Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO.ClCCl>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]1[O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[N:1]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COc1ccc(O)c(N)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-4-methoxyphenol (1 g, 7.1 mmol), a compound of formula (d) in 20 mL MeOH was added 2,4-dichlorobenzaldehyde (1.2 g, 7.1 mmol), a compound of formula (e). The mixture was heated at 45° C. for 12 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in 50 mL dichloromethane. To the solution was added DDQ (1.7 g, 7.8 mmol), and the mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was then diluted with an additional 30 mL of dichloromethane and washed sequentially with saturated NaHCO3 (2×50 mL) and brine. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to yield 2-(2,4-dichlorophenyl)-5-methoxybenzoxazole, a compound of formula (f), which was purified using flash column chromatography.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:23]1[CH:24]=[CH:25][C:26]2[N:32]3[C:33]([CH3:36])=[N:34][N:35]=[C:31]3[C@H:30]([CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])[N:29]=[C:28]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=3)[C:27]=2[CH:50]=1)(=O)=O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([C:28]2[C:27]3[CH:50]=[C:23]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:10])[CH:24]=[CH:25][C:26]=3[N:32]3[C:33]([CH3:36])=[N:34][N:35]=[C:31]3[C@H:30]([CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])[N:29]=2)=[CH:44][CH:45]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccccc3C)ccc2-n2c(C)nnc21
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
o-Tolylboronic acid (30.1 mg), sodium carbonate (43.0 mg) and bis(triphenylphosphine)palladium(II) chloride (12.95 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see intermediate 3) (100 mg) in DME (3 ml) and water (1 ml) was added and the reaction mixture was heated at 120° C. for 20 min (microwave) and then at 120° C. for a further 30 min (microwave). Bis(triphenylphosphine)palladium(II) chloride (12.7 mg) was added and the reaction mixture was heated at 120° C. for 30 min (microwave). The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated and washed with water (10 ml) and brine (10 ml), dried and the solvent evaporated. The residue was chromatographed (0-5% methanol:DCM). The resulting mixture was repurified by MDAP (formate modifier) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a white oil (16.8 mg). LCMS (formate): MH+ 484/486, RT 1.14 min
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl>CS(C)=O>[C:20]1([S:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COc1ccc(S(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc(O)cc1)c1cccc2ccccc12
Reaction time: 36 h
Yield: 42.2 %

