Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[C:11]([NH2:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:20]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:14]([O:13][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10][C:11]=1[NH:17][C:29](=[O:30])[CH:28]([N:20]1[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[N:23]=[C:19]1[CH3:18])[CH3:32])([CH3:15])[CH3:16]
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Reactant: CC(C)Oc1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A mixture of crude 1-(4-fluorophenyl)-5-isopropoxy-pyrazol-4-amine (prepared in step b, 0.032 g, 0.13 mmol), 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.031 g, 0.13 mmol), HATU (0.057 g, 0.13 mmol), and 100 μL of Et3N in 1 mL of CH2Cl2 was stirred at room temperature. After 30 min, the reaction mixture was diluted with 10 mL of aqueous saturated sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) provided the title compound as a colorless solid (0.030 g, 0.068 mmol, 52% for 3 steps). 1H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.70 (s, 1H), 7.68-7.57 (m, 2H), 7.30-7.19 (m, 2H), 5.16 (q, J=6.5 Hz, 1H), 4.26 (he, J=6.1 Hz, 1H), 2.47 (s, 3H), 1.80 (d, J=6.5 Hz, 3H), 1.14 (d, J=6.1, 6 H). MS: (ES) m/z calculated for C20H21F4N5O2 [M+H]+ 439.2, found 439.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][NH:11][N:10]=1.[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[N:10]=1
Reactant: CC(C)c1nnc2ccc(-c3c[nH]nc3-c3ccc(F)cc3F)nn12
Reactant: OC1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(-c3cn(C4CCOCC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
The 6-(3-(2,4-difluorophenyl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.30 g, 0.88 mmol) in THF (4 mL) was treated with tetrahydro-2H-pyran-4-ol (0.12 g, 1.1 mmol; Example #L.1.1) and Ph3P (0.35 g, 1.3 mmol). Diethyl azodicarboxylate (40 wt % in toluene, 0.52 mL, 1.32 mmol; TCI) was then added and the mixture stirred at ambient temperature for about 1 h. The reaction was concentrated under reduced pressure and then purified by silica gel chromatography using EtOAc/MeOH (stepwise gradient, 95:5 then 9:1) to isolate lower Rf major product with impurities. The material was purified further by RP-HPLC (Table 1, Method d). Concentration of the desired fractions under reduced pressure resulted in a solid that was collected by filtration and then dried to give the title compound (0.063 g, 17%) as a white solid: LC/MS (Table 1, Method a) Rt=2.40 min; MS m/z: 425.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][C@@H:19]([OH:37])[CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[C:29]=3[CH3:36])[CH2:23][CH2:22]2)=[O:16])=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][C@@H:19]([OH:37])[CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[C:29]=3[CH3:36])[CH2:25][CH2:26]2)=[O:16])=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(OC2CCN(C[C@H](O)CNC(=O)c3ccc(Cl)c(C(=O)OC(C)(C)C)c3)CC2)ccc(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(OC2CCN(C[C@H](O)CNC(=O)c3ccc(Cl)c(C(=O)O)c3)CC2)ccc(Cl)c1Cl
Reaction time: 1.5 h

Procedure:
tert-Butyl 2-chloro-5-[({(2R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)carbonyl]benzoate (0.14 g) in DCM (5 mL) was treated with trifluoroacetic acid (1.5 mL) and the mixture was stirred for 1.5 h. The solvent was evaporated. The product was purified by RPHPLC (Symmetry, 0.1% ammonium acetate/acetonitrile) to yield the title compound as a white solid. (0.05g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:20](Cl)[N:19]=[C:18]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C(C)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:20]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:16]([Cl:15])[N:17]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:19]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 50 °C
Yield: 92 %

Procedure:
44 g (0.21 moles) of 4-tert-butyl-benzenesulfonamide, 72 g (0.21 moles) of 4,6-dichloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidine and 0.7 g of tetrabutylammonium bromide are added to a suspension of 35 g (0.25 moles) of potassium carbonate in 720 ml of methyl isobutyl ketone (MIBK), kept in an inert atmosphere (nitrogen). Once the addition is complete, the suspension is heated to reflux, operating so as to azeotropically remove the water that forms during the reaction. The reaction is kept at reflux for 5 hours. Once the reaction is complete, the suspension is cooled to 50° C. and diluted with 0.2 liters of water. Hydrochloric acid 35% is then added until obtaining a pH between 2.0 and 3.0. The suspension is cooled to 5° C./10° C. and the product is left to crystallise for 10 hours. The suspension is filtered and 120 g in wet form of the title compound are obtained equal to 100 g in dry form (0.19 moles) (yield 92%; purity 99.6% HPLC).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH:20][CH2:21][CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:18]([N:20]([CH2:21][CH:22]([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: CCNCC(OCC)OCC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OCC

