Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:12])([CH3:11])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]([CH2:36][C@H:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:33](Cl)=[O:34])[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29]>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]([CH2:36][C@H:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:33]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][C:3]([O:2][CH3:1])([CH3:12])[CH3:11])[N:6]=2)=[O:34])[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29]
Reactant: COC(C)(C)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(C)(C)Cn1ccc(NC(=O)C(C[C@H]2CCC(F)(F)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round bottom flask was placed 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in Example 94, 61 mg, 0.36 mmol), 2,6-lutidine (54 μL, 0.49 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionyl chloride (prepared as in Example 106, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then diluted with methylene chloride (10 mL) transferred to a separatory funnel and the layers separated. The aqueous layer was then extracted methylene chloride (3×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 35% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 130 mg, 77%) as an off-white foam: ES-HRMS m/e calcd for C23H30N3O4SClF2 (M+H)+ 518.1687, observed 518.1684; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.64-2.31 (m, 8H, 4×CH2), 3.14 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.91 (m, 1 H, ArCHCO), 3.97 (s, 2 H, NCH2), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.48 (d, J=2.2 Hz, 1H, Ar), 7.60 (d, Jo=8.2 Hz, 1H, Ar), 7.71 (s, 1H, Ar), 8.02 (d, Jo=8.2 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:12][S:13]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2)(=[O:15])=[O:14].[Cl:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH:36]1[CH2:38][CH2:37]1)O>ClCCl>[Cl:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH:36]1[CH2:38][CH2:37]1)[C:22]1[C:21]2[C:25](=[C:17]([CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[CH:18]=[CH:19][CH:20]=2)[NH:24][CH:23]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: Cc1ccc(C(O)C2CC2)c(Cl)c1
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cccc23)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
135 mg (0.61 mmol) of indium(III) chloride and 0.07 ml (0.92 mmol) of trifluoroacetic acid were added to 132 mg (0.61 mmol) of the compound from Example 86A and 100 mg (0.51 mmol) of the compound from Example 152A in 5 ml of dichloromethane, and the mixture was stirred at RT overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 29.0 mg (15% of theory) of the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]([CH2:39][OH:40])[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:40][CH2:39][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[CH2:31]1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: OCC1CNc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CC(CO)c2ccccc21

Procedure:
100 mg (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 45 mg (0.30 mmol) (2,3-dihydro-1H-indol-3-yl)-methanol, 0.10 mL (0.71 mmol) TEA and 88 mg (0.27 mmol) TBTU in 1.0 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and the solvent was evaporated down by about half. The precipitate formed was suction filtered and dried.
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH2:20])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8].[CH3:36][NH:37][C:38](Cl)=[O:39]>ClCCl>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH:20][C:38]([NH:37][CH3:36])=[O:39])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8]
Reactant: CNC(=O)Cl
