Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li][CH2:12]CCC.[CH2:16]([C:20]1[C:24]([CH2:25]Cl)=[C:23]([CH3:27])[O:22][N:21]=1)[CH2:17][CH2:18][CH3:19].C[Si](C=[N+]=[N-])(C)C>C1COCC1.CO.C(OCC)C>[CH3:12][O:9][C:8]([C:4]1[S:3][C:2]([CH2:1][CH2:25][C:24]2[C:20]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:21][O:22][C:23]=2[CH3:27])=[N:6][C:5]=1[CH3:7])=[O:10]
Reactant: [Li]CCCC
Reactant: CCCCc1noc(C)c1CCl
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)OC)s1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
To a stirred solution of 2,4-dimethylthiazole-5-carboxylic acid (1.26 g, 8.0 mmol) in THF (60 mL) at −78° C. and under argon was added BuLi (1.6M in hexanes, 10 mL, 16.0 mmol) dropwise. After 2 h at −75° C. a solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (1.5 g, 8.0 mmol) in THF (10 mL) was added dropwise. After 3.5 h the reaction mixture was quenched with citric acid solution (5%, 30 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated to give the intermediate acid compound as a yellow oil. To a solution of intermediate acid in MeOH (30 mL) and diethylether (14 mL) was added trimethylsilyldiazomethane (2M in diethylether, 12 mL, 24 mmol) under ice cooling. Then the reaction mixture was quenched by addition of acetic acid (conc., 0.7 mL), evaporated and extracted with ethyl acetate. The combined extracts were washed with NaOH (2 N), water, dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, 0 to 4% methanol in dichloromethane) afforded the title compound (1.51 g, 63%) as a yellow oil. MS: m/e=323.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1B(O)O.Br[C:14]1(Br)[NH:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:17][CH:16]=[CH:15]1.[C:27](=[O:30])([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].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>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:7]3[CH:6]=[C:5]([O:8][CH3:9])[CH:4]=[CH:3][C:27]=3[OH:30])[N:19]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(O)c(B(O)O)c1
Reactant: O=C([O-])[O-]
Reactant: BrC1(Br)C=CC=C(c2ccccn2)N1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cc(OC)ccc4O)n3)n2)c1
Yield: 44 %

Procedure:
6,6′-Bis(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared by reaction of 2-hydroxy-5-methoxyphenylboronic acid (650 mg, 3.87 mmol) with 6,6-dibromo-2,2′-bipyridyl (520 mg, 1.64 mmol), sodium carbonate (2N solution, 4 ml) and tetrakis(triphenylphosphine) palladium (40 mg) in ethylene glycol dimethyl ether (16 ml) at reflux under nitrogen for 11 hours. The solid was filtered from the cooled reaction and washed with ether and water. The residue was dissolved in toluene and filtered through a short column of silica, washing through with further toluene. The combined filtrate and washings were concentrated under vacuum to give the desired product as a yellow solid (286 mg, 44%); δH [2H6]-DMSO 8.30,(2H, d), 8.13,(4H, m), 7.56,(2H, s), 6.88,(4H, m), 3.73,(6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:17]([Cl:28])[CH:16]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38].C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[Cl:28][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:36](=[O:39])[CH:37]=[CH2:38])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Sc4ccccc4)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.9 %

Procedure:
Dissolved 1.00 g (2.48 mmol) 6-amino-4-[(3-chloro-4-thiophenoxyphenyl)amino]-3-quinolinecarbonitrile in 2.0 ml DMF and 12 ml THF and chilled to 0° C under N2. Added 380 μl (2.73 mmol) triethylamine and 227 μl (2.73 mmol) acryloyl chloride. Removed ice bath at 15 minutes and at 1.5 hours stripped solvent and slurried residue with dilute sodium bicarbonate. Collected solids and washed with water. Recrystallized from ethyl acetate and dried in vacuo, giving 293 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=457.3. 459.3.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:3]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:18]4[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:16][CH2:17]3)=[O:11])=[N:6][CH:5]=2)=[O:28])[CH2:31][CH2:30]1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Reactant: NC1CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC3CC3)cn2)CC1
Yield: 77 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using cyclopropylamine. And then, the product was recrystallized with isopropanol and petroleum ether to give a desired compound.
Reaction SMILES: [Cl:1]OC(C)(C)C.[Cl-:7].[NH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][N+:11]1([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CO>[Cl-:1].[Cl:7][N:8]([Cl:1])[C:9]([CH3:19])([CH3:18])[CH2:10][N+:11]1([CH3:17])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OCl
Reactant: CC(C)(N)C[N+]1(C)CCOCC1
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C[N+]1(C)CCOCC1)N(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.8 %

