Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.CCCCCC.[CH3:21][N:22]([CH3:36])[C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:26]1([OH:29])[CH2:27][CH2:28][C:23]([N:22]([CH3:21])[CH3:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:25]1
Reactant: c1ccc2scnc2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)C1(c2ccccc2)CCC(O)(c2nc3ccccc3s2)CC1
Temperature: -80 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of benzothiazole (622 mg, 4.60 mmol) in dry THF (30 ml) was cooled to −85° C. under a stream of argon. n-butyllithium (5.52 mmol, 3.45 ml of a 1.6 molar hexane solution) was added dropwise in such a way that a reaction temperature of −78° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2 hours at −80° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (1.00 g, 4.61 mmol) in dry THF (8 ml) was added dropwise at −80° C. The mixture was stirred for 30 minutes at −80° C. and then 3 days at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (30 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out b y flash chromatography with cyclohexane/ethylacetate (V:V=7:3) over silica gel. 746 mg 1-benzothiazol-2-yl-4-dimethylamino-4-phenylcyclohexanol with a melting point of 155–157° C. were obtained.
Reaction SMILES: [ClH:1].O[C@H](COC1C=CC(C(C)(C)C)=CC=1)[CH2:4][NH:5]C(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52](OC)=[CH:51][CH:50]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]([C:4]#[N:5])[CH:54]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C#N)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 339 (M-15,.1), 234 (15), 233 (100), 121 (21), 102 (7), 90 (6).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH2:7][NH:8]S(C(C)(C)C)=O)[O:4][N:3]=1.[ClH:15].O1CCOCC1>CO>[ClH:15].[Br:1][C:2]1[CH:6]=[C:5]([CH2:7][NH2:8])[O:4][N:3]=1
Reactant: CC(C)(C)S(=O)NCc1cc(Br)no1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCc1cc(Br)no1
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid (3-bromo-isoxazol-5-ylmethyl)-amide (128 mg, 0.455 mmol) in MeOH (5 mL) was added a 4 M solution of HCl in dioxane (0.350 mL, 1.40 mmol) dropwise. After 2 hours and 10 minutes, the reaction mixture was concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].C(=O)(O)[O-].[Na+]>O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 165 °C
Yield: 91.6 %

Procedure:
A heterogeneous mixture of 2-amino-4-fluorobenzoic acid (8.7 g, 56 mmol) and formamidine acetate (29.2 g, 280 mmol) was stirred and heated at 165° C. for 2 hours. The reaction mixture was suspended in water and the mixture was carefully basified with saturated sodium bicarbonate solution followed by stirring for 1 hour. The brown solid was collected by filtration, washed with water and air dried to afford 8.42 g (91%) of 7-fluoroquinazolin-4(3H)-one. MS 165.0 (ES+).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[CH3:26][NH:27][CH3:28]>>[ClH:1].[ClH:1].[CH:21]1([N:18]2[CH2:19][CH2:20][CH:15]([CH2:14][C:11]3[N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:27]([CH3:28])[CH3:26])=[CH:4][CH:5]=4)[O:13][N:12]=3)[CH2:16][CH2:17]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CNC
Reactant: ClCc1ccc(-c2nc(CC3CCN(C4CCCC4)CC3)no2)cc1
Product: CN(C)Cc1ccc(-c2nc(CC3CCN(C4CCCC4)CC3)no2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 23, starting from 4-[5-(4-chloromethylphenyl)[1,2,4]oxadiazol-3-ylmethyl]-1-cyclopentylpiperidine and dimethylamine. HPLC: Rt=4.43 min.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24](=O)[O:25]C3C=CC=CC=3)=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40]([NH:43][C:24]([NH:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[N:7]=[C:3]2[CH2:1][CH3:2])=[CH:20][CH:19]=1)=[O:25])(=[O:42])=[O:41]
Reactant: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[2-ethyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 2-chlorobenzenesulfonamide. MS (ESI) m/z 527 [M+H]+, 525 [M−H]−, 1H-NMR (CDCl3)δ1.25 (3H, t, J=7.5 Hz), 2.71 (2H, q, J=7.5 Hz), 2.85 (2H, t, J=7.0 Hz), 3.47-3.54 (2H, m), 6.57 (1H, br), 7.07 (2H, t, J=8.8 Hz), 7.19 (1H, s), 7.26 (2H, s), 7.40-7.46 (1H, m), 7.57-7.61 (2H, m), 7.73-7.78 (2H, m), 8.00 (2H, d, J=7.5 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2F)([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC1(Cc2cc(F)ccc2F)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 110 °C

