Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C=O)C>[N:38]1([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
In a round bottomed flask, 3-nitro-5-trifluoromethylbenzoic acid (5.0 g, 21.3 mmoles) was dissolved in 40 mL of dry DMF, to this solution was added hydroxybenzotriazole (5.8 g, 42.5 mmoles) and EDCI (8.2 g, 42.5 mmoles) and the solution stirred for 1 hour at room temperature. At the end of this time morpholine (2.2 g. 25.5 mmoles) was added and the reaction stirred overnight. The solution was then concentrated to dryness, and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined extracts dried with magnesium sulfate, filtered and concentrated. Chromatography with silica gel and eluting with a ethyl acetate/hexane gradient of 0-35% over 80 minutes gave morpholin-4-yl-(3-nitro-5-trifluoromethyl-phenyl)-methanone (1.8 g). 1H NMR (300 MHz, DMSO-d6) δ 8.6 (d, 2H), 8.3 (s, 1H), 3.8-3.6 (bm, 4H), 3.56 (b, 2H), 3.33 (bs, 2H).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:21]([O-])=O)[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-Indan-1-yl-(6-nitro-quinolin-2-yl)-amine (1.5 g, 5.0 mmol) were dissolved in ethyl acetate (60 mL). Upon addition of palladium on carbon (10%) the reaction mixture was stirred for 2 h at ambient temperature under an atmosphere of hydrogen. Then the catalyst was filtered off, the filter washed with ethyl acetate and the filtrate evaporated. (R)—N2-Indan-1-yl-quinoline-2,6-diamine was obtained as a yellow foam (1.3 g, 96%); MS: m/e=276.4 (M+H+).
Reaction SMILES: CS(O[CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9])(=O)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:7]([CH3:12])([CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:28][CH:27]=1
Reactant: COc1ccc(S)cc1
Reactant: COC(=O)C(C)(C)C(CCCCc1ccccc1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C(C)(C)C(CCCCc1ccccc1)Sc1ccc(OC)cc1
Temperature: 60 °C
Yield: 23.6 %

Procedure:
Methyl 3-methanesulfonyloxy-2,2-dimethyl-7-phenylheptanoate (7.7 g, 23 mmol) and 4-methoxybenzenethiol (5.5 mL, 45 mmol) are dissolved in MeOH (40 mL) and potassium carbonate (4.8 g, 35 mmol) is added and the reaction is heated at 60° C. for 24 hours. The solvent is removed in vacuo and CH2Cl2 (100 mL) added and then washed with NaHCO3 (60 mL), 1 N HCl (60 mL) and brine (100 mL). The solvent is removed in vacuo and the residue purified by column chromatography (silica, 40% petroleum ether in CH2Cl2) to yield methyl 3-(4-methoxyphenylsulfanyl)-2,2-dimethyl-7-phenylheptanoate (2.1 g, 24%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.33 (m, 2H), 7.29-7.12 (m, 5H), 6.82-6.79 (m, 2H), 3.79 (s, 3H), 3.55 (s, 3H), 3.18-3.15 (m, 1H), 2.60-2.53 (m, 2H), 1.85-1.73 (m, 1H), 1.57-1.40 (m, 5H), 1.26 (s, 3H), 1.20 (s, 3H); MS (FAB) m/e 386 (M+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:11]1=2.O>ClCCCl>[C:5]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH3:9])[C:11]1[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][C:12]2=1)(=[O:7])[CH3:6]
Reactant: COC(=O)c1cc2c3ccccc3n(C)c2s1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc2c3cc(C(C)=O)ccc3n(C)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of 870 mg AlCl3 in 50 ml dry 1,2-dichloroethane was added 465 μl acetyl chloride. The mixture was stirred for 30 min. at room temperature. 800 mg of (6) was added, and stirring continued overnight. Another 870 mg AlCl3 and 465 μl acetyl chloride was added, and stirring continued overnight. Water was added, and the organic phase dried and evaporated to dryness giving a brown powder, which was crystallized from acetic acid and petrol ether giving (64). Yield 210 mg. M. p. 196°-8° C.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.[CH:14]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([CH2:16][CH3:17])[CH3:15].C(O)(C)C.Cl>C(O)(C)C>[CH:14]([N:18]1[CH2:23][CH2:22][C:21]2[NH:2][C:4]3[C:13]([C:20]=2[CH2:19]1)=[C:8]1[C:9]([CH3:12])=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)N1CCC(=O)CC1
Reactant: Cc1csc2ccc(NN)cc12
Agent: Cl
Solvent: CC(C)O
Product: CCC(C)N1CCc2[nH]c3ccc4scc(C)c4c3c2C1

Procedure:
11 g of 5-hydrazino-3-methylbenzothiophene hydrochloride and 8.5 g of 1-sec.-butyl-4-piperidone are boiled in 35 ml of isopropanol, and during this procedure isopropanol/HCl are added dropwise. The mixture is then evaporated, the residue is taken up in water and the mixture is rendered alkaline and extracted with methylene chloride. After washing and drying the organic phase, it is evaporated and the residue is recrystallised from cyclohexane. Melting point: 136°-137° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@H:8]2[CH2:9][C@@H:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].B1C2CCCC1CCC2.C([O-])(C)(C)C.[K+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>C1COCC1.CCCCC>[CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:7][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: O=C(CBr)c1ccccc1
Reactant: C=C1CC[C@H]2C[C@@H]1C2(C)C
Agent: B1C2CCCC1CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C)C2CCC(CCC(=O)c3ccccc3)C1C2
Temperature: -78 °C
Reaction time: 3 h
Yield: 5.5 %

Procedure:
1.36 g (−)-β-pinene (10 mmol) was dissolved in 5 ml THF. 21 ml of a 0.5-molar solution of 9-BBN in THF (10.5 mmol) was added to this solution at 0° C. The reaction mixture was slowly brought to room temperature and stirred for a further 3 hours. The resulting solution was cooled to −78° C., and a solution of 1.12 g potassium tert-butanolate (10 mmol) in 10 ml THF was then added to the cooled reaction solution. After a short time, 2 g α-bromacetophenone (10 mmol) was added in portions with constant stirring. The reaction mixture was slowly brought to room temperature and stirred for 4 hours at room temperature. The resulting product mixture had 50 ml n-pentane added to it, and washed three times in each case with 10 ml of a 3N sodium hydroxide solution and with 10 ml water. The organic phase was dried over magnesium sulfate. Solvent was removed from the filtrate at reduced pressure. The raw product was purified by column chromatography. 140 mg (10%) of the aforesaid product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][CH:11]=[C:10]([CH2:18][C:19]3[CH:20]=[CH:21][C:22](F)=[N:23][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:27][NH:28][CH2:29][C:30]([NH2:32])=[O:31].N12CCCN=C1CCCCC2>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH:15]([F:16])[F:17])=[CH:12][CH:11]=[C:10]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:28]([CH3:27])[CH2:29][C:30]([NH2:32])=[O:31])=[N:23][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNCC(N)=O
Reactant: Fc1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2)cn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CN(CC(N)=O)c1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2)cn1
Temperature: 160 °C
Yield: 3 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 5-(3′-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (I-153, 210 mg, 0.577 mmol), 2-methylamino-acetamide hydrochloride (216 mg, 1.73 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (488 uL, 3.46 mmol). The mixture was heated to 160° C. for 3 hours and then diluted with dichloromethane (5 mL). The organic portion was washed with 0.5M HCl (3 mL) and the aqueous washes were combined and extracted with dichloromethane (2×3 mL). The organic portions were combined, washed with brine (4 mL), dried (MgSO4) and concentrated. The crude material was purified by Teledyne CombiFlash system utilizing a 12 g RediSepRf silica gel cartridge and a gradient elution of 0-30% methanol/dichloromethane, followed by preparative TLC (20×20 cm, 1000 microns) using 5% methanol/dichloromethane as the eluent to produce 8 mg of P-621?? as a dark brown semi-solid in 3% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.98 (s, 3H), 3.83 (s, 2H), 4.03 (s, 2H), 6.53 (d, J=9 Hz, 1H), 7.10 (t, J=74 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.30 (dd, J=8, 2 Hz, 1H), 7.36 (d, J=2 Hz, 1H), 7.40-7.50 (m, 5H), 8.01 (d, J=2 Hz, 1H) ppm. MS (APCI+): 432.1 (M+1). LC/MS: 86%.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[O:15].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH3:24].CC(=O)OCC>CN(C=O)C>[CH2:23]([N:12]1[C:13]2[CH:1]=[C:2]([CH:14]=[O:15])[CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:24]
Reactant: CCBr
Reactant: O=Cc1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of 9H-carbazole-2-carbaldehyde (3.7 g, 18.97 mmol, 1.00 equiv) in DMF (50 mL). To this was added K2CO3 (5.23 g, 37.90 mmol, 2.00 equiv) followed by addition of bromoethane (10 g, 91.74 mmol, 4.80 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by TLC (EA:PE=1:3). Upon completion, the reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL), combined organic layers were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10) affording 9-ethyl-9H-carbazole-2-carbaldehyde as yellow solid (2.6 g, 61%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].O>C(#N)C>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)CCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.775 mmol) in acetonitrile (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and N,N-dimethylethylenediamine (82 mg, 0.93 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (240 mg, 95% yield) as orange crystals.
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[CH3:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C)C=O>[I-:1].[CH3:25][CH:24]([C:19]1[CH:18]=[CH:17][C:16]2[N:15]3[C:8]4[CH:7]=[CH:6][C:5]5[CH:4]=[C:3]([N:31]6[CH2:32][CH2:33][CH:28]([CH3:27])[CH2:29][CH2:30]6)[CH:12]=[CH:11][C:10]=5[N+:9]=4[CH:13]=[C:14]3[CH:23]=[CH:22][C:21]=2[CH:20]=1)[CH3:26]
Reactant: CC1CCNCC1
Reactant: CC(C)c1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1CCN(c2ccc3c(ccc4n5c(ccc6cc(C(C)C)ccc65)c[n+]34)c2)CC1

Procedure:
A mixture of 4.7 g. of 3-fluoro-10-(1-methylethyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 20 ml. of dimethylformamide and 4.0 ml. of 4-methylpiperidine is stirred and heated at reflux for 1 hour, then evaporated at reduced pressure. The residue is stirred with 75 ml. of ethyl acetate and the resulting precipitate is collected by filtration. The solid is stirred with 150 ml. of 1% aqueous triethylamine hydroiodide, collected by filtration, washed with water and dried. This product is 10-(1-methylethyl-3-(4-methyl-1-piperidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide; m.p. 266°-269° C., after crystallization from methanol/acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]1([CH3:64])[CH:45]=[CH:44][C:43]([S:46]([O:49][CH2:50][CH2:51][CH2:52]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:48])=[O:47])=[CH:42][CH:41]=1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:52][CH2:51][CH2:50][O:49][S:46]([C:43]2[CH:42]=[CH:41][C:40]([CH3:64])=[CH:45][CH:44]=2)(=[O:47])=[O:48])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 mg (0.22 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxy-benzyl)-L-glutamate (Example 1b) in 10 mL N,N-dimethylformamide were added 210 mg (0.64 mmol) of cesium carbonate and 413 mg (1.07 mmol) of 1,3-propanediol di-p-toluenesulfonate (Aldrich) and the resulting suspension was stirred overnight at room temperature. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in dichloromethane and 1 M hydrochloric acid. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product obtained in this manner was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [SH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][SH:7].[C:8]([O:12][CH2:13][CH:14]1[O:16][CH2:15]1)(=[O:11])[CH:9]=[CH2:10]>>[C:8]([O:12][CH2:13][CH:14]1[O:16][CH2:15]1)(=[O:11])[CH2:9][CH2:10][S:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:7][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH:14]1[O:16][CH2:15]1)=[O:11]
Reactant: C=CC(=O)OCC1CO1
Reactant: SCCOCCS
Product: O=C(CCSCCOCCSCCC(=O)OCC1CO1)OCC1CO1

Procedure:
2-mercaptoethyl ether, 18.3 g (0.13 mole), was reacted with glycidyl acrylate, 34 g (0.26 mole), at 25°-35° C., to give diglycidyl 4,10-dithia-7-oxatridecanedioate according to the following reaction: ##STR7##
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])(=[O:3])[CH3:2].[C:11]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1>CO>[C:11]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:2][C:1](=[O:3])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:10]2)[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccccc1O
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCN(C(=O)c3ccccc3)CC2)Oc2ccccc21
Temperature: 25 °C
Yield: 68961.6 %

Procedure:
A solution of 2-acetylphenol (5 g, 0.037 mmol), 1-benzoyl-4-piperidone (7.5 g, 0.037 mmol), pyrrolidine (2.6 g, 0.037 mol) and CH3OH (50 ml) was heated at reflux for 8 hours. After cooling to room temperature overnight, the solid was filtered to yield 8.2 g of 1'-benzoyl-3,4-dihydro-spiro[(2H)-1-benzopyran-2,4'-piperidin]-4-one. The mother liquor was concentrated to dryness and the residue triturated with ether to yield an additional 1.7 g (83% total yield).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[C:5]=1[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38]([Cl:41])[C:39]=1Cl>CS(C)=O>[CH2:26]([O:25][CH2:24][CH2:23][C:5]1[C:6](=[O:22])[O:7][C:8]2[C:13]([C:4]=1[NH:3][C:39]1[C:38]([Cl:41])=[CH:37][N:36]=[CH:35][C:34]=1[Cl:33])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: COc1ccc2c(N)c(CCOCc3ccccc3)c(=O)oc2c1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(CCOCc3ccccc3)c(=O)oc2c1OC1CCCC1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (230 mg, 60%, 5.8 mmol) was added portionwise to a solution of 4-amino-3-(2-(benzyloxy)ethyl)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (800 mg, 1.86 mmol) and DMSO (20 mL). After 10 min at rt, 3,4,5-trichloropyridine (1.0 g, 5.47 mmol) was added. The reaction was then heated at 50° C. overnight, allowed to cool to rt, quenched with drops of water, poured into 0.5M KH2PO4 (15 mL), and then extracted with ethyl acetate (50 mL×2). The combined extracts were washed with brine (50 mL), dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate:petroleum ether) to give 3-(2-(benzyloxy)ethyl)-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].[C:12](Cl)(Cl)=[S:13]>O.C(OCC)C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]2[N:2]=[C:12]([SH:13])[O:11][C:4]=2[CH:5]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(N)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc2nc(S)oc2c1

Procedure:
2-amino-5-methoxyphenol hydrochloride (6 g) in 80 ml of water was stirred at room temperature while thiophosgene (3.92 g) was added dropwise as a solution in 30 ml of diethyl ether at a rate such that the resultant exotherm was controlled.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17](I)=[N:18][C:19]=3[NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[O:7][C@@H:6]1[CH2:30][O:31][C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2].C([Sn]([C:48]#[N:49])(CCCC)CCCC)CCC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:48]#[N:49])=[N:18][C:19]=3[NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[O:7][C@@H:6]1[CH2:30][O:31][C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-2-(acetyloxymethyl)-5-[6-(cyclopentylamino)-2-iodopurin-9-yl]oxolan-3-yl acetate (0.9 g, 1.53 mmol) in N,N-dimethylformamide (40 ml) was added tributyltin cyanide (0.58 g, 1.84 mmol) and tetrakis(triphenylphosphine)palladium (0.27 g, 0.23 mmol), and the mixture was stirred at 120° C. f overnight. Solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and filtered through celite. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel, eluting with a mixture of ethanol/hexane 1:1, to provide (2R,3R,4R,5R)-4-acetyloxy-2-(acetyloxy-methyl)-5-[2-cyano-6-(cyclopentylamino)purin-9-yl]oxolan-3-yl acetate (0.65 g).
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][OH:28]>>[CH3:27][O:28][C:2]([NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[O:3]
Reactant: CO
Reactant: COC(=O)CC/C(C)=C/Cc1c(N=C=O)c2c(c(C)c1OC)COC2=O
Product: COC(=O)CC/C(C)=C/Cc1c(NC(=O)OC)c2c(c(C)c1OC)COC2=O

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (1.0 g) in 10 ml methanol was heated to reflux for 4 hours and then evaporated to dryness. The residue was recrystallized from acetone/hexane to give 0.41 g of methyl (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate. The ester (0.35 g) and 0.05 g of LiOH-H2O in 9 ml 2:1 MeOH-H2O was heated at reflux for 4 hours. The mixture was acidified, extracted with ethyl acetate, and the organic layer was dried over MgSO4. The organic layer was concentrated and the residue was further purified by silica gel chromatography (eluant 60:40:2 hexane:ethyl acetate:acetic acid) to give 0.21 g of (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, mp 155°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]=2[CH:23]=1)=[O:12].[H-].[Na+].[CH3:26]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]=2[CH:23]=1)=[O:12]
Reactant: COc1ccc(Cl)c(CC(=O)c2ccc3oc(=O)n(C)c3c2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)c(C(C)C(=O)c2ccc3oc(=O)n(C)c3c2)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 60 %

Procedure:
5-[2-(2-Chloro-5-methoxy-phenyl)-acetyl]-3-methyl-3H-benzooxazol-2-one (500 mg, obtained in Example 192, step 1) was dissolved in DMF (15 mL). The mixture was cooled to 0° C. To this solution was added sodium hydride (55% in mineral oil, 72 mg). The mixture was stirred for 50 minutes at 0° C. Methyl iodide (0.104 mL) was added dropwise over a period of 10 minutes. Stirring was continued at 0° C. for 1.5 hours. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=7:3) to give the title compound as a colorless gum (312 mg, 60%). MS (m/e)=346.1 [M+H+].