Procedure:
tert-Butyl hypochlorite (0.49 mg, 4.5 mmol) was added to a stirred solution of 4-(2-amino-2-methylpropyl)-4-methylmorpholin-4-ium chloride (380 mg, 1.8 mmol) in methanol (25 ml) and stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo, and purified by prep-HPLC to give 64 mg (13% yield) of 4-(2-(dichloroamino)-2-methylpropyl)-4-methylmorpholin-4-ium chloride. 1H NMR (D2O) δ 4.16-3.98 (m, 4 H), 3.86 (s, 2 H), 3.78-3.58 (m, 4 H), 3.43 (s, 3 H), 1.66 (s, 6H); MS (ESI+) calculated for C9H19Cl2N2O+: 241.09, Found: 241 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH2:18][OH:19]>CC#N>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][CH2:17][CH2:18][OH:19])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCCO)c1
Temperature: 75 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a stirred solution of 4-nitro-1H-pyrazole (27) (1.0 g, 8.9 mmol) in MeCN (15 mL) was added K2CO3 (1.8 g, 13.2 mmol) and 3-bromo-propanol (880 μL, 9.7 mmol). The mixture was stirred at 75° C. for 6 hours. The solvent was evaporated in vacuo and the residue partitioned between H2O (15 mL) and EtOAc (15 mL). The layers were separated and the aqueous phase extracted with EtOAc (2×15 mL). The combined organics were dried (MgSO4), filtered and the solvent evaporated in vacuo to afford the title compound as a pale yellow oil (1.41 g, 93%); LCMS, Rt=1.31 min (MeOH-FA method), m/z 172 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([CH3:22])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[H][H]>C(O)(=O)C.[Pt]=O>[ClH:1].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[NH:21][C:20]([CH3:22])=[N:19][CH2:18][C:7]=3[CH2:8][NH:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC1=NCC2=C(N1)c1ccc(Cl)cc1C(c1ccccc1Cl)NC2
Product: Cl

Procedure:
A solution of 3.8 g (10.7 mmole) of 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d][2]benzazepine in 50 ml of acetic acid was hydrogenated at room temperature and atmospheric pressure in the presence of 0.5 g of prehydrogenated platinum oxide. After 3 hours about 500 ml (ca 2 equivalent) of hydrogen was absorbed and the catalyst was separated by filtration. The filtrate was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride, washed with an excess of dilute ice cold sodium hydroxide, and dried over anhydrous sodium sulfate. The methylene chloride solution was diluted with an excess of methanolic hydrogen chloride and concentrated at reduced pressure. The residue was triturated with isopropanol and the crude product was collected by filtration. Recrystallization from methanol gave the pure product, m.p. 275°-276° C.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:9]([Zn]CC)C.ClCI>ClCCCl.CCCCCC.CCOC(C)=O.Cl>[C:1]12([CH2:7][OH:8])[CH2:9][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: OCC1=CCCCC1
Reactant: CC[Zn]CC
Agent: Cl
Agent: ClCI
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: OCC12CCCCC1C2
Reaction time: 0.17 h

Procedure:
To a solution of cyclohex-1-en-1-ylmethanol (0.6 g, 5.35 mmol) in DCE (5 mL) at 0° C., was added 1 N diethylzinc in hexane (8.56 mL), the reaction mixture was stirred for 10 min, then chloroiodomethane (1.242 ml, 17.12 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h, and then stirred at rt for 16 hr. The reaction was diluted with EtOAc and 1 N HCl, the organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was charged to a 25 g silica gel cartridge which was eluted with a 20 min gradient of 0-40% EtOAc in hexane to afford bicyclo[4.1.0]heptan-1-ylmethanol (0.12 g). 1H NMR (400 MHz, CDCl3) ppm 3.27-3.38 (2H, m), 1.81-1.92 (2H, m), 1.54-1.78 (2H, m), 1.11-1.37 (4H, m), 0.81 (1H, dddd, J=9.16, 7.22, 5.46, 1.51 Hz), 0.46 (1H, dd, J=9.29, 4.52 Hz), 0.24 (1H, t, J=5.02 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH:28]=O)=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O>C(O)(=O)C.C(O)C.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[CH:28][CH:27]=[CH:26]4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=CC=O)c3O2)cc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4ncccc4c3O2)cc1