Procedure:
To a stirring suspension of magnesium strip (763 mg) in diethyl ether (7 mL) was added a crystal of iodine followed by (0.4 mL of 2-(bromomethyl)-1,4-difluorobenzene under nitrogen. The reaction mixture was initiated with a high intensity heat gun, 2-(bromomethyl)-1,4-difluorobenzene 5.0 g, 24.25 mmol) in diethyl ether (7 mL) was added slowly maintaining gentle reflux. After addition was completed the reaction mixture was stirred at reflux for 100 min, cooled to room temperature. To this reaction mixture a solution of 1-benzylpiperidin-4-one (4.57 g, 24.25 mmol) in diethyl ether (12 mL) was added dropwise with vigorous stirring. After addition was completed the reaction mixture was left at room temperature overnight. Aqueous NH4Cl solution was added and stirred at room temperature until hydrolysis was completed, extracted with diethyl ether. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.2% NH4OH) to give intermediate 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol (2.74 g) containg large quantities of unknown impurities. To a suspension of NaH (55%, 1.12 g, 26.0 mmol) in toluene (10 mL) was slowly added a solution of 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol in toluene (15 mL). After addition was completed the reaction mixture was stirred at 110° C. (in a pre heated oil bath), after 5 min, DMF (9 mL) was added and stirring was continued at reflux temperature for 2 h. The reaction mixture was cooled to room temperature, H2O (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.2% NH4OH) to give the subtitled compound (190 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.C1([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)=[CH:21][N:22]3OC)CC1.[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].C([O:44][CH2:45][CH3:46])(=O)C>>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:32]3[CH2:33][CH:34]=[C:29]([C:20]4[C:19]5[C:23](=[CH:24][CH:25]=[CH:26][C:18]=5[O:44][CH2:45][CH:46]5[CH2:36][CH2:35]5)[NH:22][CH:21]=4)[CH2:30][CH2:31]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COn1cc(C2=CCNCC2)c2c(C3CC3)cccc21
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: CCOC(C)=O
Agent: O=C(O)C(=O)O
Product: C1=C(c2c[nH]c3cccc(OCC4CC4)c23)CCN(CCCOc2cccc3[nH]ccc23)C1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(4-cyclopropy1-methoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridine (which was prepared by condensing 4-cyclopropylmethoxyindole with 4-piperidone monohydrate hydrochloride in refluxing methanol with potassium hydroxide). The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 20% overall yield as a white foam . FDMS m/e=441 (M+ of free base).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][NH:14]2)=[CH:10][C:9]=1[CH3:17].ClC(Cl)(Cl)C([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:24][CH2:23]1)=O>ClCCl>[ClH:7].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][N:14]2[S:36]([C:30]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([N:25]3[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]3)[CH:29]=2)(=[O:37])=[O:38])=[CH:10][C:9]=1[CH3:17]
Reactant: Cc1cc2c(cc1Cl)NCC2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCc3cc(C)c(Cl)cc32)cc1N1CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.3 %

Procedure:
Pyridine (0.28 ml) was added to a stirred solution of 6-chloro-5-methyl-2,3-dihydro-1H-indole (WO-9501976) (0.116 g) and 3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride (D4) (300 mg) in dichioromethane (4 ml) at room temperature. After 18 h the solution was washed with 1M hydrochloric acid (5 ml), water (5 ml), dried (MgSO4) and concentrated to an oil. The oil was dissolved in 1,4-dioxan (13 ml) and a 0.15 M potassium hydroxide solution (6.5 ml) was added. The solution was stirred at room temperature for 4 h then concentrated to remove the organic solvent, diluted with water (10 ml) and the solution extracted with dichloromethane (20 ml). The organic phase was dried (Na2SO4), acidified with 1M ethereal hydrogen chloride (2 ml), concentrated to a solid and stirred with acetone to afford the title compound (0.175 g, 55%). MH+ 422/424.
Reaction SMILES: [CH2:1]([O:19][C:20]1[C:21]([O:23][C@H:24]([C@H:27]([CH2:29][OH:30])[OH:28])[C:25]=1[OH:26])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClC(Cl)(Cl)C(O)=O>C(Cl)(Cl)Cl>[C:31]1([NH:37][C:38]([O:30][CH2:29][C@H:27]([OH:28])[C@H:24]2[O:23][C:21](=[O:22])[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:25]2[OH:26])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1=C(O)[C@@H]([C@@H](O)COC(=O)Nc2ccccc2)OC1=O
Temperature: 60 °C
Yield: 68.5 %

