Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2].[C:32](C1C=CC([C@@H]2C(C#N)=C(C)N(C3C=CC=C(C(F)(F)F)C=3)C(=O)N2)=C([S@](C)=O)C=1)#N.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:32])=[C:5]([S@:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[S@](C)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[S@](C)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
The reaction was carried out under argon. The diastereomer mixture of (RS,4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile and (SS,4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (535 mg, 1.2 mmol) was initially charged in absolute THF (12 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (1.45 ml; 1.2 eq.) was added at −78° C. After 20 min of stirring at −78° C., iodomethane (854 mg; 5 eq.) was added and the mixture was stirred for 16 h with gradual warming from −78° C. to RT. The reaction mixture was then concentrated under reduced pressure, saturated ammonium chloride solution (50 ml) was added and the mixture was then extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over solid sodium sulfate, filtered and concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a solid (488 mg, 88% of theory).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.CC(C)=O>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:4][CH:3]=1
Reactant: COc1ccccc1Cc1ccc(Cl)nn1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(C)=O
Product: Oc1ccccc1Cc1ccc(Cl)nn1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
2-(6-Chloro-3-pyridazinylmethyl)anisole (prepared as described in Example 33(c)) (2.35 g) was dissolved in dry dichloromethane (20 ml) and cooled with stirring to -50°. Boron tribromide (3 ml) was then added dropwise, and the solution was allowed to warm to room temperature. After 0.5 hours the orange reaction mixture was poured into ice/water (200 ml) and acetone added to dissolve the precipitated solid. The mixture was extracted with dichloromethane, the organic extracts were separated, washed with water, dried, and evaporated. The residue was recrystallised from ethyl acetate and petroleum spirit to give 2-(6-chloro-3-pyridazinylmethyl)phenol (1.75 g, 80%), m.p. 132-132.5°.
Reaction SMILES: [C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][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][CH2:21][CH3:22].[Ag+:25].[Br:26]N1C(=O)CCC1=O>CC(C)=O>[Ag:25][Br:26].[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][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][CH2:21][CH3:22].[Ag+:25]
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Solvent: CC(C)=O
Product: Br[Ag]

Procedure:
While the polymer dispersion of silver behenate was maintained at 50° C. and was being stirred at 500 rpm, an acetone solution of N-bromosuccinimide (0.7 g of N-bromosuccinimide+50 ml (25° C.) of acetone) was added. The mixture was stirred further for 60 minutes to form a polymer dispersion of silver bromide and silver behenate.
Reaction SMILES: S([O:5][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][NH:20][C:21]([C:23]1[CH:24]=[N:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1)=[O:22])(C)(=O)=O.[N+:36]([O-])([O-:38])=[O:37]>C1(C)C=CC=CC=1>[O:5]([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][NH:20][C:21]([C:23]1[CH:24]=[N:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1)=[O:22])[N+:36]([O-:38])=[O:37]
Reactant: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCCCOS(C)(=O)=O)cn2)CC1
Reactant: O=[N+]([O-])[O-]
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCCCO[N+](=O)[O-])cn2)CC1

Procedure:
To a solution of N-(14-mesyloxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide in toluene was added Amberlyst A-26 (a nitrate form) and the mixture was heated under reflux for 3 hours. The ion-exchange resin was filtered off and the filtrate was distilled off. The residue thus obtained was chromatographed over a silica gel column to afford 0.85 g of the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12]C(C)(C)C)=[O:11])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:18]=[CH:17][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C2CCCO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(C2CCCO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of tert-butyl 4-(tetrahydrofuran-2-yl)benzoate (350 mg, 1.41 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated to give 4-(tetrahydrofuran-2-yl)benzoic acid (200 mg, 74%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([SH:21])[CH:17]=[C:18]([Cl:20])[CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=2)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1nc(Sc2cc(Cl)cc(Cl)c2)ccc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 6-chloro-3-nitropicolinonitrile (3.70 g, 0.02 mol), 3,5-dichlorobenzenethiol (3.60 g, 0.02 mol) and K2CO3 (5.6 g, 0.04 mol) in 100 ml of acetonitrile is carried at 70° C. for 16 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using an aqueous phase. The organic phase is dried with sodium sulfate and the residue is purified by silica gel chromatography (AcOEt/petroleum ether) to yield 5.4 g (80%) of a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]2)[CH2:18][CH2:17]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:17][CH2:18][CH:19]([CH2:22][N:23]3[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]3)[CH2:20][CH2:21]2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN2CC[C@@H](F)C2)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1NC1CCC(CN2CC[C@@H](F)C2)CC1
Yield: 68.4 %