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (5.09 μL, 0.063 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.010 g, 0.025 mmol) in dichloromethane (200 μL). Methylcarbamic chloride (0.003 g, 0.030 mmol) was added, and the reaction stirred at rt for 18 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with 1 N aqueous HCl, and the organic phase was separated and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-(3-methylureido)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 455 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH:26]=O)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39][NH2:40].C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[F:34][C:35]([F:48])([F:49])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1)[CH2:39][NH:40][CH2:26][CH2:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]2[CH:28]=[CH:29][C:11]([C:9]3[O:10][C:6]4[C:5]([CH:31]([CH3:32])[CH3:33])=[CH:4][C:3]([C:1]#[N:2])=[CH:30][C:7]=4[N:8]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:21]1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC=O)CC4)cc3)oc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCNCc5cc(C(F)(F)F)cc(C(F)(F)F)c5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-oxoethyl)cyclohexyl]methyl}benzamide (25 mg, 0.056 mmol) in methanol (2 ml) were added 3,5-bis(trifluoromethyl)benzylamine (20 mg, 0.082 mmol) and sodium cyanoborohydride (10 mg, 0.159 mmol). The mixture was stirred overnight at room temperature, at which point LC/MS analysis showed a new peak at the desired molecular weight. The reaction mixture was then diluted with 10 ml of saturated sodium bicarbonate solution and 10 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted with 2×10 ml of ethyl acetate. The combined organics were washed with 10 ml of brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (11.9 mg, 0.018 mmol, 31.5% yield). Mass spectrum (ESI) 671.5 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 2H); 7.96 (d, J=8.5 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H); 7.83 (s, 2H), 7.75 (s, 1H), 7.51 (s, 1H), 6.35 (br t, J=5.5 Hz, 1H), 5.30 (s, 2H), 3.85 (s, 2H), 3.48 (septet, J=6.5 Hz, 1H), 3.35 (t, J=6.5 Hz, 2H), 2.65 (t, J=6.5 Hz, 2H), 1.80 (m, 4H), 1.60 (m, 1H), 1.46 (d, J=7.0 Hz, 6H), 1.40-1.52 (m, 1H), 0.90-1.15 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)CC)C.[F:32][C:33]1[C:34]([CH3:42])=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37].[OH-].[Na+]>ClCCl>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([F:32])[C:34]=4[CH3:42])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Reactant: Cc1c(F)cccc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.08 g of 3-fluoro-2-methylbenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred for 2 hours at room temperature and then 2 ml of 1 N NaOH added. The volatiles are evaporated under vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred for 2 hours and evaporated and the residue diluted with 2 ml of 1 N NaOH and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried (Na2SO4). The solvent is removed and the residue triturated with diethyl ether-hexane to give 0.15 g of white solid: Mass Spectrum (CI)474(M+H, Cl35); 476(M+H, Cl37).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:32][C@@H:33]([C@@H:40]1[C@@:44]2([CH3:62])[CH2:45][CH2:46][CH:47]3[C@@:52]4([CH3:61])[CH2:53][CH2:54][CH:55]([O:57][C:58](Cl)=[O:59])[CH2:56][C:51]4=[CH:50][CH2:49][CH:48]3[CH:43]2[CH2:42][CH2:41]1)[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:58]([O:57][CH:55]1[CH2:56][C:51]2[C:52]([CH3:61])([CH:47]3[CH:48]([CH2:49][CH:50]=2)[CH:43]2[C:44]([CH3:62])([CH:40]([CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:41][CH2:42]2)[CH2:45][CH2:46]3)[CH2:53][CH2:54]1)=[O:59])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCNC(=O)OC1CCC2(C)C(=CCC3C2CCC2(C)C(C(C)CCCC(C)C)CCC32)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The hydrochloride salt of 3-[(6-Amino-hexanoyl)-ethoxycarbonylmethyl-amino]-propionic acid ethyl ester AC (4.7 g, 14.8 mmol) is taken up in dichloromethane. The suspension is cooled to 0° C. on ice. To the suspension diisopropylethylamine (3.87 g, 5.2 mL, 30 mmol) is added. To the resulting solution cholesteryl chloroformate (6.675 g, 14.8 mmol) is added. The reaction mixture is stirred overnight. The reaction mixture is diluted with dichloromethane and ished with 10% hydrochloric acid. The product is purified by flash chromatography (10.3 g, 92%).
