Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH:5]([C:7]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH:8]=1)=[O:6].[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[OH:6][CH:5]([C:7]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH:8]=1)[CH:1]=[CH2:2]
Reactant: O=Cc1coc(Cc2ccc(F)cc2)c1
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CC(O)c1coc(Cc2ccc(F)cc2)c1
Reaction time: 15 h

Procedure:
46.5 ml of a 1.5M solution of vinylmagnesium chloride in tetrahydrofuran are initially taken in 60 ml of absolute tetrahydrofuran at 0° C. 11.9 g of 3-formyl-5-(p-fluorobenzyl)-furan in 60 ml of absolute tetrahydrofuran are added dropwise at 0°-10° C. to the stirred mixture in the absence of moisture, and stirring is continued for 15 hours at room temperature. 100 ml of a saturated ammonium chloride solution and 20 ml of glacial acetic acid are added carefully to the reaction mixture, the precipitate dissolving. The mixture is extracted three times by shaking with ether, after which the combined ether extracts are washed with water, dried over sodium sulfate and evaporated down under reduced pressure. The oil obtained (14 g) is purified by column chromatography over silica gel using toluene/acetone (9/1) as the eluent. 7.1 g of 3-(1-hydroxy-2-propenyl)-5-(p-fluorobenzyl)-furan are obtained as an oil (nD22 : 1.5370). ##STR15##
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])=[CH:22][CH:21]=1)#[CH:19]>C(N(CC)CC)C.O1CCCC1.[Cu]I.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([C:19]#[C:18][C:20]2[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])=[CH:22][CH:21]=2)=[CH:3][CH:4]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C(=O)OCCCCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCOC(=O)c1ccc(C#Cc2ccc(C(=O)OCCCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, heptyl 4-iodobenzoate (2a) (3.64 g, 10.5 mmol) was dissolved in anhydrous triethylamine (8.6 mL), and anhydrous tetrahydrofuran (4.0 mL), triphenylphosphine (39.3 mg, 0.150 mmol), copper (I) iodide (43.8 mg, 0.230 mmol), and Pd(PPh3)2Cl2 (27.9 mg, 0.0397 mmol) were added. Thereafter, a solution of heptyl 4-ethynylbenzoate (4a) (2.64 g, 10.8 mmol) in anhydrous tetrahydrofuran (2.0 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 3 hr. The reaction solution was filtered through celite and, after removal under reduced pressure, diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:10). Subsequent recrystallization from methanol/ethanol (5:1, v/v) gave bis[4-(heptyloxycarbonyl)phenyl]acetylene (5a) (4.64 g, yield 95%) as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]1([NH:54][C:55]2[C:56](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:57](O)=[O:58])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:57](=[O:58])[C:56]3[CH:60]=[CH:61][CH:62]=[CH:63][C:55]=3[NH:54][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(O)c1ccccc1Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3Nc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) with N-phenylanthranilic acid (21 mg) and N,N-diisopropylethylamine (33 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, phenethyl alcohol and DBU in DME. EI-MS m/e (%): 306 (M+, 4), 202 ([M—C6H5CH═CH2]+, 48), 104 (21).
Reaction SMILES: [NH3:1].Br[C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1>CO>[CH2:16]([N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH2:1])=[N:8][CH:7]=2)[CH2:11][CH2:12]1)[CH3:17]
Reactant: N
Reactant: CCN1CCN(Cc2ccc(Br)nc2)CC1
Solvent: CO
Product: CCN1CCN(Cc2ccc(N)nc2)CC1
Temperature: 70 °C
Yield: 54.5 %