Procedure:
To a solution of 2-O-octadecyl-L-ascorbic acid (0.8 g, 2 mmole) and phenylisocyanate (0.24 g, 2 mmole) in chloroform (20 ml) was added trichloracetic acid (0.1 ml). The mixture was heated at 60° C. for one hour, which was washed with water, dried and concentrated to give a product. The product was recrystallized from isopropyl ether - ethyl acetate to give 6-O-phenylcarbamoyl-2-O-octadecyl-L-ascorbic acid (0.75 g), m.p. 149°-150° C. C31H49NO7 (Found: C,68.14; H,9.08; N,2.74%. Anal. Calcd: C,67.98; H,9.02; N,2.56).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:11].[H-].[Na+].CI.[CH3:16]C(=O)OCC.[Cl-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:16])=[CH:4][C:3]=1[CH3:11].[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:16])[CH:6]=2
Reactant: CCOC(C)=O
Reactant: Cc1cc2cn[nH]c2cc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cc1cc2cn(C)nc2cc1Br
Product: Cc1cc2cnn(C)c2cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-bromo-5-methyl-1H-indazole (31, 211 mg, 1 mmol) in 5 ml dry THF was carefully added sodium hydride (200 mg, 60%). The suspension was stirred at r.t for 2 h before addition of methyl iodide (93 μl, 1.5 eq). After stirring at r.t. for 3 h, the reaction mixture was worked up with EA/brine. Org. phase was dried over sodium sulfate, concentrated and then subjected to silica gel column chromatography (0-50%-100% B; A: hexane; B: 50% EA in hexane) to give 101.4 mg of 6-bromo-1,5-dimethyl-1H-indazole (32) as white solid (yield: 45.0%; purity>95%) and 99.9 mg of 6-bromo-2,5-dimethyl-2H-indazole (33) as white solid (yield: 44.4%; purity>95%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:17](=O)[CH3:18])[CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][N+:8]([O-])=O)[CH3:2].[F:21][C:22]1[CH:28]=[CH:27][C:25](N)=[CH:24][CH:23]=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][N:8]([C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=2)[C:17]=1[CH3:18])=[O:20])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(C[N+](=O)[O-])c1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)cn(-c2ccc(F)cc2)c1C
Yield: 52.4 %

Procedure:
A mixture of 2-acetyl-4-nitro-3-phenyl-butyric acid ethyl ester (4.26 g, 14.3 mmol), 4-fluoroaniline (1.75 g, 15.73 mmol), and TsOH monohydrate (136 mg, 0.72 mmol) in toluene (40 mL) was refluxed overnight, while the generated water was collected with a Dean-Stark distillation head; then the reaction was cooled, diluted with EtOAc, washed with diluted sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution respective, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified on column to give the desired title compound (2.422 g); ESI MS (m/z): 324 (M+H+).
Reaction SMILES: C([O:8][CH:9]([CH2:36]OC1C=CC(F)=CC=1)[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[C:15](=[O:33])[CH2:14][S:13]1(=O)=O)C1C=CC=CC=1.[CH2:45](OCC#C[C@@H](OC(=O)C)CCCCC)[C:46]1C=CC=[CH:48][CH:47]=1>>[OH:8][C@@H:9]([CH2:36][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:15](=[O:33])[CH2:14][S:13]1
Reactant: O=C(CCCCCCN1C(=O)CS(=O)(=O)C1CCC(COc1ccc(F)cc1)OCc1ccccc1)OCc1ccccc1
Reactant: CCCCC[C@@H](C#CCOCc1ccccc1)OC(C)=O
Product: CCCCC[C@H](O)CCC1SCC(=O)N1CCCCCCC(=O)O

Procedure:
This compound is prepared essentially by the method as described in Example 5, Step E, except that the benzyl 7-{2-(3-benzyloxy-4-[4-fluorophenoxy]butyl)-1,1,4-trioxo-3-thiazolidinyl}heptanoate is replaced by 1-benzyloxy-4(S)-acetyloxy-2-nonyne and no chromatographic purification is needed. The title compound is obtained as a mobile oil which is used immediately in Step A-6 below.
Reaction SMILES: C(=O)([O:7][CH2:8][C:9]([C:12]1[CH:16]=[C:15]([N:17]2[CH2:21][C@@:20]3([CH2:26][CH2:25][CH2:24][C@@:23]([CH2:28][N:29]4[C:33]5[CH:34]=[C:35]([C:38]#[N:39])[CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)([CH3:27])[CH2:22]3)[O:19][C:18]2=[O:40])[O:14][N:13]=1)([CH3:11])[CH3:10])OC(C)(C)C.C([O-])([O-])=O.[K+].[K+].O.CO>CC#N.O>[OH:7][CH2:8][C:9]([C:12]1[CH:16]=[C:15]([N:17]2[CH2:21][C@@:20]3([CH2:26][CH2:25][CH2:24][C@@:23]([CH2:28][N:29]4[C:33]5[CH:34]=[C:35]([C:38]#[N:39])[CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)([CH3:27])[CH2:22]3)[O:19][C:18]2=[O:40])[O:14][N:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)OCC(C)(C)c1cc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC(C)(CO)c1cc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)on1
Temperature: 110 °C
Yield: 25.2 %

