Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:24][CH:23]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1-c1c(Cl)cnn1C
Yield: 15 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-trifluoromethylphenyl isocyanate in a similar manner as described in Example 1.53, providing 8 mg (15%) of Compound 80 (Note: Compound 80 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=427 (M+H37Cl, 22), 425 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.48 (s, 1H), 8.24 (s, 1H), 7.56 (d, J=8 Hz, 2H), 7.50 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.28 (d, J=4 Hz, 1H), 7.27 (s, 1H), 6.96 (d, J=12 Hz, 1H), 3.62 (s, 3H), 3.46 (s, 3H).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH2:17])[C:10]=2[CH:9]=1.C(N(CC)CC)C>C1COCC1>[F:7][C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:17][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[C:10]=2[CH:9]=1
Reactant: NC1CCCCc2ccc(F)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC1CCCCc2ccc(F)cc21
Reaction time: 8 h
Yield: 71.2 %

Procedure:
2.3 g (18 mmol) of ethanesulfonyl chloride were added dropwise with ice-cooling to a solution of 2.68 g (15 mmol) of 3-fluoro-5-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene and 1.5 g (60 mmol triethylamine in 40 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the precipitated product was filtered off with suction. 2.9 g of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene were obtained, m.p. 118-121° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[S:22][CH:23]=1>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[N:20]=2)=[CH:29][CH:28]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(-c2ccc(Cl)cc2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole: MS (ES) m/z 432 (M+1) and 434 (M+1, isotope).
Reaction SMILES: [CH3:1][OH:2].[C:3]1([N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(N(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41](Cl)(=[O:44])[CH:42]=[CH2:43]>C1C=CC=CC=1>[CH3:1][O:2][C:41](=[O:44])[CH:42]=[CH2:43].[C:16]1([N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CO
Reactant: C=CC(=O)Cl
Agent: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C=CC(=O)OC

Procedure:
(Procedure 1): Triphenylamine methyl alcohol as a triphenylamine derivative and an acrylic acid chloride were dissolved in benzene, and then the resultant benzene solution was stirred at 0° C. for five hours so as to cause the triphenylamine methyl alcohol to react with the acrylic acid chloride. After the reaction, the benzene solution was evaporated under reduced pressure so as to obtain a triphenylamine methyl acrylate monomer as a crude crystal. Next, the crude crystal was recrystallized by benzene for purification. The reaction scheme of the triphenylamine methyl alcohol and the acrylic acid chloride is shown in Scheme 1.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]1[N:5]=[C:6]([C:15]([OH:29])(C)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Sn](C)(C)C)=[CH:19][C:18]=2[F:27])[N:7]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:8]=1.Br[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=1>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:31][C:2]([CH3:30])([CH3:1])[CH2:3][C:4]1[N:5]=[C:6]([C:15](=[O:29])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=3)=[CH:19][C:18]=2[F:27])[N:7]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:8]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc([Sn](C)(C)C)cc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2ccc(F)cn2)cc1F

Procedure:
Palladium tetrakis(triphenylphosphine) (42 mg, 0.04 mmol) was added to a degassed, ambient temperature solution of 4-(2,2-dimethylpropyl)-2-{2-[2-fluoro-4-(trimethylstannyl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (200 mg, 0.37 mmol) and 2-bromo-5-fluoropyridine (129 mg, 0.74 mmol) in 1,4-dioxane (5 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CSc1ncc2ncnc(O)c2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1

