperature for 2 days, followed by an addition of water to stop the reaction. Subsequently, according to the same processes as in Example 1, crude 1-(3-hydroxypropyl)-5,6-dimethylbenzimidazole was obtained. The conversion to this compound from 5,6-dimethylbenzimidazole was found to be 90%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:21]2[S:22][CH:23]=[CH:24][C:20]=2[C:19](C=O)=[CH:18][CH:17]=1.[Cl-].[CH2:28]([O:30][CH:31]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:29].[C:56](=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH2:35]([O:34][C:32](=[O:33])/[C:31](/[O:30][CH2:28][CH3:29])=[CH:56]/[C:19]1[C:20]2[CH:24]=[CH:23][S:22][C:21]=2[C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:17][CH:18]=1)[CH3:36]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2ccsc12
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2sccc12)OCC

Procedure:
In analogy to the procedure described in example 91 c], 7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophene-4-carbaldehyde (example 98 a]) was treated with (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride [Tetrahedron 50(25), 7543-56(1994)]in 2-propanol in the presence of potassium carbonate to yield the 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-acrylic acid ethyl ester. The 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-acrylic acid ethyl ester was further saponified in analogy to the procedure described in example 99 to yield the 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-acrylic acid as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][O:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:20][CH2:19][CH2:18][CH2:17][O:16][CH3:15])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: COCCCN
Product: COCCCNc1cc(Cl)nc(-c2ccccc2)n1

Procedure:
In the same manner, 4,6-dichloro-2-phenylpyrimidine is reacted with 3-methoxypropylamine to produce 4-chloro-6-(3-methoxypropylamino)-2-phenylpyrimidine, which is then reacted with p-chlorothiophenol to afford 4-(4-chlorophenylthio)-6-[(3-methoxypropyl)amino]-2-phenylpyrimidine.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=O.N[C:14]1[C:18](C)=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[CH3:17][C:18]1[CH:14]=[N:15][N:16]2[C:5]([C:7]3[CH:11]=[CH:10][S:9][CH:8]=3)=[CH:4][CH:3]=[N:2][C:12]=12
Reactant: Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1ccsc1
Solvent: CC(=O)O
Product: Cc1cnn2c(-c3ccsc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-thienyl)-2-propen-1-one and 0.01 mole of 3-amino-4-methylpyrazole in glacial acetic acid is heated at reflux temperature for 8 hours. The solvent is removed in vacuo to give the product of the example.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[C:18](=[C:20]([CH2:29][CH3:30])[N:21]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[N:22]=3)[N:19]=2)[C:7]([O:10][CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[CH:32](=O)[CH3:33]>>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[C:18](=[C:20]([CH2:29][CH3:30])[N:21]([CH:23]4[CH2:24][CH2:25][N:26]([CH2:32][CH3:33])[CH2:27][CH2:28]4)[N:22]=3)[N:19]=2)[C:7]([O:10][CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCNCC3)nc2c(=O)[nH]1
Reactant: CC=O
Product: CCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCN(CC)CC3)nc2c(=O)[nH]1

Procedure:
The title compound was prepared by the method of example 51 using the title compound of example 118 and acetaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([CH2:6][CH2:7][NH:8]C(=O)OCC1C=CC=CC=1)(=[O:5])=[O:4].CCOCC.[ClH:25]>>[Cl-:25].[CH3:1][N:2]([CH3:19])[S:3]([CH2:6][CH2:7][NH3+:8])(=[O:5])=[O:4]
Reactant: Cl
Reactant: CN(C)S(=O)(=O)CCNC(=O)OCc1ccccc1
Solvent: CCOCC
Product: CN(C)S(=O)(=O)CC[NH3+]
Product: [Cl-]
Temperature: 90 °C

Procedure:
Benzyl 2-[(dimethylamino)sulfonyl]ethylcarbamate (8.8 g, 30.7 mmol) was suspended/dissolved in 6N HCl (75 mL) and the mixture was heated to 90° C. The solids dissolved. After 1.5 hours the reaction was cooled and extracted with ether. The aqueous layer was evaporated to give a sticky white solid. The ether layer was found to contain unreacted starting material. This was retreated with 6 N HCl at room temperature overnight. The reaction was washed with ether and the aqueous layer combined with the previously isolated product and evaporated to give a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].CCN=C=NCCCN(C)C.Cl.C1C=CC2N([OH:32])N=NC=2C=1.N1C=CN=C1CN(C[C:47]1[CH:70]=[CH:69][C:50]([CH2:51][N:52]([CH2:58][CH2:59][CH2:60][CH2:61]N(CCC)CCC)[CH2:53]CC(O)=O)=CC=1)CC1NC=CN=1>CN(C=O)C>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:47](=[O:32])[CH2:70][CH2:69][CH2:50][CH2:51][N:52]1[CH2:53][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: On1nnc2ccccc21
Reactant: CCCN(CCC)CCCCN(CCC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c(NC(=O)CCCCN2CCCCC2)c1
Yield: 214.8 %

