Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CN(C)[CH:8]=[CH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[NH:18][C:17](=[O:22])[C:16]3[NH:23][CH:24]=[CH:25][C:15]=3[C:14]=2[CH:13]=1)=O.[CH2:27]([C:29]([O-:31])=[O:30])[CH3:28]>CC(N(C)C)=O>[NH2:4][C:3]1[N:5]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[NH:18][C:17](=[O:22])[C:16]4[NH:23][CH:24]=[CH:25][C:15]=4[C:14]=3[CH:13]=2)[CH:9]=[CH:8][N:2]=1.[CH2:27]([C:29]([O-:31])=[O:30])[CH3:28]
Reactant: N=C(N)N
Reactant: CN(C)C=CC(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Nc1nccc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)n1
Temperature: 130 °C
Reaction time: 96 h
Yield: 56.1 %

Procedure:
83 mg (0.87 mmol) of guanidine hydrochloride is added to a suspension of 204 mg (0.58 mmol) of 8-(3-dimethylamino-acryloyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 2.3 mL of anhydrous dimethylacetamide. The mixture is stirred at 130° C. for 4 days then the solvent is evaporated. The residue is triturated with methanol to give a solid which is collected by filtration then washed with methanol and then diisopropyl ether. After drying, 114 mg (56%) of 8-(2-amino-pyrimidin-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a brown solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26](=[O:37])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18](OCC)[O:19]CC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26](=[O:37])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]=[O:19]
Reactant: CCOC(COc1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1Cl)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CCOc1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1Cl
Reaction time: 3.5 h

Procedure:
At 0° C. 2 mL TFA and 0.15 mL water was added to a solution of 50 mg (0.011 mmol) of N-[3-chloro-4-(2,2-diethoxy-ethoxy)-phenyl]-2-(2,4-dichloro-phenoxy)-acetamide in 2 mL dichloromethane and the mixture was stirred for 3.5 hours. 200 ml of 2 M aqueous sodium carbonate solution was added and exhaustively extracted with dichloromethane. The combined org. extracts were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, EtOAc/hexane 1:1).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][O:17][CH2:18][CH:19]=[CH2:20])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:26](Cl)=[O:27].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:18]([O:17][CH2:16][C:9]1[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([NH:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:26](=[O:27])[C:25]1[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([CH3:22])[CH:24]=1)=[O:21])[CH:19]=[CH2:20]
Reactant: C=CCOCc1c(OC)cccc1C(=O)NNC(C)(C)C
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C=CCOCc1c(OC)cccc1C(=O)NN(C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a flask containing 2.0 g (0.0068 mol) of 2-allyloxymethyl-3-methoxy-benzoic acid N′-tert-butyl-hydrazide dissolved in 15 mL of CH2Cl2, was added 1.27 g (0.0075 mol) of 3,5-dimethylbenzoyl chloride in 10 mL of CH2Cl2 and 2.84 g of K2CO3 (0.02 mol) in 30 mL of H2O. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted and partitioned, and the organic phase was dried and solvent was removed in vacuo. The product was purified by silica gel chromatography; eluting in 25% ethyl acetate:hexane fractions, to yield 2.40 g of pure 3,5-dimethyl-benzoic acid N′-(2-allyloxymethyl-3-methoxy-benzoyl)-N-tert-butyl-hydrazide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.2 (t, 1H) 7.1 (s, 1H), 7.05 (d, 2H), 6.95 (m, 2H), 5.9 (m, 1H), 5.2-5.3 (q, 2H), 4.5 (d, 2H), 3.9 (m, 2H), 3.80 (s, 3H), 2.245 (s, 6H), 1.547 (s, 9H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:34])(=[O:35])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
Lithium hydroxide monohydrate (0.08 g, 0.19 mmol) was added to a stirred solution of {6-fluoro-4-[4-(4-fluoro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.023 g, 0.047 mmol) in a 3:1 mixture of THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-fluoro-4-[4-(4-fluoro-phenyl-sulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.017 g, 76%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (br. s, 1 H), 7.99 (dd, J=9.20, 6.40 Hz, 1 H), 7.89 (s, 1 H), 7.85 (m, J=8.30 Hz, 2 H), 7.41 (d, J=8.31 Hz, 2 H), 7.34-7.38 (m, 1 H), 7.10-7.15 (m, 3 H), 6.50 (dd, J=11.00, 3.20 Hz, 1 H), 3.83 (s, 2 H), 2.01 (s, 3 H). MS calcd. for C25H18F2NO4S [(M−H)−] 466, obsd. 466.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:13]1.CCN(CC)CC>C(Cl)Cl>[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:13]1
Reactant: CCOC(=O)c1ccc(N2CCC(O)C2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCC(=O)C2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
To a round bottom flask was added CH2Cl2 (30 ml), 2M oxalyl chloride (4.31 mL, 8.63 mmol). The resulting solution was cooled to −78° C. DMSO (1.225 mL, 17.26 mmol) was then slowly added to the solution over 10 min. The reaction was then stirred at −78° C. for 15 min. The ethyl 4-(3-hydroxypyrrolidin-1-yl)benzoate (1.45 g, 6.16 mmol) pre-dissolved in CH2Cl2 (15 ml) was added to the reaction mixture over 10 min. The resulting solution was stirred at −78° C. for 2 hrs. After this time, Et3N (3.78 mL, 27.1 mmol) was added to the reaction mixture and the resulting solution was slowly warmed to 0° C. over 20 min. The reaction mixture was then diluted with CH2Cl2 (100 ml). The reaction mixture was wash with saturated aqueous NaHCO3 (100 ml), water (100 ml) and saturated aqueous NaCl (100 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated to give crude product. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex) to give the product ethyl 4-(3-oxopyrrolidin-1-yl)benzoate (1.31 g, 5.62 mmol, 91% yield) as yellow solid. Anal. Calcd. for C13H15NO3 m/z 233.2, found: 234.0 (M+H)+.
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C.Br[CH2:36][CH2:37][CH2:38][OH:39]>C(O)CCC>[CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:36][CH2:37][CH2:38][OH:39])[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
4-Benzhydrylpiperidine (10 mmol, 2.87 g) is slurried in n-butanol (30 mL), and K2CO3 (s) (2.76 g, 10 mmol) or diisopropylethylamine (20 mmol, 2.5 g) and 3-bromopropanol (10 mmol, 1.39 g) are added to the slurry. The stirred mixture is refluxed for about 7 hours under N2 (g), filtered, and concentrated in vacuo. The residue is dissolved in hot CHCl3, filtered and concentrated in vacuo to yield crude product as an oil (3.0-3.1 g) which is used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[N+]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)N[CH2:21][CH2:20]2)([O-])=O.IC.[OH-].[Na+].CN([CH:33]=[O:34])C>O>[C:5]([C:25]1[CH:24]=[CH:23][C:19](/[CH:20]=[CH:21]/[C:33]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:34])=[CH:18][CH:17]=1)([CH3:10])([CH3:6])[CH3:4]
Reactant: CN1CCc2cc([N+](=O)[O-])ccc21
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CN1CCc2cc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)ccc21