Procedure:
This compound may be obtained in the following way: a mixture of 10 g 4-hydroxy-6-methylthio-pyrimido[5,4-d]pyrimidine, 16 ml hexamethyldisilazane, 32.5 g 3-chloro-4-fluoro-aniline and 1 g p-toluenesulphonic acid hydrate are heated at boiling point for 12 hours. Then 500 ml methanol is added and the mixture heated at boiling point for a further hour. The solvents are distilled off in a rotary evaporator, the residue is dissolved in methylene chloride, the solution is extracted with 100 ml 2N sodium hydroxide and dried over magnesium sulfate. After distilling off the solvent in a rotary evaporator the residue is triturated with 200 ml ether, filtered off and washed several times with ether.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C([Li])(C)(C)C.[CH:16](=[O:18])[CH3:17]>C1COCC1.CCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:16]([OH:18])[CH3:17]
Reactant: COCOc1cccnc1
Reactant: CC=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COCOc1cnccc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A solution of 3-(methoxymethoxy)pyridine (9.8 g, 70 mmol) and THF (40 mL) was added to a stirring mixture of tert-butyllithium (91 mL of a 1.7 M solution with pentane, 160 mmol) and THF (100 mL) at −780° C. After 1 h, acetaldehyde (9.9 mL, 180 mmol) was added, and the reaction mixture was stirred for 3 h and then warmed to RT. After 21 h, the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3, the layers were separated, the organic material was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (1:1 hexane-ethyl acetate) to afford 4.6 g (36%) of 1-(3-(methoxymethoxy)pyridin-4-yl)ethanol as a colorless solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:20][CH2:19]1>C(O)(=O)C>[CH2:1]([N:8]([CH2:18][CH2:19][OH:20])[C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1NCc1ccccc1
Reactant: C1CO1
Solvent: CC(=O)O
Product: NC(=O)c1ccccc1N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
o-Benzylaminobenzamide (62 g) was added to a cold solution of 85 ml ethylene oxide in 500 ml acetic acid, the mixture stirred 22 hours at room temperature and concentrated on the rotovap to remove 250 ml acetic acid. The remainder was made alkaline with 10% NaOH and the solid filtered washed with water and recrystallized from 300 ml ethyl acetate to give 48.5 g. product, m.133-7°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:7]([F:17])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:2][CH2:3][CH2:4][C:5]2[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:7]([F:17])[CH:6]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(CCN)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1F
Reaction time: 2 h
Yield: 93.6 %

Procedure:
1 g of methyl 4-(2-aminoethyl)-2-fluorophenoxyacetate hydrochloride is added to a mixture of 30 ml of ethyl acetate, 1.58 g of potassium carbonate and 15 ml of water, and a solution of 0.78 g of 4-chlorophenylsulfonyl chloride in 15 ml of ethyl acetate is added dropwise thereto at room temperature. After the mixture is stirred for 2 hours, the ethyl acetate layer is separated therefrom, washed, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate, isopropylether and n-hexane. 1.39 g of methyl 4-[2-(4-chlorophenyl)sulfonylaminoethyl]-2-fluorophenoxyacetate are obtained as colorless prisms.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28]Cl)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.CN(C=O)C.CC#N.[I-].[Na+].[CH3:45][S:46]([O-:48])=[O:47].[Na+]>Cl.CN(C=O)C>[CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28][S:46]([CH3:45])(=[O:48])=[O:47])[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCl)cc3n2C2CCC2)cc1)C1CC1
Reactant: CS(=O)[O-]
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCS(C)(=O)=O)cc3n2C2CCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
To a solution of {4-[6-(2-Chloro-ethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (800 mg, 1.67 mmol) in 1:4 DMF/CH3CN (8 mL) is added sodium iodide (2.50 g, 16.7 mmol). The resulting mixture was refluxed overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). Organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether and used without further purification. To 4 mL of a DMF solution containing the iodoethyl intermediate (0.56 mmol) was added the sodium methane sulfinate (113 mg, 1.11 mmol), and the reaction was stirred at room temperature overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and concentrated. The mixture was purified over silica gel column (CH2Cl2) to provide 100 mg (35% yield) of {4-[3-Cyano-1-cyclobutyl-6-(2-methanesulfonyl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester, as an off-white powder.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](OC)[C:16]=1[N+:23]([O-])=O)(=[O:3])[CH3:2].[CH3:26][OH:27]>[Pd]>[CH3:26][O:27][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6]1[N:23]=[C:16]3[C:15](=[CH:14][C:5]=1[N:4]2[C:1](=[O:3])[CH3:2])[CH:20]=[CH:19][CH:18]=[CH:17]3
Reactant: CO
Reactant: COc1cccc(C=C2C(=O)c3ccccc3N2C(C)=O)c1[N+](=O)[O-]
Agent: [Pd]
Product: COc1cccc2c1c1nc3ccccc3cc1n2C(C)=O
Reaction time: 3 h
Yield: 53 %