Procedure:
To a solution of {(2R)-7-nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (3.50 g, 8.35 mmole) in 200 mL of acetic acid/ethanol (1:1) was added 2.35 g (42.1 mmole) of iron powder and the mixture was heated at reflux under nitrogen for 8 hours. After the reaction was complete, 150 mL of water was added and the mixture filtered through a pad of celite. The filtrate was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and evaporated in vacuum. The residue was column chromatographed on silica gel using a gradient elution commencing with 20% ethyl acetate/hexane and ending with 70% ethyl acetate/hexane to give 1.85 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 8.8 δ (1 H); doublet 8.2 δ (1 H); doublet 7.8 δ (2 H); doublet 7.6 δ (1 H); multiplet 7.35 δ (1 H); multiplet 7.25 δ (3 H); multiplet 4.6 δ (1 H); multiplet 4.3-4.4 δ (3 H); multiplet 4.2 δ (1 H); singlet 2.4 δ (3 H).
Reaction SMILES: C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[C:25]2[N:26]=[C:27]([N:35]([CH3:37])[CH3:36])[N:28]=[C:29]([C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)[C:24]=2[S:23][CH:22]=1.C([Sn](CCCC)(CCCC)[C:43]1[O:44][CH:45]=[CH:46][CH:47]=1)CCC.O>CN(C=O)C>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:29]1[C:24]2[S:23][CH:22]=[C:21]([C:43]3[O:44][CH:45]=[CH:46][CH:47]=3)[C:25]=2[N:26]=[C:27]([N:35]([CH3:37])[CH3:36])[N:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CN(C)c1nc(-c2ccco2)c2scc(Br)c2n1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1nc(-c2ccco2)c2scc(-c3ccco3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A mixture of AsPh3 (73 mg, 0.24 mmol) in DMF (2 mL) was treated with Pd(OAc)4 (13 mg, 0.06 mmol), stirred at room temperature for 10 min, treated with 7-bromo-N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (194 mg, 0.6 mmol) and 2-(tributylstannyl)-furan (340 μL, 1.1 mmol), heated to 100° C. for 16 h, cooled, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:9) to give the title compound (27 mg, 15%) as a orange solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:23]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2].O>[N:27]1([C:23](=[O:26])[CH:24]=[CH:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: Ic1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1
Reactant: C=CC(=O)N1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1)N1CCOCC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of (4-iodo-phenyl)-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.265 g, 0.65 mmol) in 2 mL dimethylformamide was added 4-acryloylmorpholine (0.110 g, 0.78 mmol), Pd(OAc)2 (0.029 g, 0.13 mmol), and triethylamine (0.20 mL, 1.43 mmol). The reaction was stirred at 90° C. for 2 hr. Triphenylphosphine (0.101 g, 0.38 mmol) and additional Pd(OAc)2 (0.032 g, 0.14 mmol) were added and the reaction mixture was stirred at 90–100° C. for 18 hr. The reaction mixture was cooled, water was added, and the aqueous solution was washed ethyl acetate (3×). The combined organic layers were dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (33% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded the title compound of Step A. MS 423.0 (M+1)+
Reaction SMILES: C([C:3]1[CH:4]([C:9]([O:11]CC)=[O:10])C[CH2:6][CH2:7][CH:8]=1)#N.[OH-:14].[K+].[CH2:16]([OH:18])[CH3:17]>>[CH:3]1[CH2:8][CH2:7][CH2:6][CH:17]([C:16]([OH:14])=[O:18])[C:4]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C1CCCC=C1C#N
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Product: O=C(O)C1=CCCCC1C(=O)O