Procedure:
Add liquid ammonia (50.0 kg) to a degassed mixture of 1-(6-bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine (14.2 kg), cuprous oxide (200 g), and MeOH (57 kg) at T≦40° C. Heat the mixture at 65-75° C. overnight. Cool to 20-30° C. and filter over a Celite® pad. Concentrate the filtrate and add DCM (113 kg) and adjust the pH to 12-14 with sodium hydroxide 2N (23 kg) separate the phases and wash the organic phase with DCM (58×2 kg) and combine the organic layers. Filter the mixture through Celite® and concentrate. Dissolve the residue in toluene (9.7 kg) and crystallize by the addition of MtBE (8.3 kg) to give 6.0 kg of the title compound. Obtain further purification through a toluene recrystallization. MS (ES+): m/z=221 (M+H)+.
Reaction SMILES: CS(O[C@H:6]1[C:30]2[C@:25]([CH3:32])([CH2:26][CH2:27][C:28](=[O:31])[CH:29]=2)[C@@H:24]2[C@H:8]([C@H:9]3[C@:21]([CH3:33])([CH2:22][CH2:23]2)[C@@H:12]([C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]3)[C@H:7]1OS(C)(=O)=O)(=O)=O.[N-:39]=[N+:40]=[N-:41].[Na+].C(O)(=O)C>CO>[N:39]([C:6]1[C:30]2[C@:25]([CH3:32])([CH2:26][CH2:27][C:28](=[O:31])[CH:29]=2)[C@@H:24]2[C@H:8]([C@H:9]3[C@:21]([CH3:33])([CH2:22][CH2:23]2)[C@@H:12]([C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
In a manner similar to that described in Example 6C, treat 6β,7β-dimethanesulfonyloxy-4-cholestene-3-one with sodium azide in aqueous methanol in the presence of acetic acid. Isolate and purify the resultant product in a manner similar to that described to obtain 6-azido-4,6-cholestadiene-3-one.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[N:9]1([S:14]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)(=[O:16])=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1.CN[C:25]1[CH:30]=CC=[CH:27][CH:26]=1>CC#N>[CH3:18][N:17]([C:21]1[CH:20]=[CH:27][CH:26]=[CH:25][CH:30]=1)[S:14]([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)(=[O:15])=[O:16]
Reactant: CNc1ccccc1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: CN(c1ccccc1)S(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (3 g, 8.3 mmol) in dry CH3CN (dried over MgSO4) was added N-methylaniline (740 mg, 6.9 mmol) under nitrogen. The mixture was stirred at room temperature for 16 h. After the solvent was removed, the residue was extracted with EtOAc (50 mL×3). The organic layer was washed with brine (50 mL) and water (50 mL). After the solvent was removed, the residue was purified by column chromatography (eluting with 30˜60% EtOAc) to give the title compound, which was used in next step without further purification (1 g, 51%). LCMS (ESI): m/z 237.9 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][C:14](=O)[CH3:15])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[CH:13]=[C:14]([CH3:15])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:25])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccccc2)c1-c1ccccc1

Procedure:
Aniline (10 mmol, 0.9 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized from ethanol (m.p. 130° C.-131.7° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=O)[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C@@H:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[NH2:33].[Na].[NH4+].[OH-]>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[CH:26]([NH:33][CH:32]([C:34]5[C:43]6[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=6)[CH:37]=[CH:36][CH:35]=5)[CH3:31])[CH3:27])[C:21]4=[O:30])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reactant: C[C@H](N)c1cccc2ccccc12
Agent: [NH4+]
Agent: [Na]
Agent: [OH-]
Solvent: ClCCl
Product: CC(NC(C)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.018 mol), (S)-α-methyl-1-naphthalenemethanamine (0.0187 mol) and sodium tris(acetato-O)hydroborate (I-) (0.028 mol) in CH2Cl2 (150 ml) was stirred at room temperature overnight. A diluted NH4OH solution was added. The mixture was stirred for 1 hour. The precipitate was filtered off, washed with H2O and with CH2Cl2 (20 ml) and dried. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 3.3 g (32%) of [R-(R*,S*)(S*)]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[1-metyl-2-[[1-(1-naphthalenyl)ethyl]amino]propyl]-3H-1,2,4-triazol-3-one (interm. 108).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)OCC(=O)Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:22]([NH:21][CH2:20][CH2:19][Cl:18])=[O:23])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: O=C=NCCCl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)NCCCl)C1O
Temperature: 25 °C
Yield: 83 %

Procedure:
To a mixture of 400 mg (1.70 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 40 ml of dichloromethane were added 200 μl (1.87 m mol) of 2-chloroethyl isocyanate with stirring at the room temperature, followed by stirring for 6 hours. The precipitated crystals were separated by filter to obtain 480 mg (yield: 83%) of the intended compound as colorless crystals.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].CCN(C(C)C)C(C)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1.[C:50](N1C2C=CC=CC=2N=N1)(=[NH:52])[NH2:51]>CN(C=O)C>[C:39]1([CH3:49])[CH:40]=[CH:41][C:42]([S:45]([OH:48])(=[O:46])=[O:47])=[CH:43][CH:44]=1.[C:50]([N:7]1[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]1)(=[NH:51])[NH2:52]
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reactant: N=C(N)n1nnc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(C(=N)N)CC1
Reaction time: 24 h