Procedure:
A mixture of 344 mg (2.0 mmol) 4-methoxybenzene sulfinic acid, 688 mg (4.0 mmol) 1-naphthyl boronic acid, 1.39 mL (10.0 mmol) triethylamine, 363 mg (2.0 mmol) cupric acetate, 350 mg 4A molecular sieves, and 10 mL dry dimethylsulfoxide was stirred under a stream of air for 36 hours. The mixture was then poured into dilute aqueous hydrochloric acid, extracted into ethyl acetate, and the organic layer washed with water, aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate/hexane as eluant to afford 240 mg (40%) of 4-(1-napthylsulfonyl)phenol as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]3[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=3)[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)c1cc(F)cc(F)c1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3cc(F)cc(F)c3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.123 g, 0.442 mmol) was reacted with N-(2-azidoethyl)-3,5-difluorobenzamide (0.100 g, 0.442 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(3,5-difluorobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), δ 7.39 (m, 3H), δ 6.88 (t, 1H), δ 6.43 (s, 1H), δ 6.38 (bs, 2H), δ 4.55 (s, 2H), δ 3.93 (s, 2H), δ 2.56 (t, 2H), δ 2.24 (s, 2H), δ 1.55 (m, 14H), δ 1.23 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 164.3, 164.2, 161.9, 150.3, 149.3, 148.2, 137.6, 122.4, 111.0, 110.8, 107.3, 107.1, 106.8, 106.6, 85.5, 49.3, 40.4, 29.9, 29.5, 29.1, 28.7, 28.2, 27.9, 27.5, 25.4 ppm; HRMS (ESI) calcd for C24H31F2N7O3 (M+) 503.2456. found 503.2458, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-3,5-difluorobenzamide hydrochloride (0.115 g, 59% yield). 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), δ 7.42 (d, 2H), δ 7.29 (t, 1H), δ 6.51 (s, 1H), δ 4.84 (t, 2H), δ 3.96 (q, 2H), δ 2.89 (t, 2H), δ 2.49 (t, 2H), δ 1.79 (m, 2H), δ 1.75 (m, 2H), δ 1.44 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 164.5, 164.4, 127.6, 126.9, 110.6, 110.6, 110.3, 108.5, 107.1, 106.8, 106.6, 52.5, 39.5, 30.4, 27.9, 27.8, 27.6, 24.0, 23.8, 23.1 ppm; HRMS (ESI) calcd for C19H23F2N7O (M+) 403.1932. found 403.1926.
Reaction SMILES: [N:1]1([C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(OC(=O)[NH:38][CH:39]([C:48]([C:50]1[O:54][C:53]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[N:52][C:51]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:49])[CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CN1CCOCC1.N[C@H](C(O)=O)CC(C)C>CN(C=O)C.C(Cl)Cl>[C:55]1([C:53]2[O:54][C:50]([C:48]([C@@H:39]([NH:38][C:15]([C@@H:10]([NH:9][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:49])=[C:51]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[N:52]=2)[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: CC(C)(C)OC(=O)NC(CCc1ccccc1)C(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CCc1ccccc1)C(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
N-[(4-Morpholinyl)carbonyl]-L-leucine (100 mg, 0.35 mmol) (prepared as described in Example 1) was dissolved in 10 mL DMF and cooled to 0° C. To the solution was added EDC (77 mg, 0.4 mmol) and HOBt (54 mg, 0.4 mmol) and the reaction was stirred for 1 h. In a separate flask, [1-(2,4-diphenyloxazole-5-carbonyl)-3-phenylpropyl]carbamic acid tert-butyl ester (158 mg, 0.31 mmol) was dissolved in 4 mL CH2Cl2 and 2 mL TFA was added. After stirring for 1 h, the solvents were evaporated, the residue was dissolved in 5 mL DMF and N-methylmorpholine (406 mg, 0.4 mmol) was added. The resulting solution was added to the previously prepared solution of activated leucine derivative at 0° C. The reaction mixture was stirred at room temperature for 3 h, cooled to 0° C., and quenched with 100 ml of a 10% solution of citric acid in water. The resulting mixture was extracted with 3×100 mL EtOAc. The combined organic extracts were washed with 2×100 mL of saturated bicarbonate and 1×100 mL brine. The organic layer was dried over Na2SO4, filtered and concentrated to a residue that was purified by chromatography (florisil, 30%-50% EtOAc in hexane) to give the title compound as a white solid (90mg, 84%) m.p. 83-5° C., MS (ES) 609 (M+).
Reaction SMILES: [CH2:1]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[O:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:12]=[N:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:15][CH:14]=2)=[CH:21][CH:20]=1)=[O:29]
Reactant: CCCCCCCCOc1ncc(-c2ccc(O)cc2)cn1
Reactant: O=C(O)[C@H]1CCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ncc(-c2ccc(OC(=O)[C@H]3CCCO3)cc2)cn1

Procedure:
901 mg (3 mmol) of 4-(2-n-octyloxy-5-pyrimidinyl)phenol, 464.5 mg (4 mmol) of (R)tetrahydrofuran-2-carboxylic acid and also 49 mg (0.4 mmol) of 4-dimethylaminopyridine are added at room temperature to a solution of 825 mg (4 mmol) of dicyclohexylcarbodiimide in 20 ml of dry dichloromethane while stirring. After stirring for 10 hours at room temperature, the reaction solution is evaporated down in vacuo. Chromatographic purification and recrystallization from n-hexane yield 710 mg (59%) of colorless crystals with [α]D25 =-8.8° (c=2, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[S:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Cl
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)s2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)s4)cc3)o2)cc(OC)c1Cl

Procedure:
1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (80% EtOAc-hexanes) gave the product as a pale yellow solid (0.106 g, 26% yield). MS: m/z 485.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16](O)([CH3:18])[CH3:17])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8].[Cl-:20].[Ca+2].[Cl-].Cl.O>C1(C)C=CC=CC=1.[Cu]I.[Cu]>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([Cl:20])([CH3:18])[CH3:17])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8]
Reactant: COC(=O)NCc1cc(C#CC(C)(C)O)ccc1Cl
Reactant: [Cl-]
Agent: [Cu]
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)NCc1cc(C#CC(C)(C)Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 133.1 %

