Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:34][C:35]1([C:40](Cl)=[O:41])[CH2:38][CH:37]([CH3:39])[CH2:36]1>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[C:11]([O:22][C:40]([C:35]2([CH3:34])[CH2:38][CH:37]([CH3:39])[CH2:36]2)=[O:41])[CH:10]=1)=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC1CC(C)(C(=O)Cl)C1
Reactant: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1O
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C1(C)CC(C)C1

Procedure:
Following a procedure similar to that described in Example 13A above, when 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 1,3-dimethylcyclobutanecarbonyl chloride there is obtained 3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 13B, there is obtained 3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21]C(C)(C)[O:23][C@@H:19]2[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]2[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]2)[CH2:17]1.C(N(CC)C(C)C)(C)C.[C:55]([C:59]1[CH:60]=[C:61]([NH2:66])[C:62]([NH2:65])=[CH:63][CH:64]=1)([CH3:58])([CH3:57])[CH3:56].C([O-])(O)=O.[Na+]>CN(C)C=O>[NH2:66][C:61]1[CH:60]=[C:59]([C:55]([CH3:57])([CH3:56])[CH3:58])[CH:64]=[CH:63][C:62]=1[NH:65][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@H:18]2[CH2:17][C@@H:16]([N:11]3[CH:10]=[N:9][C:8]4[C:12]3=[N:13][CH:14]=[N:15][C:7]=4[NH:6][CH2:5][C:4]3[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=3[O:2][CH3:1])[C@H:20]([OH:21])[C@@H:19]2[OH:23])[CH:37]([CH3:38])[CH3:39])[CH2:29]1
Reactant: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@@H](O)[C@H]2O)c(OC)c1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.19 g, 3.13 mmol) added to a solution of 3-{3-[{[(3aR,4R,6R,6aS)-6-{6-[(2,4-dimethoxybenzyl)amino]-9H-purin-9-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl}{isopropyl)amino]cyclobutyl}propanoic acid (1.30 g, 2.09 mmol) and N,N-Diisopropylethylamine (1.20 ml, 6.89 mmol) and 4-tert-butylbenzene-1,2-diamine (0.411 g, 2.50 mmol) in N,N-Dimethylformamide (12.9 ml). The reaction was stirred for 2 hours, NaHCO3 (saturated) was added and the mixture extracted with EtOAc (3×) and the combined organics was dried over MgSO4 filtered and concentrated. The residue was purified by flash chromatography (DCM→DCM/7N NH3 in MeOH 95:5) to yield the desired amide (1.4 g) as a solid.
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C@@H:16]([CH2:18][CH3:19])[CH3:17])[C:11]=1[O:20]C(=O)N[C@@H](C1C=CC=CC=1)C)(CC)C.[OH-].[Na+]>C(OC)(C)(C)C>[C@H:3]([C:13]1[C:12]([C@@H:16]([CH2:18][CH3:19])[CH3:17])=[C:11]([OH:20])[CH:10]=[CH:15][CH:14]=1)([CH2:4][CH3:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CC[C@@H](C)c1cccc([C@H](C)CC)c1OC(=O)N[C@H](C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC[C@@H](C)c1cccc(O)c1[C@H](C)CC
Temperature: 57.5 °C

Procedure:
To a 100-ml three-necked flask equipped with a magnetic stirrer, a reflux condenser, a thermocouple and an N2 inlet, was added tetrahydrofuran (THF) (9 ml), (R,R,R)-1-phenylethylcarbamic acid-2,6-di-sec-butylphenyl ester (1 g, 2.8 mmol), and 1.0 M sodium hydroxide (11.4 ml, 11.4 mmol). The resulting clear mixture was heated under N2 at 55-60° C. using a heating mantle and continued to stir at this temperature while monitoring the progress of the reaction by HPLC. After the reaction was finished (6-8 h) as judged by HPLC, the reaction mixture was cooled to 15° C. and filtered to remove precipitated urea. The filtered cake was washed with cold THF (5 ml). The filtrate and the wash were combined, acidified to pH 2-3 with 3.0 M hydrochloric acid (HCl) (3.5 ml). After stirring for 10 minutes (min), ether (10 ml) was added and then resulting mixture was vigorously stirred for 15 min after which layers were separated. The organic layer was washed with 3.0 M HCl (3 ml), brine (5 ml), dried magnesium sulfate (MgSO4), filtered to remove the drying agent, and then concentrated on a rotavap to give a semi solid yellow residue which was stirred with methyl tertiary butyl ether (MTBE) (3 ml) for 15 min and then filtered. The filtered cake was washed with MTBE (2 ml). The filtrate and the wash were combined, and then concentrated on a rotavap to give the title compound as a yellow oil (0.6 g, 100% crude yield) that was found to be greater than 93 A % pure by HPLC. The 1H NMR (DMSO-d6) was found to be consistent with the structure.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][CH:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[S:37][C:36]([C:38](OCC)=[O:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)[CH3:25].CO>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:36]3[S:37][C:33]([N:29]4[CH2:30][CH2:31][CH2:32][N:26]([CH:24]([CH3:25])[CH3:23])[CH2:27][CH2:28]4)=[CH:34][CH:35]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: CCOC(=O)c1ccc(N2CCCN(C(C)C)CC2)s1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C(C)C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
Trimethylaluminium (0.751 ml, 1.50 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (148 mg, 0.60 mmol) and ethyl 5-(4-propan-2-yl-1,4-diazepan-1-yl)thiophene-2-carboxylate (178 mg, 0.60 mmol) in toluene (3.002 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was added to methanol (50 mL) and treated with HCL (2M aqueous solution, to pH7 or below) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure material. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (123 mg, 41%) as a yellow solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:8][CH:9]=2)[C:13]1=[O:16])[CH:18]=[CH:19][CH3:20]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccc(OC3CCCC3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Yield: 69 %