Procedure:
Following general procedure II, 1-(6-chloro-4-((4-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone (58 mg, 0.143 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (62 mg, 0.21 mmol) to afford the desired product (52 mg, 60%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.12 (s, 2H), 5.74-5.69 (m, 1H), 5.53-5.43 (m, 1H), 4.12-3.84 (m, 2H), 3.31-3.17 (m, 2H), 2.76 (s, 3H), 2.50-2.43 (m, 2H), 2.18-1.96 (m, 3H), 1.74-1.62 (m, 2H), 1.50-1.38 (m, 2H); ESI MS m/z 531 [M+H]+; HPLC 96.7% (AUC), tR=10.05 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH:16][NH2:17])=[O:15])#[N:12]>C(O)C.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[C:13]([C:11]#[N:12])[C:14]([NH:16][NH2:17])=[O:15]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: N#CCC(=O)NN
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc(O)c(O)c1)C(=O)NN
Yield: 50.2 %

Procedure:
To 0.69 g (5 mmol) 3,4-dihydroxybenzaldehyde and 0.55 g (5.5 mmol) cyanoacethydrazide in 40 ml ethanol was added 2 drops piperidine. After 21/2 hours of reflux, the reaction mixture was cooled, filtered and washed with cold ethanol to give 0.55 g (50% yield) of product, an orange solid, m.p. 220° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[S:5][CH:6]=1.[Cu](C#N)[C:17]#[N:18].N>CN(C)C=O.CCOCC>[Si:9]([O:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:17]#[N:18])[CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: N#C[Cu]C#N
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)cs1
Agent: N
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C#N)cs1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of [(4-bromo-2-thienyl)methoxy]t-butyldimethylsilane (9.0 g, 29 mmol) [reference literature: J. Med. Chem., vol. 45, 5005 (2002)] in N,N-dimethylformamide (20 ml) was added copper cyanide (4.7 g, 53 mmol) with stirring, and the resulting mixture was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ether (80 ml), and after adding a 28% aqueous solution of ammonia (50 ml), the resulting mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was extracted with ether, and the extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:50 to 1:4) as the eluent to afford the title compound (4.3 g) in a yield of 58% as a colourless oily product.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])[CH3:3].[ClH:24].[O:25]([NH2:27])[CH3:26].N1C(C)=CC=CC=1C>C1COCC1>[ClH:24].[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]([NH:27][O:25][CH3:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])([CH3:4])[CH3:3]
Reactant: CON
Reactant: CC(C)(C)c1cc(C(Br)c2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CONC(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 24 h

Procedure:
Over a 20 minute period a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-α-phenylbenzyl bromide, Example 17, (6.23 g, 0.0166 mole) in 100 mL THF is added to a mixture of methoxylamine hydrochloride (4.18 g, 0.05 mole) and 5.62 g (0.0524 mole) of 2,6 lutidine in 175 mL THF. The reaction mixture is heated under reflux for 16 hours. An additional 5.62 g (0.0524 mole) of 2,6 lutidine and 2.0 g (0.0239 mole) of methoxylamine hydrochloride is added and reflux is continued for 24 hours. The mixture is evaporated to dryness and the residue is taken up in Et2O, washed with H2O, 1N HCl, saturated NaHCO3 and brine. After evaporation to dryness the residue is treated with 5 mL of 20% ethereal HCl (w/v). Creamy white crystals form and are filtered off and recrystallized from EtOAc-Et2O to give an off-white solid, 3.6 g (57 %), m.p. 183°-185° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([F:22])[C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[F:22][C:21]1[C:15]2[C:16](=[N:17][N:13]([CH2:9][CH2:10][C:11]#[C:12][C:2]3[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=3)[N:14]=2)[CH:18]=[C:19]([F:23])[CH:20]=1
Reactant: Nc1cccc(Br)n1
Reactant: C#CCCn1nc2cc(F)cc(F)c2n1
Product: Nc1cccc(C#CCCn2nc3cc(F)cc(F)c3n2)n1
Yield: 62.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 6-bromo-pyridin-2-ylamine (60 mg, 0.35 mmol) and 2-but-3-ynyl-4,6-difluoro-2H-benzo[d][1,2,3]triazole (72 mg, 0.35 mmol, Example 135(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 1:1) to yield 65 mg (0.22 mmol, 63%) of 6-(4-(4,6-difluoro-2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-amine as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:13])[CH:5]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN1CCOCC1.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Nc1cc(=O)[nH]c(N)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1

Procedure:
A stirred suspension of 500 g of methyl 2-amino-1,6-dihydro-6-oxo-4-pyrimidinecarbamate in 1.45 l of N-methylmorpholine and 9 l of methylene chloride is heated to reflux temperature. Subsequently, 815 g of toluene-4-sulfonyl chloride are added thereto and the mixture is stirred at reflux for 16 hours. The mixture is evaporated at 40° in a water-jet vacuum and the residue is treated with 9 l of water. The insoluble material is filtered off under suction and washed firstly with 5 l of water and thereafter with 5 l of ether. After drying at 40° in vacuo, there is obtained light brown methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate of melting point 188°-190°. A sample recrystallized from acetonitrile has a melting point of 190°-192°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:42][CH3:43])=[C:39]([OH:41])[CH:40]=1.Cl>C(O)(C)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([O:42][CH3:43])=[C:39]([OH:41])[CH:40]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: COc1ccc(N)cc1O
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1O