Procedure:
0.50 g of methyl N-[2-chloro-5-(3-hydroxy-3-methyl-1-butynyl)benzyl]carbamate was dissolved in 10 ml of toluene. This solution was added at 0° C. to a mixture comprising 0.15 g of calcium chloride, 0.11 g of copper(I) iodide, 0.01 g of copper and 10 ml of concentrated hydrochloric acid, followed by stirring at 0° C. for 5 hours. This reaction solution was poured into water and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.54 g of methyl N-[2-chloro-5-(3-chloro-3-methyl-1-butynyl)benzyl]carbamate as a brown viscous liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].Cl.[CH3:25][O:26][C:27](=[O:52])[CH:28]([NH:41][C:42](=[O:51])[C:43]1[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=1[Cl:50])[CH2:29][C:30]1[O:34][N:33]=[C:32]([CH:35]([NH2:40])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:52])[CH:28]([NH:41][C:42](=[O:51])[C:43]1[C:44]([Cl:50])=[CH:45][CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:29][C:30]1[O:34][N:33]=[C:32]([CH:35]([NH:40][C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=1
Reactant: COC(=O)C(Cc1cc(C(N)CC(C)C)no1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: Cl
Product: COC(=O)C(Cc1cc(C(CC(C)C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)no1)NC(=O)c1c(Cl)cccc1Cl
Yield: 51 %

Procedure:
The title compound was prepared in the manner described in example 2B using 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic acid and 3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-benzoylamino)-propionic acid methyl ester hydrochloride. 51% yield; white solid. MS (m/z) 724.2 and 726.2 (M+1).
Reaction SMILES: [NH2-].[Na+].CS[C:5](=[S:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2C=CC=CC=2)=[O:22])=[CH:19][CH:18]=1.Cl>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:5](=[S:14])[CH2:23][C:21]([C:20]1[CH:29]=[CH:30][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:22])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CSC(=S)OCc1ccccc1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CC(=S)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a suspension of sodium amide (1.6 g) in toluene (50 mL) was added a mixture of dithiocarbonic acid O-benzyl ester S-methyl ester (4.0 g) and 4-methoxybenzophenone (3.0 g) at room temperature and the mixture was stirred at room temperature overnight. Hydrochloric acid solution (2 mol/L, 80 mL) was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/dichloromethane=5/1-2/1) to give the title compound (3.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:12][O:13][CH3:14])[N:6]=[CH:7]2.C(N(CC)CC)C.[C:22](=S)=[S:23].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[N:1]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:12][O:13][CH3:14])[N:6]=[CH:7]2)=[C:22]=[S:23]
Reactant: S=C=S
Reactant: COCc1cc2c(N)cccc2cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCc1cc2c(N=C=S)cccc2cn1
Reaction time: 4 h

Procedure:
A solution of 5-amino-3-methoxymethylisoquinoline (22.9 g) in pyridine (80 cc) is added dropwise, whilst stirring and at a temperature of about -10° C., to a solution of triethylamine (17 cc) and carbon disulphide (55 cc) in pyridine (80 cc). After 4 hours at -10° C., a solution of dicyclohexylcarbodiimide (25.2 g) in pyridine (80 cc) is added dropwise. Stirring is maintained for 3 hours at a temperature which changes from -10° to 20° C., and then for 20 hours at a temperature of about 20° C. The mixture is evaporated to dryness at 60° C. under reduced pressure (20 mm Hg), the residue is taken up in methylene chloride (800 cc), and insoluble material is removed by filtration and the filtrate is evaporated to dryness at 40° C. under reduced pressure (40 mm Hg). The residue is taken up in diisopropyl ether (1 liter; an insoluble material is removed by filtration and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). 5-Isothiocyanato-3-methoxymethylisoquinoline (18.5 g), m.p. 88° C., is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[I-].[Na+].[F:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:31][CH:30]=1>CN(C)C=O>[F:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([CH:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)=[O:34])=[CH:41][CH:42]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Temperature: 20 °C
Reaction time: 7 h
Yield: 24.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (4.2 g), triethylamine (2.1 cc), sodium iodide (2.2 g) and 4-(4-fluorobenzoyl)piperidine (3.1 g) in dimethylformamide (50 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 7 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallizatior from boiling acetonitrile (15 cc), 2-{3-[4-(4-fluorobenzoyl)piperidino]propyl}naphtho[1,8cd]isothiazole 1,1-dioxide (1.65 g) is obtained, m.p. 132° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[C:16]([O:37][CH2:38][CH3:39])=[C:17]([CH:23]4[CH2:26][N:25](C(OCC5C=CC=CC=5)=O)[CH2:24]4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.O>[Pd].CO>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[CH:20]=[C:19]([Cl:21])[C:18]([CH3:22])=[C:17]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:16]=3[O:37][CH2:38][CH3:39])[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reaction time: 2 h
Yield: 40.3 %