Procedure:
1-Methyl-5-nitroindoline. To a round-bottomed flask equipped with magnetic stirring was added 5-nitroindoline (0.82, 5.0 mmol, Aldrich), iodomethane (0.71 g, 5.0 mmol, Aldrich), sodium hydroxide (0.24, 6 mmol) and DMF (20 mL). The reaction mixture was stirred at 25° C. for 3 h, diluted with water (50 mL), extracted with EtOAc (3×40 mL) and the combined extracts were concentrated in vacuo. Purification by silica gel chromatography 97:3 hexane:EtOAc) provided the title product. MS (ESI, pos. ion) m/z: 179 (M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C:13]1[C:21]([CH2:22]/[CH:23]=[C:24](\[CH3:31])/[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:20]([O:32][CH3:33])[C:19]([CH3:34])=[C:18]2[C:14]=1[C:15](=[O:35])[O:16][CH2:17]2.Cl>N1C=CC=CC=1>[CH3:33][O:32][C:20]1[C:19]([CH3:34])=[C:18]2[C:14]([C:15](=[O:35])[O:16][CH2:17]2)=[C:13]([O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:21]=1[CH2:22]/[CH:23]=[C:24](\[CH3:31])/[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
p-Toluenesulfonyl chloride (30 g) was added to a solution of methyl (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (40 g) in pyridine (200 ml) at 0° C. After 6 hours the solution was poured on to ice and acidified to pH 3 with dilute hydrochloric acid. The solution was extracted with ethyl acetate and the extract was dried and evaporated to afford methyl (E) 6-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: Br[C:2](=[C:6]([OH:8])[CH3:7])[C:3](=O)C.[C:9]([NH2:12])(=[S:11])[CH3:10]>CC(C)=O>[C:6]([C:2]1[S:11][C:9]([CH3:10])=[N:12][CH:3]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)C(Br)=C(C)O
Reactant: CC(N)=S
Solvent: CC(C)=O
Product: CC(=O)c1cnc(C)s1
Reaction time: 8 h