Procedure:
To a 2 mL microwave vial was added tert-butyl (2-(5-((5S,7S)-7-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)isoxazol-3-yl)-2-methylpropyl) carbonate (30 mg, 0.053 mmol), K2CO3 (5.15 μg, 0.037 μmol), water (0.500 mL) and MeOH (0.5 mL). The vial was capped and heated to 110° C. for 3 h. The mixture was then filtered through paper, and the paper washed with MeOH (2 mL), then concentrated. This mixture was purified on reverse phase Gilson HPLC: 30 mm×150 mm Waters Sunfire column, neutral conditions 10-100% MeCN/H2O, 14 min, 40 mL/min to give 1-(((5S,7S)-3-(3-(1-hydroxy-2-methylpropan-2-yl)isoxazol-5-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (6.2 mg, 24% yield). MS (m/z) 464.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:17](=[O:18])[NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH3:8])=[N:3][O:2][CH3:1]
Reactant: CONC(=O)CCl
Reactant: COc1ccccc1N=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CON=C(CCl)OC(=O)Nc1ccccc1OC
Temperature: 25 °C

Procedure:
N-Methoxychloroacetamide (12.3 grams; 0.1 mole), benzene (60 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methoxyphenylisocyanate (15 grams; 0.1 mole) dissolved in benzene (30 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 3 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-[N-(2-methoxyphenyl)carbamoyloxy]-2-methoxyiminoethane.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[NH2:29]>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[CH:18][C:17]=1[NH:29][S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CN1CCN(c2ccc(Br)c(N)c2)CC1
Product: CN1CCN(c2ccc(Br)c(NS(=O)(=O)c3ccc4ccccc4c3)c2)CC1

Procedure:
The title compound (E118) was prepared from naphthalene-2-sulfonyl chloride (100 mg, 0.44 mmol) and 2-bromo-5-(4-methylpiperazin-1-yl)phenylamine (D27) (120 mg, 0.44 mmol) using the method of Example 1 (85 mg, 35%) MH+=460/462.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[C:20](=[O:21])[CH2:19][NH:18][C:17]3=[O:22])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][C@H:26]([CH2:34][OH:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[N+:36]([C:39]1[N:40]=[CH:41][NH:42][CH:43]=1)([O-:38])=[O:37].C1(C(C2C=CC=CC=2)CNC2N=C(N3C=C([N+]([O-])=O)C=N3)N=C3C=2N=CN3[C@@H]2C[C@H](NC(=O)CO)[C@@H](O)[C@H]2O)C=CC=CC=1>>[OH:23][C@H:13]1[C@@H:12]([OH:24])[C@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([N:42]2[CH:43]=[C:39]([N+:36]([O-:38])=[O:37])[N:40]=[CH:41]2)=[N:3][C:4]=3[NH:25][C@H:26]([CH2:34][OH:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][C@@H:14]1[N:16]1[C:20](=[O:21])[CH2:19][NH:18][C:17]1=[O:22]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=C1CNC(=O)N1[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O
Product: O=C1CNC(=O)N1[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(-n4cnc([N+](=O)[O-])c4)nc32)[C@H](O)[C@@H]1O

Procedure:
3-{(1S,2R,3S,4R)-4-[2-Chloro-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-imidazolidine-2,4-dione (Intermediate VB) and 4-nitro-imidazole, as described for N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate QD).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[C:5]([SH:12])[CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C.C(O)(=O)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][S:12][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:3][CH:4]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrCc1ccccc1OCc1ccccc1
Reactant: O=C(O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
Sodium hydride (6.5 g, 50% dispersion in oil) in DMF (100 ml) was cooled (0° C., ice bath) and 4-thiobenzoic acid (10 g) was added. After stirring for 30 minutes at 0° C., 2-bromomethylphenyl benzyl ether (18.6 g) as a solution in DMF (100 ml) was added. The reaction was stirred at ambient temperature for 18 hours, cooled (ice bath), water was added, and the mixture acidified with acetic acid. The resulting solid was isolated by filtration and recrystallised from methanol to give 4-[2-benzyloxybenzylthio]benzoic acid (24 g) (mpt. 144° C.).
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([NH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3].[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].OC([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@H](N(C)C(=O)CC2)CC3)CC1)C.C(Cl)(=O)CCCCCCCCC=C>>[CH3:24][C:25]([CH3:30])([CH3:29])[C:26]([O:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([NH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3])=[O:27]
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)C(=O)Cl
Agent: C=CCCCCCCCCC(=O)Cl
Agent: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(OC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing substantially the same procedure as described in Example 6, but substituting 20-hydroxy-5α-4-azapregn-1-ene-3-one and trimethylacetyl chloride for the 20-hydroxy-4-methyl-5α-4-azapregnan-3-one and 10-undecenoyl chloride, respectively, used therein, the title compound was obtained. MS M-1 calculated for C25H39NO3, mw=402.53; observed m/e 401.