Procedure:
4-Chloro-3,5-dinitrobenzotrifluoride (5.4 grams; 0.02 mole) dissolved in toluene (50 ml) and a solution of N-ethyl-N-(2,2-diethoxyethyl)amine (3.2 grams; 0.02 mole) and triethylamine (2.02 grams; 0.02 mole in toluene (50 ml) were charged into a glass reaction vessel equipped with stirrer, thermometer and reflux condenser. The mixture was heated at reflux overnight resulting in the formation of a precipitate. The reaction mixture was then filtered and the filtrate was washed with water, dried and stripped of solvent to yield the desired product N-ethyl-N-(2,2-diethoxyethyl)-2,6-dinitro-4-trifluoromethylaniline.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:19]([CH:25]([CH3:27])[CH3:26])=[N:20][CH:21]=[CH:22][C:23]=1[Cl:24]>CN(C=O)C>[Cl:24][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([CH:25]([CH3:26])[CH3:27])[C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CC(C)c1nccc(Cl)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(Cl)ccnc2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (434 mg, 3.0 mmol) was dissolved in anhydrous DMF (15 mL), and then potassium carbonate (1.27 g, 9.2 mmol) and 3-(bromomethyl)-4-chloro-2-(propan-2-yl)pyridine (4.0 mmol) in DMF (5 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 5-10% DCM/MeOH to afford 2-({[4-chloro-2-(propan-2-yl)pyridin-3-yl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (239 mg, 25% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, J=6.7 Hz, 6H), 2.23 (bs, 3H), 3.50-3.57 (m, 1H), 4.65 (s, 2H), 6.00 (bs, 1H), 7.43 (d, J=5.2 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[C:5]([O:8][CH2:9][C:10]([CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:11])(=[O:7])[CH3:6]>C1COCC1>[C:14]([O:13][CH2:12][C:10]([C:1]#[CH:2])([OH:11])[CH2:9][O:8][C:5](=[O:7])[CH3:6])(=[O:16])[CH3:15]
Reactant: C#C[Mg]Br
Reactant: CC(=O)OCC(=O)COC(C)=O
Solvent: C1CCOC1
Product: C#CC(O)(COC(C)=O)COC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
An ethynylmagnesium bromide solution (0.5 M in THF) was cooled to −78° C. under nitrogen. A solution of 1,3-diacetoxyacetone (0.5 g) in THF (3.0 mL) was added, and the resulting mixture was stirred for 30 min at −78° C., then at 0° C. for 5 min, quenched with 1.0 N aq. HCl (3 mL) and extracted in EtOAc. Evaporation gave crude 2-ethynyl-2-hydroxypropane-1,3-diyl diacetate, contaminated with about 50 mol % of 1,3-dacetoxyacetone. The crude material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](Br)[CH3:10])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl.[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH2:25]>C(OCC)(=O)C>[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH:25][CH:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[CH3:10]
Reactant: COc1ccc(Cl)c(N)c1
Reactant: CC(Br)c1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)c(NC(C)c2cnc(Cl)nc2Cl)c1
Temperature: 90 °C