Procedure:
Commercially available 3,4-diaminobenzonitrile (0.461 g) was dissolved in DMF (18.4 ml) and added with WSCI hydrochloride (0.996 g), HOBt (0.702 g), and the compound (0.844 g) obtained in Example 60-1 and the whole was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure. The residue was added with water and subjected to separation/extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.04 g) as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([N:18]1[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)=[N:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH2:27]([N:19]1[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)=[CH:16][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:18]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C=C(c2ccc(OCc3ccccc3)cc2)N(Cc2ccccc2)N1
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)nn1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Ethyl 5-(4-benzyloxyphenyl)-2H-pyrazole-3-carboxylate (6 g) is added portionwise to a stirred suspension of sodium hydride (0.75 g) in tetrahydrofuran (250 mL) at room temperature. Stirring is continued at this temperature for a further 30 minutes when benzyl bromide (3.57 g) is added in one portion. The reaction mixture is heated to reflux for 5 hours, then evaporated in vacuo. The residue is treated with water (250 mL), the resulting yellow solid washed well with water, then dissolved in tetrahydrofuran and filtered to remove a small amount of insoluble white solid. The filtrate is evaporated and the residual yellow solid purified by flash chromatography on silica eluting initially with dichloromethane then with a mixture of ethyl acetate and dichloromethane (1:9 v/v) to give ethyl 2-benzyl-5-(4-benzyloxyphenyl)-2H-pyrazole-3-carboxylate (1.2 g) and ethyl 1-benzyl-5-(4-benzyloxyphenyl)-2H-pyrazole-3-carboxylate (2 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][N:7]=1>C(O)C>[CH2:1]([O:3][C:12]([C:10]1[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH:11]=1)=[O:13])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccnc(O)c1
Solvent: CCO
Product: CCOC(=O)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
Acetyl chloride (20 mL) was added slowly to ethanol (80 mL) at room temperature. The clear solution was stirred for 5 minutes and then 2-hydroxy-4-pyridinecarboxylic acid (5.0 g, 35.9 mmol) was added as a solid. The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and the majority of the ethanol was evaporated. The residue was diluted with chloroform and water and the aqueous layer was neutralized by the careful addition of K2CO3. The organic layer was separated and the aqueous layer was extracted further with chloroform. The combined organic layer was dried over sodium sulfate and concentrated to give the title compound (5.74 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1I.[Cu][C:19]#[N:20].NC1C=CC(C2SC3C=CC=CC=3N=2)=CC=1Cl>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: N#C[Cu]
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1I
Agent: Nc1ccc(-c2nc3ccccc3s2)cc1Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2nc3ccccc3s2)ccc1N

Procedure:
2-(4'-amino-3'-iodophenyl)benzothiazole (0.123 g, 0.35 mmol) was treated with copper (I) cyanide (63 mg, 0.7 mmol) in DMF according to procedure for preparation of 2-(4'-amino-3'-chlorophenyl) benzothiazole. The crude product was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (2:3) to give a pale yellow powder (0.032 g, 36%%), m.p. 207.3-211.0° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.CCOC(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:11][C:13](=[O:14])[CH3:15])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C1CCCC1=O
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C1(CCC(C)=O)CCCC1=O
Yield: 67 %

Procedure:
A solution of methyl 2-oxocyclopentanecarboxylate (2.000 ml, 14.07 mmol), methyl vinyl ketone (1.381 ml, 16.88 mmol) and triethylamine (2.94 ml, 21.10 mmol) in toluene (20 mL) was heated at 40° C. for 24 h. The reaction was brought to room temperature, diluted with EtOAc, washed with sat. NH4Cl, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-50% heptane/EtOAc to afford a colorless oil as methyl 2-oxo-1-(3-oxobutyl)cyclopentanecarboxylate (2.0 g, 9.42 mmol, 67.0% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=O)[C:27]([F:30])([F:29])[F:28])[CH2:21][CH2:20]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.B.C1COCC1.[NH4+].[Cl-].O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]2[CH2:20][CH2:21][C@@H:22]([NH:25][CH2:26][C:27]([F:29])([F:30])[F:28])[CH2:23][CH2:24]2)(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(NC1CCC(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)CC1)C(F)(F)F
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(N[C@H]1CC[C@@H](NCC(F)(F)F)CC1)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of N-(4-(2′,4′-difluorobiphenyl-4-ylsulfonamido)cyclohexyl)-2,2,2-trifluoroacetamide (350 mg, 0.76 mmol) in THF (20 mL) was stirred under argon at room temperature and BH3/THF (1 M, 3.8 mL) was added. The mixture was heated to 50° C. and stirred for 4 hours, after which LCMS analysis indicated the reaction to be proceeding, but significant starting material was present. Further BH3/THF (1 M, 2.5 mL) was added and the mixture was heated at 50° C. overnight. The mixture was then cooled and NH4Cl (sat. aq., 10 mL) was added cautiously, followed by water to dissolve all the solids. The mixture was then extracted with EtOAc (3×20 mL) and the combined extracts were dried over MgSO4. After evaporation of the solvents, the crude material was purified by column chromatography on SiO2 (30% acetone/hexane) affording a viscous pale yellow oil (270 mg, 79%), which LCMS indicated to be only 78% pure and a mixture of diastereomers.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[I-].[Na+].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.BrC[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(#N)C.ClCCl>[N:9]1([CH2:1][CH:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: C1CCNC1
Reactant: COC(=O)Cc1ccccc1OCCCBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1OC(C)CN1CCCC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
18.4 g of potassium carbonate, 4.5 g of sodium iodide and then 9.54 g of pyrrolidine are successively added to a solution of 36 g of methyl 2-(3-bromopropoxy)phenyl-acetate in 400 cm3 of acetonitrile. The reaction mixture is refluxed for 5 hours and then stirred at 20° C. for 20 hours and diluted with 800 cm3 of dichloromethane. The solution is washed with 80 cm3 of water and then twice with 80 cm3 of brine. The chloromethylenic phase is dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.5 cm, height 48 cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and methanol mixture (90/10 by volume) and collecting fractions of 500 cm3. Fractions 3 to 8 are pooled and concentrated to dryness at 50° C. under reduced pressure (2.7 kPa). 24.9 g of methyl {[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetate are obtained in the form of an orange-colored oil.