Procedure:
A solution of 9.45 g of 6-cyclopentoxy-1-indanone, 9.0 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxy-propane was boiled under reflux for 63 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). There were obtained 8.1 g (69%) of (RS)-2-(2-buten-1-yl)-6-cyclopentoxy-1-indanone as a yellow oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:31])[C:16]([CH2:29][CH3:30])=[C:17]([C:27]#[N:28])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1)=[O:13])[CH3:10].O>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:31])[C:16]([CH2:29][CH3:30])=[C:17]([C:27]#[N:28])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:21][CH:20]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(-c2ccc(C=O)cc2)c(C#N)c(CC)n1C
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C(O)c3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Add phenyl magnesium bromide (192 uL, 0.58 mmol) to 4-cyano-5-ethyl-3-(4-formyl-phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester [(0.020 g, 0.64 mmol, prepared in example E-152] in THF with stirring at −78° C. After 30 minutes, gradually allow the reaction mixture to warm to ambient temperature. After 2 hours, pour the reaction mixture into water and extract with EtOAc. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 406.1 (M+18).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[N:11]([CH3:19])[N:10]=1.[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16]([Br:20])=[CH:17][CH:18]=2)[N:11]([CH3:19])[N:10]=1
Reactant: BrBr
Reactant: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2,6-dichlorophenyl)-5-(thien-2-yl)-1-methyl-[1,2,4]triazole (75 mg, 0.242 mmol) and bromine (39 mg, 0.242 mmol) were combined in glacial acetic acid (3mL) and the mixture was stirred overnight at room temperature, then heated to 95° C. for five hours. The reaction mixture was poured into a saturated sodium bicarbonate solution, extracted with ether, and dried over magnesium sulfate. Chromatography (SiO2, 25% Hex-CH2Cl2) delivered the title product as a waxy white solid. MP 130-132° C.
Reaction SMILES: [CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:57]=[CH:56][C:29]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:31])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](C(C)(C)C)(C)C)[CH:13]=2)[C@H:6]([CH3:58])[CH2:5]1)[CH:2]=[CH2:3].O.[F-].C([N+](CC)(CC)CC)C>C(#N)C>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:57]=[CH:56][C:29]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:31])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@H:6]([CH3:58])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc2)c2cccc(O)c2)C[C@@H]1C
Yield: 58 %

Procedure:
A portion of the benzhydrylpiperazine from above (0.36 g, 0.44 mmol) was stirred with tetraethylammonium fluoride hydrate (0.12 g, 0.67 mmol) in 10 mL of acetonitrile for 1 hr. The solvent was removed and the residue purified by chromatography on silica gel with dichloromethane:ethanol to give 0.180 g (58%) of tert-butyl N-(4-((αR*)-α-((2R*,5S*)-4-allyl-2,5-dimethyl -1-piperazinyl)-3-hydroxybenzyl)benzoyl)-L-phenylalanyl-L-leucinate as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[O:45][CH2:46][CH2:47][O:48][CH3:49]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[O:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCOc1c(CCl)cccc1OC
Product: COCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cccc1OC

Procedure:
Analogously to Method D, 0.417 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.251 g of 1-chloromethyl-3-methoxy-2-(2-methoxyethoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.20 (1:2 EtOAc-heptane); Rt=6.07.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([OH:23])=O.Cl.CON.C[N:37]1CCO[CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([NH:37][CH2:38][CH3:39])=[O:23]
Reactant: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)O)c1
Reactant: CN1CCOCC1
Agent: CON
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc(OC)cc(OC)c1-c1nc2ncccn2c1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
400 mg of 2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzoic acid, 73 mg of O-methylhydroxylamine hydrochloride, 200 mg of DAPECI and 88 mg of 4-methylmorpholine are dissolved in 1 ml of DMF and stirred at RT for 1 hour. The solvent is removed, and the residue is purified by column chromatography (heptane/ethyl acetate), giving 90 mg (21%) of 2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]pyrimidin-2-yl]-N-ethyl-3,5-dimethoxybenzamide (A17) as solid; MS-FAB (M+H+) 489.7; Rf (polar method): 1.61 min.
Reaction SMILES: CO[C:3]([C:5]1([CH3:17])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH2:18]([N:20]([CH2:28][CH3:29])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH3:19].CC[Mg+].[Br-]>C1COCC1>[CH2:28]([N:20]([CH2:18][CH3:19])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:3]([C:5]2([CH3:17])[CH2:14][CH2:13][C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:4])=[CH:23][CH:22]=1)[CH3:29]
Reactant: COC(=O)C1(C)CCc2cccc(OC)c2C1
Reactant: CCN(CC)c1ccc(N)cc1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(NC(=O)C2(C)CCc3cccc(OC)c3C2)cc1
Yield: 11.2 %