Procedure:
To a solution of the product of Example 151B (14.5 g, 88 mmol) in acetone (220 mL) was added thioacetamide (6.6 g, 88 mmol) and stirred overnight. The solid was filtered to give the title compound as the hydrogen bromide salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.54 (s, 3 H) 2.71 (s, 3 H) 8.46 (s, 1 H). MS (DCI) m/z 142 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:4]=1[NH:18][C:19](=O)[CH3:20])#[N:2].P(=O)(O)(O)[OH:23]>>[CH3:20][C:19]1[NH:2][C:1](=[O:23])[C:3]2[CH:7]=[C:6]([CH3:8])[N:5]([C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])[C:4]=2[N:18]=1
Reactant: CC(=O)Nc1c(C#N)cc(C)n1-c1c(C)cc(C)cc1C
Reactant: O=P(O)(O)O
Product: Cc1cc(C)c(-n2c(C)cc3c(=O)[nH]c(C)nc32)c(C)c1
Temperature: 130 °C
Yield: 67 %

Procedure:
A mixture of compound (4) (32.1 g, 0.144 mol) and 85% phosphoric acid (30 mL) was heated at 130° C. for 30 minutes. The resulting mixture was cooled to room temperature, poured into ice water with vigorous stirring, and the resulting precipitate was filtered and dried under vacuum to afford 21.6 g (67%) of compound (5) as a pink solid.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][N:22]([CH3:24])[CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:45][CH2:46][CH2:47][C:48](=[O:75])[CH2:49][CH2:50][C:51](=[O:74])[CH2:52][CH2:53][C:54](=[O:73])[CH2:55][CH2:56][C:57](=[O:72])[CH2:58][CH2:59][C:60](=[O:71])[CH2:61][CH2:62][O:63][C:64](=[O:70])[CH2:65][CH2:66][CH2:67][CH2:68][Br:69]>CC(C)=O>[Br-:69].[CH2:1]([O:19][CH:20]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][N+:22]([CH2:68][CH2:67][CH2:66][CH2:65][C:64]([O:63][CH2:62][CH2:61][C:60](=[O:71])[CH2:59][CH2:58][C:57](=[O:72])[CH2:56][CH2:55][C:54](=[O:73])[CH2:53][CH2:52][C:51](=[O:74])[CH2:50][CH2:49][C:48](=[O:75])[CH2:47][CH2:46][OH:45])=[O:70])([CH3:24])[CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(CCO)CCC(=O)CCC(=O)CCC(=O)CCC(=O)CCOC(=O)CCCCBr
Reactant: CCCCCCCCC=CCCCCCCCCOCC(CN(C)C)OCCCCCCCCC=CCCCCCCCC
Solvent: CC(C)=O
Product: CCCCCCCCC=CCCCCCCCCOCC(C[N+](C)(C)CCCCC(=O)OCCC(=O)CCC(=O)CCC(=O)CCC(=O)CCC(=O)CCO)OCCCCCCCCC=CCCCCCCCC
Product: [Br-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
A mixture of 4 (395 mg, 0.64 mmol) and 8 (330 mg, 0.74 mmol) in acetone (5 ml) was stirred in a sealed-tube at RT for 24 h and than at 80° C. for another 24 h. After cooling, the solvent was evaporated in vacuo. Purification by flash chromatography on silica (gradient; 5% to 10% methanol in dichloromethane) gave ME52 as an orange oil (300 mg, 47%).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].[CH2:6]([N:10]=[CH:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:22]([F:25])([F:24])[F:23])=[CH:14][C:13]=1F)[CH2:7][CH2:8][CH3:9]>C(OCC)C.[Cl-].[Mn+2].[Cl-]>[CH2:6]([N:10]=[CH:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:22]([F:25])([F:24])[F:23])=[CH:14][C:13]=1[CH:1]1[CH2:3][CH2:2]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN=Cc1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: BrC1CC1
Agent: [Mn+2]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CCCCN=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
Cyclopropylbromide (3.84 g, 32 mmol) was added to magnesium (771 mg, 32 mmol) in 20 mL diethylether and refluxed for 10 min. Manganese(II) chloride (160 mg, 1.27 mmol) and butyl-[1-(2-fluoro-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine (intermediate AK, 4 g, 13 mmol) was added. The reaction mixture was refluxed for 2 h. The reaction mixture was quenched with 8 mL water and filtered through dicalite. The organic phase was separated and dried on sodium sulfate, filtered and evaporated. The crude material, brown oil (3.54 g, 82%) was used without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[CH:20]=O)=[O:6])[CH:2]=[CH2:3].C(O)C.[C:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]1[CH2:20][NH:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1C=O
Reactant: Nc1cccc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A mixture of (2S,4S)-2-formyl4-BOCsulfanyl-pyrrolidine-1-carboxylic acid allyl ester (compound(1)) ( 711 mg), ethanol(25 ml), 1-naphthylamine(333 mg) and 3A molecular sieves(4.5 g.) was stirred under an argon atmosphere at ambient temperature for 6 hours. Acetic acid (0.4 ml) was added followed by sodium cyanoborohydride(l 70 mg). The mixture was then stirred for a further 20 hours when the sieves were removed by filtration. The filtrate was concentrated under reduced pressure and the residue applied to a silica column and eluted with ethyl acetate/hexane(20:80) to give (2S,4S)-1-allyloxycarbonyl-2[(naphthalen-1-ylamino )-methyl]-4-BOCsulfanylpyrrolidine (compound(31)) as a clear oil (560 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[O:17][C:16]([SH:18])=[N:15][N:14]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[O:17][C:16]([S:18][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=4)=[N:15][N:14]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COCn1ncc2cc(-c3nnc(S)o3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1ncc2cc(-c3nnc(SCc4cccc(C(F)(F)F)c4)o3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.6 %