Procedure:
Morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride (0.2 g, 0.47 mmol) was dissolved in 3 mL of DMF and 2 equiv of Hunig's base was added followed by 1-carbamimidoyl-1,2,3-benztriazole p-toluenesulfonate (0.16 g, 0.47 mmol). The reaction was stirred 24 hours at which time the solvent was removed in vacuo. The resulting paste was purified by preparative HPLC to give the title compound; MS, m/z 434, M+1-p-toluene sulfonate).
Reaction SMILES: [CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([C:16]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])[CH2:15][CH2:14]1>>[CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[CH:24][C:16]=2[CH:13]2[CH2:14][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1NC1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Product: O=C(NC1CCCC1NC1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, brown oil, MS: m/e=381.4 [(M+H)+], was prepared in accordance with the general method of example 5 from (1RS,2SR)-N-cyclopentyl-cyclopentane-1,2-diamine (intermediate AE) and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:22]3[CH:23]=[CH:24][C:25]([C:27]4[C:28]5[C@H:35]([CH3:36])[CH2:34][C@@H:33]([OH:37])[C:29]=5[N:30]=[CH:31][N:32]=4)=[CH:26][C:21]=3[S:20][N:19]=2)[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:38].[ClH:1].[NH2:10][CH2:9][CH:8]([C:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]3[C:28]4[C@H:35]([CH3:36])[CH2:34][C@@H:33]([OH:37])[C:29]=4[N:30]=[CH:31][N:32]=3)=[CH:26][C:21]=2[S:20][N:19]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc4c(C(CNC(=O)OC(C)(C)C)c5ccc(Cl)cc5)nsc4c3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc4c(C(CN)c5ccc(Cl)cc5)nsc4c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of tert-butyl 2-(4-chlorophenyl)-2-(6-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]isothiazol-3-yl)ethylcarbamate (41 mg, 0.076 mmol) in DCM was treated with 4N HCl in dioxane (0.5 mL). The reaction was stirred at room temperature overnight. The reaction was concentrated and triturated with ether (twice) to yield (5R,7R)-4-(3-(2-amino-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol trihydrochloride (32 mg, 77%). LCMS (APCI+) m/z 437, 439 [M+H]+; Rt=2.48 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:35])[F:34])=[CH:18][N:17]=1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:39])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:34])([F:35])[F:36])=[CH:18][N:17]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
To a solution of 3-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzamide (5) (0.021 g, 0.042 mmol) in anhydrous methanol (2.00 mL) was added 37% aqueous formaidehyde (0.012 mL, 0.16 mmol) and sodium triacetoxyborohydride (0.044 g, 0.21 mmol) under a N2 atmosphere. The mixture was then stirred for 1.5 hours. The resulting mixture was concentrated under reduced pressure and diluted with EtOAc (10 mL) and washed with sat. aqueous NaHCO3 (10 mL). The Aqueous was further extracted with EtOAc (10 mL) and the combined organic layers were washed with brine (10 mL) and water (10 mL) then dried using a phase separation cartridge. The organics were concentrated under reduced pressure and purified using silica gel column chromatography (0-30% MeOH/EtOAc+1% 2 M ethanolic NH3). The product was then taken up in minimal hot acetonitrile and water and freeze dried to give the title compound (6) (0.016 g, 74%) as a white solid; 1H NMR (400 MHz, d6-Acetone) δ 8.62 (s, 1H), 8.27 (dd, J=8.3, 4.1 Hz, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.41 (m, 3H), 6.99 (d, J=1.7 Hz, 1H), 6.89 (dd, J=8.2, 1.6 Hz, 1H), 6.55 (s, 1H), 3.98 (s, 3H), 3.20 (m, 4H), 2.90 (m, 2H), 2.57 (m, 1H), 2.22 (s, 3H), 1.98 (td, J=11.2, 3.8 Hz, 2H), 1.78 (m, 4H). LCMS Method C: rt 4.97 min; m/z 514.2 [M+H]+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:19]1[N:23](COCCO)[C:22]2[N:29]=[C:30]([NH2:34])[N:31]=[C:32]([OH:33])[C:21]=2[N:20]=1>CN(C)C=O.CN(C)C1C=CN=CC=1>[O:3]([CH2:4][CH2:5][N:11]([C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[C@H:12]([C:16]([O:18][N:23]1[CH:19]=[N:20][C:21]2[C:32](=[O:33])[NH:31][C:30]([NH2:34])=[N:29][C:22]1=2)=[O:17])[CH:13]([CH3:14])[CH3:15])[CH3:1]
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COCCN(C(=O)OCc1ccccc1)[C@H](C(=O)On1cnc2c(=O)[nH]c(N)nc21)C(C)C
Reaction time: 8 h
Yield: 141.3 %