Procedure:
(±)-2,4-Dichloro-5-(1-bromoethyl)-pyrimidine (0.20 g; 0.79 mmol) (from Example 1c supra), N,N-diisopropylethylamine (0.40 mL; 2.27 mmol) (Aldrich) and 2-chloro-5-methoxyaniline hydrochloride (0.15 g; 0.77 mmol) (Aldrich) were combined (neat) and heated in an oil bath at 90° C. for 16 hours. Upon cooling, the mixture was taken up in ethyl acetate and washed with water and then brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography (Biotage 40M; 5:95 to 15:85 ethyl acetate-hexanes gradient) gave (±)-(2-chloro-5-methoxy-phenyl)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-amine. (Yield 0.12 g; 45.9%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][CH:15]=1.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C>C1COCC1>[F:13][C:14]1[N:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:15]=1[B:26]([OH:31])[OH:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cccc(-c2cccnc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OB(O)c1ccc(-c2cccnc2)nc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of diisopropylamine (0.531 ml, 3.79 mmol) (Aldrich) in THF (4 mL) was treated with 1.6 M n-butyllithium in hexanes (2.368 ml, 3.79 mmol) (Aldrich) at −40° C. and the pale yellow solution was stirred for 1 h and then cooled to −78° C. A solution of 6-fluoro-2,3′-bipyridine (550 mg, 3.16 mmol) in THF (5 mL) was added by cannula slowly over 2 min. The resulting bright orange solution was stirred at −78° C. for 1.5 h and then a solution of triisopropyl borate (1.089 ml, 4.74 mmol) (Aldrich) in THF (4 mL) was added slowly. The resulting mixture was stirred at −78° C. for 30 min and then the cooling bath was removed. After the reaction mixture had warmed up to room temperature, the yellow heterogeneous mixture was quenched with 1 N NaOH(aq) (10 mL) and stirred for 30 min. The separated aqueous layer was removed and carefully acidified with 5 N HCl until acidic (pH 5about6) and the resulting cloudy mixture was extracted with EtOAc (20 mL). Most of the product remained in the aqueous phase so the water was removed on the freeze-dryer overnight resulting in a white fluffy product contaminated with salt. m/z (ESI, +ve ion) 219.1 (M+H)+. 1H NMR (400 MHz, MeOH) δ 9.22 (1H, s); 8.62 (1H, d, J=4.5 Hz); 8.51 (1H, d, J=8.0 Hz); 8.12 (1H, t, J=7.9 Hz); 7.89 (1H, dd, J=7.3, 2.8 Hz); 7.59 (1H, dd, J=8.0, 4.9 Hz).
Reaction SMILES: CS(N)(=O)=O.[CH:6]1([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:8][CH2:7]1.[Cl:13][C:14]1[C:15]([O:24][CH:25]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]2)=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19](O)=[O:20]>CO>[Cl:13][C:14]1[C:15]([O:24][CH:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([NH:12][S:9]([CH:6]1[CH2:8][CH2:7]1)(=[O:11])=[O:10])=[O:20]
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Agent: CS(N)(=O)=O
Solvent: CO
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with cyclopropanesulfonamide and to replace 4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid and methanol with cyclopropyl sulfonamide, the title compound was obtained as a colorless solid (0.047 g, 31%): 1H NMR (300 MHz, DMSO-d6) δ 12.02 (br s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.37 (d, J=12.6 Hz, 1H), 4.85 (br s, 1H), 3.07-2.98 (m, 1H), 2.07-1.87 (m, 8H), 1.09-1.05 (m, 4H); 19F NMR (282 MHz, DMSO-d6) δ −92.3 (d, J=231 Hz, 1F), −98.5 (d, J=231 Hz, 1F), −109.9 (s, 1F); MS (ES−) m/z 410.0, 412.0 (M−1).
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]1O.C(=O)(O)[O-].[Na+].C(OCC)C>CN(C)P(N(C)C)(N(C)C)=O>[CH:16]1[C:14](=[O:15])[N:13]=[C:11]2[N:10]([C@@H:1]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]3[O:12]2)[CH:17]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Temperature: 135 °C
Yield: 91.8 %

Procedure:
To a suspension of uridine (200 g, 819 mmoles) in hexamethylphosphoramide (HMPA) (400 ml) was added sodium bicarbonate (5.3 g, 63.1 mmoles, 0.077 equivalents (eq.)) and diphenyl carbones (228.1 g, 1064.7 mmoles, 1.3 eq.). The mixture was heated to 135° C. for 11 h. After cooling to room temperature, diethyl ether (2 l) was added and the precipitate was filtered off. The solid was washed three times with ether (3×1l). Water (1 l) was added to the filtrate, the aqueous layer was separated and extracted three times with methylene chloride (3×1 l). The aqueous phase was evaporated to dryness. The combined solids were recrystallized from hot methanol to yield 170 g (92%) of 2,2′-anhydrouridine. The spectral properties agreed with those reported in the literature (Hampton and Nichol (1966) Biochemistry 5:2076).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8](O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O>C(O)(C)(C)C>[C:4]([OH:6])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:1]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccccc1O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
One hundred g of 2,5-dihydroxy benzoic acid and 1,441 g of 80% sulfuric acid were heated to 50° C. and mixed. Tert-butylalcohol (144 g) was added to the dispersion liquid and stirred at 50° C. for 30 minutes. Thereafter, the operation, where 144 g of tert-butylalcohol was added to the dispersion liquid and stirred for 30 minutes, was performed 3 times. The reaction liquid was cooled to room temperature, and slowly added to 1 kg of ice water. The resultant precipitate was collected by filtration, and washed with water and then hexane. The precipitate was dissolved in 200 mL of methanol and reprecipitated in 3.6 L of water. After being collected by filtration, the resultant was dried at 80° C. to thereby obtain 74.9 g of a salicylic acid intermediate represented by the following formula (7).
Reaction SMILES: [C@H:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1>C(OC(=O)C)(=O)C>[CH:1]12[CH2:2][CH2:3][CH:4]([CH2:5][CH2:6]1)[C:7](=[O:9])[O:12][C:10]2=[O:11]
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)CC1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2CCC1CC2
Yield: 96.3 %