Procedure:
A suspension of 5-[1-(methoxymethyl)-1H-indazol-5-yl]-1,3,4-oxadiazole-2-thiol (525 mg, 2.00 mmol), 3-(trifluoromethyl)benzyl chloride (0.372 mL, 2.40 mmol), and potassium carbonate (415 mg, 3.00 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 hr. The reaction mixture was poured into water, the precipitate was collected by filtration, purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from hexane/tetrahydrofuran to give the title compound (821 mg, yield 98%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][OH:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH:11]2[CH2:16][OH:17])[N:3]=1
Reactant: O=Cc1nccc(Cl)n1
Reactant: OCC1COCCN1
Product: OCC1COCCN1Cc1nccc(Cl)n1

Procedure:
The title compound was prepared according to the general procedure in Example 45, Step 1 using 4-chloropyrimidine-2-carbaldehyde (0.573 g, 4.02 mmol) and morpholin-3-ylmethanol (0.565 g, 4.82 mmol) as the starting materials.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][C:37]([Cl:44])=[N:38][C:39]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.NC(C)C[C@H:50]([S:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1)[CH2:51][CH3:52].C([N:62](CC)CC)C>O1CCOCC1>[C:1]([O:9][C@@H:10]1[C@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@H:11]1[N:34]1[C:35]2[N:36]=[C:37]([Cl:44])[N:38]=[C:39]([NH:62][C@H:51]([CH3:52])[CH2:50][S:53][C:54]3[S:55][CH:56]=[CH:57][N:58]=3)[C:40]=2[N:41]=[CH:42]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC[C@H](CC(C)N)Sc1nccs1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](CSc1nccs1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 40 h
Yield: 64.8 %

Procedure:
To a solution of 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.5 g, 2.4 mmol) in dry dioxan (50 ml), the above 2-[(R)-2-aminopropyl-1-propylthio]thiazole dihydrochloride (1.5 g, 7.1 mmol) and triethylamine (0.78 g, 7.7 mmol) were introduced at 20° C. After stirring at 50° C. for 40 h the reaction mixture was concentrated to a yellow oil, which was purified by flash chromatography eluting with a mixture of heptane and ethyl acetate (1:1), to afford the title 2',3',5'-tri-O-benzoyl-2-chloro-N-[(R)-1-(2-thiazolyl)thio-2-propyl]adenosine (1.2 g, 63%) as a foam, TLC Rf 0.19 [SiO2 ; heptane/ethyl acetate (1:1)].
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21](C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[CH:26]([N:28]([CH3:30])N)=[O:27].C1CCN2C(=NCCC2)CC1>C(O)C>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[N:21]([N:28]([CH:26]=[O:27])[CH3:30])[CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: CN(N)C=O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(N(C)C=O)c2nc3cc(Cl)c(F)cc3cc2c1=O
Yield: 86.9 %

Procedure:
The 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine is prepared under the conditions of Example 1 but starting from 19.25 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate, 4.05 g of N-formyl-N-methylhydrazine and 1.6 g of DBU in 200 cm3 of ethanol. 16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a colourless solid melting at 296°-298° C., which can be used for the subsequent steps without further purification.
Reaction SMILES: O1CCCC1.[O:6]([CH2:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[O:6]([CH2:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ccccc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 29.9 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (6-phenoxymethyl-pyridin-3-yl)-acetohydroximoyl chloride (89.0 mg, 0.322 mmol) described in Manufacturing Example 54-1-6 and 3-ethynyl-pyridin-2,6-diamine (25.0 mg, 0.188 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (78.6 μL, 0.564 mmol) at room temperature, which was stirred for 4.5 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1→3:1) to obtain the title compound (21.0 mg, 29.9%).