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (prepared according to a procedure similar to that described in Example 27, Step C) and 5-amino-2-(methyloxy)phenol were heated in isopropanol with catalytic conc. aq. HCl using conditions similar to those described in Example 27, Step D. HRMS C31H23N6O3F2 (M+H)+ calcd 565.1794, found 565.1795.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1F>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:8][CH:6]1[CH2:7][N:2]([CH3:1])[CH2:3][C:4]2[O:11][CH:10]=[CH:9][C:5]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CN1Cc2occc2C(O)C1
Product: CN1Cc2occc2C(Oc2cccc(Cl)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[OH-].[Li+]>CO.O>[F:14][CH:2]([F:1])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(F)F)[nH]c1=O

Procedure:
7.4 g (36.4 mmol) of methyl 6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 100 ml of methanol, and a solution of 1.3 g (54.6 mmol) of lithium hydroxide in 50 ml of water was added. After two hours of heating under reflux, the mixture was concentrated to a volume of about 50 ml and the solution was washed with dichloromethane. The aqueous phase was then acidified with 2N hydrochloric acid and extracted with ethyl acetate. Drying and concentration of the extract gave 5.6 g (82% of theory) of a brownish powder.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:18]([Sn](=O)CCCC)[CH2:19][CH2:20]C.C([C@@]1(O)[C@H](OCCCC)[C@@H](C(=[SnH2])O)O[C@H]1N1C=CC(=O)NC1=O)CCC.ICCC>>[CH2:18]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])[CH2:19][CH3:20]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCC[Sn](=O)CCCC
Agent: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Solvent: CCCI
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
As per the procedure of Example 49, uridine (10 g) was treated with dibutyl tin oxide (10.2 g, 1 eq). The resulting 2′,3′-O-dibutylstannylene uridine was treated with iodopropane (8 ml, 2 eq.) at 110° C. as per Example 50 to give a mixture of the 2′ and 3′ isomers (5.5 g) as a foam.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:14]([C:13]1[CH:12]=[C:11]([C:10]2[N:9]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:8]=[C:7]3[C:6]=2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]3[CH3:1])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (step 4) (300 mg, 1.07 mmol), methyl 4-bromobutanoate (291 mg, 1.61 mmol) and cesium carbonate (697 mg, 2.14 mmol) in DMF (4 mL) was stirred at 80° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and was washed with 1M HCl (3×10 mL). After the third wash, the mixture was concentrated in vacuo. The residue was triturated with diethyl ether and dried under vacuum at 50° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(C)C)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(N(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-dimethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (144 mg, 0.35 mmol, see step (b) Example 16) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 70 mg (35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:16]#[C:17][CH3:18]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:18][C:17]#[CH:16])[CH:3]=1
Reactant: CC#CBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
3-Fluorophenol (5.10 g, 45.5 mmol) was dissolved in DMF (10 mL) and potassium carbonate (7.55 g, 54.6 mmol) was added and the mixture was stirred at ambient temperature for 30 minutes. Bromoprop-1-yne (5.05 mL, 45.5 mmol) was added and the reaction was stirred overnight at ambient temperature. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated under reduced pressure to give a yellow oil (7.27 g) that was used without further purification in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.30-7.23 (m, 1 H), 6.81-6.69 (m, 3 H), 4.70 (d, J=2.3 Hz, 2 H), 2.56 (t, 1 H); LCMS (m/z) ES+=151 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.Cl.[NH2:14][OH:15].C(O)(=O)C>O>[Cl:1][C:2]1[C:7]([CH:8]=[N:14][OH:15])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: NO
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(Cl)c(C=NO)c(Cl)n1
Temperature: 60 °C

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (7.34 g, 33.09 mmol), hydroxylamine hydrochloride (2.31 g, 33.33 mmol), acetic acid (49.6 mL), and water (3.3 mL) were mixed, and heated to 60° C. for 2 hours. The reaction mixture was diluted with water and cooled under ice bath. The precipitate was collected and dried (Yield=6.41 g, 82%). MS (m/z): 238 (M+H).
Reaction SMILES: [C:1]12([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([NH:15][C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][CH:17]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 mL of THF was added to 400 mg (1.76 mmol) of 4-(adamantan-1-yl)aniline, after which 292 mg (2.11 mmol) of potassium carbonate was added. 291 mg (1.94 mmol) of ethyl chloroglyoxylate was added at 0° C., and the mixture was stirred at room temperature for 2 hours. Thereafter, the mixture was filtered using silica gel, and the filtrate was condensed. The obtained crude product was then separated and purified by silica gel column chromatography, thereby quantitatively giving ethyl {[4-(adamantan-1-yl)phenyl]amino}(oxo)acetate.