Procedure:
A suspension of 1-acetyl-2-(3-methoxy-2-nitrophenylmethylene)-3-oxo-2,3-dihydroindole from Example 35 (460 mg, 1.36 mmol), 10% Pd/C (70 mg) and MeOH (17 mL) was stirred under H2 at atmospheric pressure (balloon) for 3 hours. Additional Pd/C (70 mg) was added, a fresh balloon of H2 was attached and the mixture was stirred at room temperature overnight. The Pd/C catalyst was filtered over celite and the filtrate was evaporated. The resulting crude yellow product (209 mg, >100%) was purified by LPLC, eluting with CH2Cl2, then CH2Cl2 /EtOAc (3:97), to obtain 208 mg (53%) of the title compound as a colorless solid, Rf 0.47 (hexane-EtOAc 1:1), mp 125.1°-125.8° C.; 1H NMR (CDCl3) δ 9.02 (s, 1H), 8.62 (dd, J=7.6; J=0.8 1H), 8.13 (d, J=8.4, 1H), 7.65 (dt, J=8.0; J=0.8, 1H), 7.59 (d, J=8.4, 1H), 7.53 (m, 2H), 7.11 (d, J=7.6, 1H), 4.18 (s, 3H), 2.97 (s, 3H); 13C NMR (CDCl3) δ 169.8, 155.2, 146.5, 141.4, 138.1, 131.9, 130.5, 128.6, 126.3, 124.3, 124.2, 122.7, 121.6, 120.5, 115.6, 106.7, 56.2, 27.7; MS (EI, m/z) 290 (M+).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C)C)C1C=CC=CC=1>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([CH:1]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: C(=Cc1ccccc1)c1ccccc1
Yield: 72.6 %

Procedure:
1.12 ml (0.005 millimol) of palladium acetate, 7.04 g (50 millimols) of benzoyl chloride, 5.22 g (50 millimols) of styrene and 6.76 g (50 millimols) of N-benzyldimethylamine in 100 ml of p-xylene are stirred for 11.5 hours at 130° C. 6.54 g (63% of theory) of stilbene are obtained. This corresponds to 6,300 mols of stilbene per mol of catalyst.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>C(CC(C)(C)C)(C)C>[CH2:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:23][CH:22]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)CC(C)(C)C
Product: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 127.9 %

Procedure:
Add 6-chloronicotinamide (7.03 g, 44.90 mmol) to a stirred solution of 4-(2-benzylamino-ethyl)-phenol (10.10 g, 44.43 mmol), potassium carbonate (15.35 g, 111.1 mmol), dimethylacetamide (138 mL), and isooctane (16 mL). Using a Dean-Stark trap, heat the reaction to reflux under nitrogen for 6 h. Cool the reaction mixtures to room temperature, filter off the solids, and concentrate most of the solvent off on a rotary evaporator. Take the residue up in ethyl acetate (200 mL) and add 1N hydrochloric acid (200 mL). Stir for 15 minutes and filter off the precipitate washing with ethyl acetate. Dissolve the solid in 400 mL of boiling 1:1 methanol/water. To this solution add 5N sodium hydroxide (35 mL) and allow the solution to cool to room temperature. Filter and wash with water to yield 19.74 g (83%) of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=348.1 (M+1); 1H NMR (CDCl3): 8.58 (d, 1H), 8.15 (dd, 1H), 7.34-7.24 (m, 7H), 7.06 (d, 2H), 6.93 (d, 1H), 6.08 (br s, 2H), 3.82 (s, 2H), 2.92 (t, 2H), 2.84 (t, 2H), 1.33 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>O1CCCC1>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1)[C:19]([CH3:20])=[O:21]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 5-amino-2-benzoxazolinone (3.39 g, 22.5 mmol) and triethylamine (3.17 ml, 22.5 mmol) in dry tetrahydrofuran (50 ml) was dropwise added acetylchloride (1.6 ml, 22.6 mmol). The reaction mixture was stirred for additional 2 hours at room temperature, whereafter the precipitate was filtered off The crystals were treated with water (100 ml), filtered off and washed with water. This treatment left the product as white crystals, M.p. 295°-300° C.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH2:58][S:59][S:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:52](OCC#N)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]>O.C1COCC1>[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH2:58][S:59][S:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:52]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (200 mg, 0.314 mmol) in water (6.25 ml) and a solution of (R)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-A) (454 mg, 1.26 mmol) in THF (3.15 ml) were added to buffer A (113 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then lyophilized. The resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution=100/0→60/40) to afford (2R)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 2m-A) (129 mg, 46%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.S1(CCCC1)(=O)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([NH:18][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: Nc1ccccc1
Solvent: O=S1(=O)CCCC1
Product: c1ccc(Nc2c[nH]c3ncccc23)cc1
Temperature: 180 °C

Procedure:
To 10 mg of 3-bromo-1H-pyrrolo[2,3-b]pyridine 582 was added 0.4 mL of sulfolane and aniline (2-3 equiv). The vial was sealed and heated at 180° C. for 10 minutes. After cooling, the desired compound was isolated by preparative HPLC/MS.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](OCC)(=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.Cl>CCO>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc2ccccc2s1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of 2-aminothiophenol (10.7 mL, 0.1 mol) in diethyl oxalate (27.3 mL, 0.2 mol) is heated at reflux for 4 hr. The solution is cooled to rt and poured into a solution consisting of water (150 mL), conc. HCl (50 mL) and 95% EtOH (70 mL). With stirring, the oil dissolved and a solid formed. The solution is cooled in an ice bath, the solid is collected by vacuum filtration and the solids are washed with a solution consisting of EtOH/water (25/75) to afford a dark solid. This material is purified by crystallization from hot (68° C.) ligroin to yield ethyl 2-benzothiazolecarboxylate (7.5 g, 36%). Elemental analysis for C10H9NO2S: Calc: C, 57.95; H, 4.38; N, 6.76. Found: C, 57.99; H, 4.28; N, 6.78.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)N.[CH3:17][CH:18]([CH3:27])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>C(O)(=O)C>[C:21]1([C:19]2[C:18]([CH3:27])([CH3:17])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]4[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=4)[CH:8]=3)[N:2]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC(C)C(=O)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CC1(C)C(c2ccccc2)=Nc2ccc(C3=NNC(=O)CC3)cc21

Procedure:
3 g. (12.5 mMole) 6-(4-hydrazinophenyl)-2,3,4,5-tetrahydropyridazin-3-one hydrochloride, 2.4 g. (16.2 mMole) α-methylpropiophenone and 40 ml. glacial acetic acid were stirred for 8 hours at 100° C. under an atmosphere of nitrogen. The glacial acetic acid was subsequently distilled off and the residue suspended in water, neutralised and filtered with suction. After recrystallisation from ethanol, there was obtained 1.6 g. (40% of theory) of the title compound; m.p. 200°-201° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(Oc2ccccc2)cc1
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chlorosulfonic acid (26 mL, 0.392 mole) was added dropwise to ice-cooled 4-fluorophenoxybenzene (36.9 grams, 0.196 mole) with mechanical stirring. When addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4-(4fluorophenoxy)benzene-sulfonylchloride (18.6 grams, 33%) was collected by filtration and dried in the air.