Procedure:
A solution of 2.9 g of cis-cyclohexane-1,4-dicarboxylic acid in 25 ml of acetic anhydride was heated under reflux for 2.5 hours. The solvent was removed by evaporation in vacuo, and the residue was triturated under diethyl ether several times. The residue was dried under high vacuum to give 2.5 g (97% yield) of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH:1]1[C:10]2[C@H:11]3[CH2:16][N:15]([CH2:28][CH2:27][CH2:26][C:25]([C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[NH2:17])=[O:30])[CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Product: Nc1cc(F)ccc1C(=O)CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 402 as a yellow oil (95 mg, 34%) from (7aR,11aS)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (150 mg, 0.70 mmol) and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (303 mg, 1.40 mmol). The title compound was spectroscopically identical to Example 415.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:20][CH2:21][CH3:22])[CH2:13][CH:14]([OH:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:10].[H-].[Na+].[Cl-].[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CN(C=O)C>[CH2:21]([O:20][CH:12]([O:11][CH2:9][CH3:10])[CH2:13][CH:14]([O:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:22]
Reactant: BrCc1ccccc1
Reactant: C=CCCC(O)CC(OCC)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC(CC(OCC)OCC)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMF (40 mL) and benzyl bromide (2.4 mL, specific gravity: 1.44 g/cm3) were added to 1,1-diethoxyhept-6-en-3-ol obtained in Preparation Example 57-(1) (3.71 g), and the mixture was cooled in an ice bath under a nitrogen atmosphere. Then, sodium hydride (60%, 883 mg) was added, followed by stirring for 60 minutes. Benzyl bromide (1.09 mL) was further added, followed by stirring for one hour. Sodium hydride (60%, 116 mg) was further added, and the mixture was stirred for one hour and 50 minutes while gradually warming to room temperature. Tetrabutylammonium iodide (680 mg) was further added, followed by stirring for one hour and 10 minutes. Water and a saturated ammonium chloride solution were slowly added. After stirring for a while, the aqueous layer was separated. The organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]=[N:21][OH:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[CH2:23]([OH:27])[CH2:24][C:25]#[CH:26].Cl[O-].[Na+]>C(N(CC)CC)C.ClCCl.O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:26]=[C:25]([CH2:24][CH2:23][OH:27])[O:22][N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:5]
Reactant: C#CCCO
Reactant: O=C(NCC1(O)CCCCCC1)c1cc(C=NO)ccc1Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCC1(O)CCCCCC1)c1cc(-c2cc(CCO)on2)ccc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 22.1 %

Procedure:
A mixture of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(hydroxyimino-methyl)-benzamide (50 mg, 0.15 mmol), but-3-yn-1-ol (27 mg, 0.38 mmol), sodium hypochlorite (1 mL, 4%) and triethylamine (2 drops) in dichloromethane (2 mL) was stirred at room temperature for 5 d. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, and brine, dried over sodium sulfate, filtered and adsorbed onto silica gel. The residue was purified by flash column chromatography (65% ethyl acetate-hexanes) to afford the title compound (13 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[CH:27]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:34]=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCCCOc1ccc2c(c1)OCO2
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Product: CCOC(=O)N1CCC(c2cn(CCCOc3ccc4c(c3)OCO4)c3ccccc23)CC1
Reaction time: 15 h

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 2.2 g (8.1 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 2.68 g (10 mmol) of 5-(3-bromo-propoxy)-benzo[1,3]dioxole. After standard work-up, 3.8 g (100% of yield) of the expected product was obtained.