Procedure:
A stirred solution of 12.0 grams (0.067 mole) of ethyl 2-cyanocyclohex-2-enecarboxylate (prepared by the method of G. Kon and B. Nandi, JCS, 1628-1633 (1933), and 75 ml of aqueous 30% potassium hydroxide in approximately 20 ml of ethanol was heated under reflux for 16 hours. The reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was cooled in an ice bath, and the pH was adjusted to 2 with sulfuric acid. The resultant precipitate was collected by filtration and was dried to yield 5.0 grams of cyclohexene-2,3-dicarboxylic acid; m.p. 201°-203° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][N:11]([C@H:19]([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:42]([C:45]1[S:49][CH:48]=[C:47]([C:50]([N:52]2[CH2:57][C:56]3([CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)[O:55][CH2:54][CH2:53]2)=[O:51])[CH:46]=1)([CH3:44])[CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O.C(O)(=O)C.CN1CCCC1=O>[Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][N:11]([C@H:19]([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:60]2[CH2:59][CH2:58][C:56]3([O:55][CH2:54][CH2:53][N:52]([C:50]([C:47]4[CH:46]=[C:45]([CH:42]([CH3:44])[CH3:43])[S:49][CH:48]=4)=[O:51])[CH2:57]3)[CH2:62][CH2:61]2)[CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: C[C@H](Cc1cccc(C=O)c1)N(C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(C[C@@H](C)N(C[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)C(=O)OC(C)(C)C)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (R)-2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl((R)-1-(3-formylphenyl)propan-2-yl)carbamate (Example 276, step i) (0.476 g) was treated with (5-isopropylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (Example 275, step i) (0.296 g), N-methyl-2-pyrrolidinone (20 mL), acetic acid (0.052 mL) and sodium triacetoxyborohydride (0.294 g), and the mixture was stirred at room temperature overnight. The solution was poured into a mixture of saturated sodium bicarbonate solution and water and extracted three times with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo, then purified by flash chromatography on silica eluted with 1:5:94 NEt3:MeOH:DCM to afford the subtitled compound. Yield 0.471 g.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: C1CCNCC1
Reactant: CC#CCOc1ncnc(Cl)c1F
Solvent: CCO
Product: CC#CCOc1ncnc(N2CCCCC2)c1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.2 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.38 g of piperidine was added therein, and the mixture was stirred for 7 hours under reflux condition. The reaction mixture was cooled to near room temperature and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.37 g of 4-(2-butynyloxy)-5-fluoro-6-piperidinopyrimidine (hereinafter, referred to as Compound (2)).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1.O>C(Cl)Cl>[CH:12]([CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1)=[O:11]
Reactant: O=C(OCc1ccccc1)N1CCC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: O=CC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DMSO (597 μL, 8.42 mmol) was added to a solution of oxalyl chloride (427 μL, 5.05 mmol) in DCM (25 mL) at −78° C. After 5 minutes, benzyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (generated in Step 1) was added. The reaction was continued for 30 minutes at −78° C. TEA (2.3 mL, 17 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over the course of 30 minutes. Water was then added. The layers were separated and the organic phase was washed sequentially with 0.1 N HCl, water, saturated NaHCO3, and brine. The organic phase was then dried over sodium sulfate and the solvent was removed in vacuo to afford the product (0.82 g, 88% over two steps).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22]C)[N:13]3[CH2:16][CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1.Cl.O.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:22])[N:13]2[CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CC1CCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To a solution of 2-[(2-cyclopropylethyl)oxy]-8-methoxy-9-(tetrahydro-3-furanylmethyl)-9H-purin-6-amine (103.8 mg) in methanol (5 mL) was added 4N HCl in 1,4-dioxane (2 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction was evaporated under reduced pressure to give a gum. Water (3 mL) was added to give a white solid. The mixture was adjusted to pH 7 by adding 2N sodium hydroxide solution and the white solid was filtered off under suction, then washed with a few drops of MeOH. The material was air dried under suction, then in a vacuum oven (50° C.) to give the title compound as white solid (77 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.[C:27](=O)([O-])[O-:28].[Na+].[Na+]>C1(C)C(C)=CC=CC=1.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.COC1C=CC(P(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)=CC=1>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:3]=2)=[O:28])=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cccc(Oc2cccc(Cl)n2)c1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc(F)cc1)c1cccc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C
Reaction time: 21 h
Yield: 112.2 %

Procedure:
10.26 g (37.5 mmol) of 2-chloro-6-[3-(trifluoromethyl)phenoxy]pyridine (content: 99.5 percent, prepared according to Example 1), 6.25 g (56.2 mmol) of 4-fluoroaniline, 4.37 g (41.3 mmol) of sodium carbonate, 26.3 mg (37.5 μmol) of dichlorobis(triphenylphosphine)palladium(II) and 0.40 g (1.125 mmol) of tris(4-methoxyphenyl)phosphine (IV, R8 =R9 =R10 =methoxy) in 37.5 ml of xylene were placed in an autoclave at room temperature. The autoclave was flushed with inert gas, a carbon monoxide pressure of 5 bar was then applied and the mixture was heated to 150° C. The CO pressure was raised to 18 bar and the mixture was stirred for 21 hours at 150° C. After cooling to room temperature and depressurization, 50 ml of xylene and 50 ml of water were added to the reaction mixture, which was filtered. The aqueous phase was extracted with 25 ml of xylene and the combined organic phases were washed with 30 ml of water. Neither unconverted educt nor by-products were detectable by GC in the xylene phase. After distillation of the solvent, the crude product (15.83 g) was obtained in the form of a yellow solid. The crude product was purified by recrystallization from methylcyclohexane. The yield was 12.13 g (86 percent) of a light beige solid. Other data concerning the product was: