Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[C:28]([NH:32][S:33]([C:36]1[C:37]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([F:49])[CH:43]=2)=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:48][C:45]1[CH:46]=[CH:47][C:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[S:33](=[O:35])(=[O:34])[NH:32][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:43][C:44]=1[F:49])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol) was dissolved in 40 mL dry diethyl ether under Ar. The solution was cooled in an ice water bath as dry pyridine (3 mL, 37.2 mmol) was added, followed by the dropwise addition of oxalyl chloride (1.6 mL, 18.6 mmol). A precipitate formed immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. 50 mL diethyl ether were added, and the mixture was filtered. The filtered off solids were washed with diethyl ether. The filtrates were combined and concentrated to give an off-white oil. The oil was redissolved in 40 mL dry DCM under Ar, cooled to 0° C., and 3 mL of pyridine were added, followed by 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (2 g, 6.2 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. The concentrate was redissolved in 250 mL EtOAc, washed with 10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. The concentrate was purified on a silica gel column eluted with 30% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a white solid. (1.4 g, 42%) APCI (AP−): 518.2 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C@H:8]2[NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C:3]1=[O:26].Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=2)[N:31]=[CH:30][N:29]=1.C(N(CC)CC)C>C(O)(C)C>[O:26]=[C:3]1[C@@H:2]([NH:1][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH2:6][CH2:5][N:4]1[C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:9][C@H:8]1[NH:21][C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-propionamidocyclohexylcarbamate (650 mg, 1.764 mmol) in 5 mL of isopropanol was added 4-chloro-6-(trifluoromethyl)quinazoline (492 mg, 2.117 mmol) and triethylamine (0.492 mL, 3.53 mmol). The mixture was stirred at 50° C. for 4 h. The solvent was removed under reduced pressure and the residue was diluted with 30 mL of 20% AcOH in water before being extracted with diethyl ether (2×20 mL). The ethereal layer was extracted with 20% AcOH solution in water (3×30 mL). The aqueous layers were combined and basified with Na2CO3 and extracted with methylene chloride (3×50 mL). The organic extracts were combined, washed with brine (40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give tert-butyl (1R,3R,4S)-4-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)-3-propionamidocyclohexylcarbamate, LC/MS found [M+H]+=565. The entirety of this crude product was dissolved in 5 mL of methylene chloride. The resultant solution was charged with TFA (3 mL), stirred at room temperature for 30 min, and then concentrated in vacuo. The residue was purified with preparative reverse-phase HPLC to give the title compound as its TFA salt in aqueous methanol solution. This solution was concentrated in vacuo to remove the methanol and the residue solution was basified with saturated NaHCO3 and extracted with methylene chloride (3×50 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound as its free base (550 mg, 1.184 mmol, 67% yield). LC/MS found [M+H]+=465. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.77 (1H, s), 8.57 (1H, s), 8.03 (1H, dd, J=9.16, 2.03 Hz), 7.88 (1H, d, J=8.65 Hz), 5.24 (1H, t, J=8.65 Hz), 4.55 (1H, d, J=3.56 Hz), 3.97-4.05 (1H, m), 3.52-3.67 (2H, m), 3.35-3.41 (1H, m), 2.47-2.58 (1H, m), 2.20-2.34 (3H, m), 1.62-2.04 (6H, m), 1.14 (3H, t, J=7.63 Hz).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:24][N:31]=[C:27]([CH2:28][CH2:29][CH3:30])[N:26]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCCc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)C3CCCC3)C2)n1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 22 mg (0.22 mmol, 1.1 eq.) of N′-hydroxybutanimidamide were reacted according to the General Method 1. Yield: 12 mg (15% of theory)
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][N:11]([CH:13]2[CH2:32][N:17]3[C:18]4[C:23]([C:24]([CH2:25][C:26]([O:28]CCC)=[O:27])=[C:16]3[CH2:15][CH2:14]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.CO>[CH2:1]([C:8]1[N:9]=[N:10][N:11]([CH:13]2[CH2:32][N:17]3[C:18]4[C:23]([C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:16]3[CH2:15][CH2:14]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(n1cc(Cc3ccccc3)nn1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(Cc3ccccc3)nn1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of propyl [7-(4-benzyl-1H-1,2,3-triazol-1-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate (1 eq) in THF/MeOH (2:1, 0.1M) at room temperature was added a 2M solution of potassium hydroxide (10 eq) The reaction mixture was stirred at room temperature for 2 h then quenched by adding HCl 10% until acidic pH and diluted with dichloromethane (DCM). Filtration through a phase separator followed by evaporation afforded the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 8.05 (s, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 7.34-7.17 (m, 5H), 7.12-7.00 (m, 2H), 5.35-5.18 (m, 1H), 4.67 (dd, 1H), 4.32 (dd, 1H), 4.02 (s, 2H), 3.69-3.50 (m, 2H), 3.07-2.92 (m, 2H), 2.52-2.30 (m, 2H). MS (+ESI) m/z: 387.2.
Reaction SMILES: OCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([NH2:29])=[O:28])=[C:19]2[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1)(=[O:15])=[O:14].[Br:39]C1C=CC(SC2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)=CC=1>>[Br:39][C:9]1[CH:8]=[CH:7][C:12]([S:13]([C:16]2[CH:17]=[C:18]3[C:23](=[C:24]([CH3:26])[CH:25]=2)[N:22]=[CH:21][C:20]([C:27]([NH2:29])=[O:28])=[C:19]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)(=[O:15])=[O:14])=[CH:11][CH:10]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(Sc4ccc(Br)cc4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCCCCCCCCCCO)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(Br)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 61, using Intermediate 60 as a substrate. ES/MS calcd. for C24H21BrN3O4S+ 526.0. Found m/z=526.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[C:18]1([S-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+]>CS(C)=O>[C:18]1([S:24][CH2:2][CH2:3][N:4]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[C:8]([NH2:17])[C:7]=3[N:6]=[CH:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nc2ccccc2c2c1ncn2CCCl
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc2ccccc2c2c1ncn2CCSc1ccccc1
Temperature: 100 °C
Yield: 80 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 8.11 mmol), sodium benzenethiolate (1.79 g, 12.16 mmol) and anhydrous dimethyl sulfoxide (40 mL) under a nitrogen atmosphere. The reaction mixture was heated to 100° C. to give a homogeneous solution that was maintained at 100° C. for 30 minutes at which time the starting material was completely consumed. The hot solution was poured into rapidly stirred water (300 mL) which caused a solid to precipitate out of solution. The solid was collected by filtration to afford an off-white solid. The material was triturated with acetonitrile and collected by filtration to give 1-[2-(phenylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (2.08 g, 6.49 mmol) as an off-white powder, m.p.233–235° C.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].CC(C)=O.Br[CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>O>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:19]=1)[CH2:13][S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CSCc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.7 %

Procedure:
Mercapto-acetic acid (1.39 ml, 20 mmol) was dissolved in a 3.3 molar aqueous solution of sodium hydroxide (12 ml, 40 mmol) and cooled in an ice bath, before an acetone (50 ml) solution of 2-Bromomethyl-4-chloro-1-nitro-benzene (T. J. McCord et al, J. Het. Chem. 1972, 119-122) (5 g, 20 mmol) was added slowly. The resulting solution was stirred for 20 hours at room temperature before being diluted with water (50 ml) and extracted with dichloromethane (25 ml). The aqueous phase was made acidic with acetic acid and extracted with dichloromethane (2×25 ml). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to give the title product as an off-white foam (3.65 g).
Reaction SMILES: [CH2:1]([C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:11][O:12][CH3:13])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.C(N(CC)CC)C.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C)C=O.O>[CH2:14]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:9][O:10][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:11][O:12][CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COCC(CO)(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCC(CO[Si](C)(C)C(C)(C)C)(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4.16 Mmol of 2,2-dibenzyl-3-methoxy-1-propanol was dissolved in 10 ml of N,N-dimethyl formamide, and 0.14 g (2.08 mmol) of imidazole was added thereto. The solution was cooled in ice-water bath to below 5° C., and 0.87 ml (6.24 mmol) of triethyl amine was added thereto. After stirring for 5 minutes, 0.88 g (5.82 mmol) of tert-butyldimethylsilyl chloride in 10 ml of N,N-dimethyl formamide was slowly added to the reaction mixture, and the mixture was stirred in ice-water bath for further 2 hours, and at room temperature for further 1 hour. The reaction mixture was diluted with 10 ml of water, and extracted using 30 ml of dichloromethane. The organic layer was separated, wished twice with 20 ml of water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 2,2-dibenzyl-1-methoxy-3-[(tert-butyldimethylsilyl)oxy]propane.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:3]1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:19][N:20]([CH:22]=[N:14][C:13]1[CH:15]=[CH:16][N:9]([C@@H:4]2[O:5][C@H:6]([CH2:7][OH:8])[C@@H:2]([F:1])[CH2:3]2)[C:10](=[O:11])[N:12]=1)[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: Nc1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)n1
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)n1
Reaction time: 8 h
Yield: 74.7 %

Procedure:
Previously dried 2',3'-dideoxy-3'-fluorocytidine (300 mg, 1.3 mmoles) was treated with dimethylformamide dimethylacetal (0.45 g, 3.8 mmoles) in anhydrous DMF (5 mL) under a nitrogen atmosphere. The contents were stirred overnight and the solvents removed by rotary evaporation. The syrupy residue remaining was crystallized from ethanol to give white crystals (276 mg, 75%) of the product N4 -dimethylaminomethylene-2',3'-dideoxy-3'-fluorocytidine which were shown to have the following properties:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[NH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(C)C1N(CC(=O)NC(C)(C)CO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 35.8 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.39 mmol) prepared in example 116d was reacted with 2-amino-2-methyl-propan-1-ol (69 mg, 0.78 mmol), N-methylmorpholine (81 mg, 0.78 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-1,1-dimethyl-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 74 mg, 35.9%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4([CH3:34])[C:26](=[O:27])[NH:25][C:24]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[N:23]4)[CH2:17][CH2:16]3)[C:9]=2[O:8][CH2:7][CH2:6]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH2:1]([N:25]1[C:26](=[O:27])[C:22]([CH2:21][N:18]2[CH2:17][CH2:16][N:15]([C:14]3[C:9]4[O:8][CH2:7][CH2:6][O:5][C:10]=4[CH:11]=[CH:12][CH:13]=3)[CH2:20][CH2:19]2)([CH3:34])[N:23]=[C:24]1[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH:2]=[CH2:3]
Reactant: CC1(CN2CCN(c3cccc4c3OCCO4)CC2)N=C(c2cccnc2)NC1=O
Reactant: C=CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCN1C(=O)C(C)(CN2CCN(c3cccc4c3OCCO4)CC2)N=C1c1cccnc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of allyl bromide (0.7 ml) in dry tetrahydrofuran (5 ml) was added dropwise at 0° C. under nitrogen to a stirred mixture of 4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-4-methyl-2-(3-pyridyl)-2-imidazolin-5-one (2.86 g; prepared in a similar manner to that described in Example 40), powdered potassium hydroxide (0.57 g) and 18-Crown-6 (0.18 g) in dry tetrahydrofuran (60 ml). The mixture was stirred at ambient temperature for 17 hours then poured onto ice-water (30 ml) and the product extracted into ether. The extracts were dried (MgSO4) and the solvents removed in vacuo to yield a foam which was triturated with ether. The precipitate was collected by filtration to yield 1-allyl-4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-4-methyl-2-(3-pyridyl)-2-imidazolin-5-one as a solid (0.53 g), m.p. 102-105° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24]>CN(C=O)C>[OH:1][CH2:2][CH2:3][S:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH:16][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=4)[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CSCCO)[C@@H](O)[C@H]1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CNc2ncnc3c2ncn3[C@@H]2O[C@H](CSCCO)[C@@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.9 %

Procedure:
A mixture of triol 1b (650 mg, 2.0 mmol), 4-nitrobenzyl bromide (2.16 g, 10 mmol), and powdered 4A molecular sieves (2.0 g) in dry DMF (15 mL was stirred for 4 days in a stoppered flask at ambient temperature, and filtered. The filtrate was concentrated under reduced pressure and the resulting crystalline mass was triturated with acetone (3×) and toluene (3×). The solid residue was dissolved in MeOH (10 mL) and treated with NH3 /MeOH (10 mL; w/v, 1:1, prepared at -10° C.). This solution was stirred for 5 h at ambient temperature and concentrated to a red gum. The gum was dissolved in hot MeOH and cooled to give a brown solid that was recrystallized from MeOH to give title compound 2 as red needles (360 mg, 39%). The mother liquors were concentrated and the residue subjected to flash chromatography (MeOH/CHCl3, 2:23) to give a red solid that was recrystallized to give further red needles (165 mg, 19%) of 2 (total 57%) with mp 157°-158° C.; UV (MeOH) max 270 nm (ε 24 700), HCl/MeOH) max 274 nm (ε 29 900), (NaOH/MeOH) max 271 nm (ε 24 500); IH NMR (Me2 SO-d6) δ 8.62 (br s, 1, NH), 8.46 (s, 1, H8), 8.26 (s, 1, H2), 8.20 (d, JAB =8.8 Hz, 2, Ar), (d, 2, Ar), 5.96 (d, J1'-2' =5.7 Hz, 1, H1'), 5.56 (d, JOH-2' =5.8 Hz, 1, OH2'), 5.39 (d, JOH-3' =5.0 Hz, 1, OH3'), 4.85 (br s, 2, CH2Ar), 4.81 (t, J2'-3' =5.4 Hz, 1, H2'), 4.18 (br q, J3'-4' =4.0 Hz, 1, H3'), 4.05 (m, J4'-5'a =6.0 Hz, J4'-5'b =7.2 Hz, 1, H4'), 3.54 (dt, J=5.5 Hz, 2, CH2OH2.97 (m, J5'a-5'b =13.8 Hz, 1, H5'a), 2.87 (m, 1, H5'b), 2.62 (t, 2, SCH2); 13C NMR (Me2SO-d6) δ 154.32 (C6), 152.56 (C2), 149.31 (Ar), 148.26 (C4), 146.35 (Ar), 140.13 (C8), 128.01 (Ar), 123.44 (Ar), 120.01 (C5), 87.44 (C1'), 84.04 (C4'), 72.71, 72.54 (C2',3'), 60.85 (CH2OH), 43.31 (CH2Ar), 34.63 (C5'), 34.30 (SCH2); MS m/z 417.0969 [C17H17N6 O5S (MC2H5O)=417.0981]. Anal. Calcd for C19 H22N6O6S (462.5): C, 49.34; H, 4.79; N, 18.17. Found: c, 48.99; H, 4.70; N, 18.04
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([NH2:29])[C:24]([CH3:30])=[CH:23]2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([NH:29][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[C:24]([CH3:30])=[CH:23]2
Reactant: COc1ccc2c(c1)cc(C)n2N
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(C)n2NC(=O)c1cnc(-c2cccc(F)c2)nc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (719 mg, 3.1 mmol) and 5-methoxy-2-methyl-indol-1-ylamine (550 mg, 3.1 mmol) in DMF (4 mL) is stirred at 50° C. for 15 min. The mixture is treated with DMTMM (856 mg, 3.1 mmol) and stirred at 50° C. for 1 h. The mixture is concentrated in vacuo, diluted with EtOAc (50 mL), and washed with saturated aqueous Na2CO3 (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-methoxy-2-methyl-indol-1-yl)-amide (180 mg, 15%, 2 steps). MS: 391 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.34 (d, 1H), 8.18 (d, 1H), 7.63 (m, 1H), 7.46 (m, 1H), 7.31 (d, 1H), 7.02 (d, 1H), 6.77 (m, 1H), 6.25 (s, 1H), 3.76 (s, 3H), 2.77 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.CC1C=CC2C(=CC=C(C)C=2)C=1.[CH3:25][OH:26]>>[CH3:12][C:7]1([CH:25]=[O:26])[C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH2:8]1
Reactant: CO
Reactant: Cc1cccc2c(C)cccc12
Agent: Cc1ccc2cc(C)ccc2c1
Product: Cc1cccc2c1C=CCC2(C)C=O

Procedure:
The experiment was carried out in the same manner as in Example 6, except that in Example 6, 1,5-dimethylnaphthalene obtained in Production Example 2 was used in place of the 2,6-dimethylnaphthalene and that methanol was added, thereby obtaining 100 g of a 1,5-dimethylnaphthalene formaldehyde resin which is a viscous liquid at ordinary temperature. The reaction condition and physical properties of the obtained resin are shown in Table 2.
Reaction SMILES: C(N(C(C)C)CC=CC1C=CC=CC=1)(C)C.C1C(O)=CC=C(C)C=1.CS(O)(=O)=O.[OH:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[CH:38]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43]>>[OH:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[C@@H:38]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:43])[CH3:44]
Reactant: Cc1ccc(O)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Agent: CC(C)N(CC=Cc1ccccc1)C(C)C
Agent: CS(=O)(=O)O
Agent: Cc1ccc(O)cc1
Product: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 130 °C
Yield: 85 %

Procedure:
10.2 g of N,N-diisopropyl-3-phenylprop-2-en-1-amine, is added 20.5 g p-cresol and 15.8 g methanesulfonic acid and heated to 130° C. for 6 hours. Chromatography shows disappearance of the peak corresponding N,N-diisopropyl-3-phenylprop-2-en-1-amine, and a fine peak at the retention time of 3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropylamine. From the reaction mixture the (+)-(R)-3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropylamine is isolated as follows: Water and toluene (200 ml each) are added to the reaction mixture and pH adjusted to 9.5. The toluene layer is isolated and washed with water. Distilling off the toluene leaves an oily mass. This is taken up in 300 ml 2-propanol, added 0.55 eq tartaric acid and 0.55 eq formic acid, After stirring overnight, the suspension is filtered. The wet filter cake is approximately 97% pure. The wet filter cake is taken up in 300 ml 2-propanol and heated to reflux, cooled to 5° C., filtered and dried (yield 85%). Purity on HPLC (achiral) 99.5%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCOCC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and morpholine (commercially available) according to the procedure described for Example A. MS (m/e): 256.0 (MH−, 100%)