Procedure:
To a mixture of benzyl 3-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate (23 mg, 0.042 mmol) and 5% palladium on carbon (10 mg) in methanol (1.6 mL) was added 0.25 M hydrogen chloride in water (0.42 mL, 0.10 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature for 2 hours. After filtered off the catalyst, the filtrate was neutralized with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give 4-amino-8-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one (7 mg, 40%). To a mixture of the crude amine in acetonitrile (0.1 mL)/methanol (0.1 mL)/tetrahydrofuran (0.1 mL) was added N,N-diisopropylethylamine (0.02 mL, 0.1 mmol), followed by acetone (0.03 mL, 0.4 mmol). The mixture was stirred for 30 minutes before the addition of sodium triacetoxyborohydride (0.044 g, 0.21 mmol). The reaction was stirred at room temperature for 4 hours, then quenched with water and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product as TFA salt. The product was isolated as a racemic mixture. LCMS calculated for C24H31ClN5O2 (M+H)+: m/z=456.2; Found: 456.1.
Reaction SMILES: [CH2:1]([N:8]([C:12](Cl)=[O:13])[C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.[CH3:16][S:17][C:18](=[NH:24])[NH:19][N:20]=[C:21]([CH3:23])[CH3:22]>C(N(CC)CC)C>[CH2:1]([N:8]1[C:12](=[O:13])[NH:24][CH:18]([S:17][CH3:16])[N:19]([N:20]=[C:21]([CH3:23])[CH3:22])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)N(Cc1ccccc1)C(=O)Cl
Reactant: CSC(=N)NN=C(C)C
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(Cc2ccccc2)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-benzyl-bis-(chlorocarbonyl)-amine and acetone-S-methyl-isothiosemicarbazone hydroiodide, with addition of triethylamine, yielded 1-benzyl-3-isopropylideneamino-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione as a pale brown powder of melting point 148°-150° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:20][C:21](=[O:39])[CH:22]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[NH:23]C(OC(C)(C)C)=O)[C@H:12]1[OH:13]>C(O)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:20][C:21](=[O:39])[CH:22]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[NH2:23])[C@H:12]1[OH:13]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1C(=O)O
Solvent: O=CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)C(N)Cc2ccc(F)cc2)[C@H]1O
Yield: 66.2 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-[β-(4-fluorophenyl)-D,L-alanylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (173 mg) was prepared by reacting 1-(6-amino-9H-purin-9-yl)-3-[N-tert-butoxycarbonyl-β-(4-fluorophenyl)-D,L-alanylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (320 mg) prepared in Example 27 and formic acid (5 ml) according to a similar manner to that of Example 45, mp. 120°-130° C. (dec.).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][S:40]([CH2:43][CH3:44])(=[O:42])=[O:41].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][N:39]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[F:32])[S:40]([CH2:43][CH3:44])(=[O:41])=[O:42])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: CCS(=O)(=O)Nc1ccccc1F
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CN(c2ccccc2F)S(=O)(=O)CC)C2CC2)C1=O
Temperature: 70 °C

Procedure:
To a mixture of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A, 70 mg, 0.153 mmol) and N-(2-fluorophenyl)ethanesulfonamide (93 mg, 0.458 mmol) in toluene (1 ml) was added cyanomethylenetri-n-butylphosphorane (0.111 ml, 0.458 mmol) at rt and the mixture was flushed with N2 for about 20 minutes. The reaction was sealed and heated to 70° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (eluent: 0% to 35% EtOAc/hexanes) to provide the title compound as a solid.