Procedure:
CBZ-L-valine (167 g) was dissolved in dimethylformamide (DMF) (750 ml) and cooled. A cold solution of N,N-dicyclohexyl-carbodiimide (DCC) (153.5 g) in DMF (266 ml) was added followed by acyclovir (111.7 g) in a single portion. 4-(dimethyl-amino)pyridine (9.4 g) was then added and the mixture stirred cold overnight. A white precipitate of the by-product was then removed by filtration. The filtrate was reduced in volume as before to give the title compound (215.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:49][N:50]2[CH:54]=[N:53][CH:52]=[N:51]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:47])[CH:40](OS(C)(=O)=O)[CH3:41])[C:35]5=[O:48])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.[N-:55]=[N+:56]=[N-:57].[Na+].O>CN(C=O)C>[N:55]([CH:40]([CH3:41])[CH:39]([N:36]1[C:35](=[O:48])[N:34]([C:31]2[CH:32]=[CH:33][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:49][N:50]6[CH:54]=[N:53][CH:52]=[N:51]6)[O:13]5)=[CH:17][CH:18]=4)[CH2:27][CH2:26]3)=[CH:29][CH:30]=2)[CH:38]=[N:37]1)[CH3:47])=[N+:56]=[N-:57]
Reactant: CC(OS(C)(=O)=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Temperature: 85 °C
Reaction time: 48 h

Procedure:
A mixture of [2S-[2α,4α(S*,S*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[1-methyl-2-[(methylsulfonyl)oxy]propyl]-3H-1,2,4-triazol-3-one (0.0039 mol) and NaN3 (0.005 mol) in DMF (50 ml) was stirred at 85° C. for 48 hours, poured out into H2O and stirred for 30 minutes. The precipitate was filtered off and dissolved in CH2Cl2. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and 2-propanol, filtered off and dried, yielding 1.1 g (41%) of [2S-[2α,4α(R*,S*)]]-2-(2-azido-1-methylpropyl)-4-[4-[4-[4-[[2-(2,4difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; (compound 19).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:26][CH:27]=[CH:28][C:7]=4[C:6]=2[CH:29]=1)[N:10]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:11]=3.C([N-]C(C)C)(C)C.[Li+].[I:38]I>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:26][CH:27]=[CH:28][C:7]=4[C:6]=2[CH:29]=1)[N:10]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:17])=[O:18])[C:11]=3[I:38]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(ccnc42)-c2cc(F)ccc2N(C)C3)cc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)c3c4c(ccnc42)-c2cc(F)ccc2N(C)C3)cc1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
To a solution of Example 41C (26.6 g, 65.3 mmol) in tetrahydrofuran (326 mL) at −75° C. under nitrogen was added lithium diisopropylamide (49.0 mL, 98 mmol) dropwise. A solution of iodine (33.1 g, 131 mmol) in 250 mL tetrahydrofuran was added dropwise and the mixture was stirred at −75° C. for 2 hours. The reaction was quenched with saturated aqueous sodium thiosulfate and extracted with ethyl acetate (twice). The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was slurried in hot 40% ethyl acetate in heptanes, cooled to room temperature and filtered and dried in vacuo to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=5.3 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.71 (d, J=10.3 Hz, 1H), 7.57 (d, J=5.4 Hz, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.33-7.22 (m, 2H), 4.01 (s, 2H), 2.89 (s, 3H), 2.32 (s, 3H). MS (ESI+) m/z 534.0 (M+H)+.