Procedure:
The ester from Example 2A (170 mg, 0.73 mmol) was dissolved in THF (2.0 mL) and a solution (3.0 mL) of N,N-Diethyl-benzene-1,4-diamine (332 mg, 2 mmol) and EtMgBr (2.0 mmol) in THF was added at 0° C. The reaction mixture was quenched with aqueous NH4Cl after 3 hours. The mixture was extracted with ethyl acetate (3×15 mL) and the combined extracts were dried over MgSO4 and purified by column chromatography to provide the titled compound (30 mg, 8%). 1H NMR (400 MHz, DMSO-D6) δ 9.03 (s, 1H), 7.33 (d, J=9.2 Hz, 2H), 7.03 (t, J=8.0 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.58 (d, J=9.2 Hz, 2H), 3.77 (s, 3H), 3.27 (q, J=7.2 Hz, 4H), 3.11 (d, J=17.2 Hz, 1H), 2.74 (t, J=6.4 Hz, 2H), 2.43 (d, J=17.2 Hz, 2H), 2.15 (ddd, J=6.4, 6.4, 13.2 Hz, 1H), 1.73 (ddd, J=7.2, 7.2, 13.6 Hz, 1H), 1.26 (s, 3H), and 1.04 (t, J=7.2 Hz, 6H). MS (ESI) positive ion 367 (M+H)+; negative ion 365 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39].O>CN(C=O)C>[CH2:36]([N:37]([CH2:40][CH3:41])[CH2:38][CH2:39][O:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:35]
Reactant: CCN(CC)CCCl
Reactant: O=c1c2ccccc2nc(C=Cc2cccc(O)c2O)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1c(O)cccc1C=Cc1nc2ccccc2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 1.3 %

Procedure:
To a solution of 75 (0.85 g, 0.023 mol) and K2CO3 (0.45 g, 0.003 mol) in DMF (5 mL) was added (2-chloro-ethyl)-diethyl-amine (0.37 g, 0.025 mol). The reaction mixture was stirred at RT for 10 hours, poured into water. The precipitate formed was filtered off, washed with water and purified by column chromatography on silica gel using EtOAc/hexane 1:4 as eluent to yield 76 (0.14 g, 15%). M. Wt. 455. LCMS [M+H]+=456.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][NH:7][CH2:6]1)=[O:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:22][C:21]([F:23])([F:24])[C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][C:11]=1[CH2:10][N:7]1[CH2:8][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: COC(=O)C1CNC1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution of methylazetidine-3-carboxylate (5 g) and 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (13.3 g) in DMF (100 mL) was added potassium carbonate (7.20 g) at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (5.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([CH2:25][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[CH:23][CH:24]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(CN4CCCC4)cc3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 6) (75 mg) was dissolved in DCM (5 mL). Pyrrolidine (19 μl) and acetic acid (8.62 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (160 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, overnight. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (59.2 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:22][NH:23][C:24](=[S:27])[NH:25][NH2:26].O>CN(C)C=O>[CH3:22][N:23]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:26][N:25]=[C:24]1[SH:27]
Reactant: O=C(O)c1ccccn1
Reactant: CNC(=S)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(S)nnc1-c1ccccn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
15 g of pyridine-2-carboxylic acid (121.8 mmol) were dissolved in 150 ml of dimethylformamide. At room temperature, 29.6 g (181.8 mmol) of carbonyldiimidazole were slowly added, during which gas was evolved. Reaction was allowed to take place at 100° C. for 30 min, and then 25.6 g (242.7 mmol) of 4-methyl-3-thiosemicarbazide were added, and the mixture was stirred at 100° C. for a further 2 h. The reaction mixture was mixed with 300 ml of water. After cooling in an ice bath, the precipitated crystals were filtered off with suction and washed with a little water. The crystals were taken up in 390 ml of 1M sodium bicarbonate solution and heated to reflux for 3 h.
Reaction SMILES: [OH-:1].[Li+].[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[C:11](N1[C@@H](C(C)C)COC1=O)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[C:11]([OH:12])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)N(C)C1CCCCC1)Cc1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)C[C@@H](Cc1ccccc1)C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.4 %

Procedure:
100 mg (2.42 mmole) of lithium hydroxide were added to a solution of 500 mg (1.21 mmole) of 3-[2(R)-benzyl-4-(N-cyclohexyl-N-methylamino)-4-oxobutyryl]-4(S)-isopropyl-2-oxazolidinone (which had been prepared by a similar procedure to those described in Preparations 12-14) in a mixture of 10 ml of tetrahydrofuran and 4 ml of water, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The aqueous layer was adjusted to a pH value of 2 by the addition of an aqueous solution of citric acid and was then extracted with methylene chloride. The latter methylene chloride extract was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure, to afford 130 mg of the title compound as an amorphous product.