Reaction SMILES: C(O)=O.C(O[CH:7](OCC)[CH2:8][CH:9]([O:14][CH3:15])[CH2:10][CH2:11][CH:12]=[CH2:13])C.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C>[CH3:15][O:14][CH:9]([CH2:10][CH2:11][CH:12]=[CH2:13])[CH2:8][CH:7]=[N:25][OH:26]
Reactant: C=CCCC(CC(OCC)OCC)OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Product: C=CCCC(CC=NO)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 80% formic acid solution (30 mL) was added to 7,7-diethoxy-5-methoxyhept-1-ene obtained in Preparation Example 57-(2) (2.98 g), and the mixture was stirred at room temperature for 10 minutes. After further adding a 75% ethanol solution (64 mL), sodium acetate (3.75 g) and hydroxylamine hydrochloride (1.92 g) were added, followed by further stirring for one hour and 20 minutes. The solvent was concentrated to about 40 mL under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution (three times), water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.95 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li]CCCC.[C:21](OC)(=[O:26])[C:22]([O:24][CH3:25])=[O:23].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH3:1][O:2][CH2:3][N:4]1[C:8]([C:21](=[O:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:7][N:6]=[C:5]1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)OC
Reactant: COCn1ccnc1Sc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCn1c(C(=O)C(=O)OC)cnc1Sc1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a cold (−78° C.), stirred solution of 1-methoxymethyl-2phenylthioimidazole (Ohta, S. et al. (1992) Chem. Pharm. Bull. 40:2681) (11) 340 mg, 1.55 mmol) in dry THF (8.0 mL) was added a solution of n-BuLi (1.47 M in hexanes, 1.26 mL, 1.85 mmol) and the mixture was stirred for 1 hour. A solution of dimethyl oxalate (540 mg. 4.58 mmol) in dry THF (2.0 mL) was added and the mixture was stirred at −78° C. for an additional 1.25 hours. The reaction mixture was treated with saturated aqueous NH4Cl (5.0 mL) and Et2O (20 mL). The phases were separated and the aqueous layer was extracted with Et2O (25 mL). The combined organic extracts were washed (brine, 10 mL), dried (MgSO4), and concentrated. Flash chromatography (35 g of silica gel, 1:1 petroleum ether-Et2O) of the crude material afforded 305 mg (66%) of 8 as a beige solid that exhibited mp 59-60° C.; IR (KBr) 1729, 1657, 1305, 1273, 1167, 1114, 784 cm−1; 1H NMR (CDCl3, 400 MHz) δ8.23 (s, 1H), 7.52-7.54 (m. 2H), 7.37-7.38 (m, 3H), 5.81 (s, 2H), 3.91 (s, 3H), 3.36 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ172.2, 161.6, 154.1, 145.4, 145.3, 133.2, 129.5, 129.2, 128.7, 75.8, 56.5, 53.0; HREIMS calcd for C14H14N2O4`S 306.0674, found 306.0674.
Reaction SMILES: C([NH:6][C@H:7]([C:9](O)=[O:10])[CH3:8])(=O)C(C)=C.N[C@H](C(O)=O)C.Cl.[NH2:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([O:31][CH3:32])=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[NH2:6][C@H:7]([C:9]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([O:31][CH3:32])=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:10])[CH3:8]
Reactant: C=C(C)C(=O)N[C@@H](C)C(=O)O
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@H](N)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](C)N)C(C)C

Procedure:
Using the Schotten-Bauman method of acylation, N-methacryloylalanine was prepared. Coupling of MA-Ala-OH (5.35 g; 0.034 mol) with HCl.Val-Ala-OMe (8.1 g) was performed in dimethylformamide by means of dicyclohexylcarbodiimide (7.0 g) in the presence of triethylamine (3.4 g). Recrystalization from CH2Cl2 /pentene gave 9.5 g of MA-Ala-Val-Ala-OMe.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[O:1][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cccc(O)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1OCCCO2

Procedure:
Methyl 2,3-dihydroxybenzoate (1.870 g, 11.12 mmol), 1,3-dibromopropane (2.25 g, 11.1 mmol) and potassium carbonate (6.15 g, 44.5 mmol) were stirred in N,N-dimethylformamide (20 ml) overnight at 60° C. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[C:24]([O:33][CH3:34])(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[SH:27].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:4][C:3](=[O:23])[C:2]=1[S:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:24]([O:33][CH3:34])=[O:32]
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: COC(=O)c1ccccc1S
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.9 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.2 mmol of methyl thiosalicylate and 2.1 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 91°-92° C.). 1H NMR (DMSO-d6) δ 2.25 (m, 2 H), 2.38 (m, 1 H), 2.62 (m, 1 H), 3.44 (q, 2 H), 3.82 (s, 3 H), 6.06 (bd, 1 H), 6.90 (t, 1 H), 7.05-7.52 (m, 11 H), 7.81 (dd, 1 H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-methyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.93 (m, 2H) 1.18-1.31 (m, 2H) 1.50-1.80 (m, 6H) 1.83-2.00 (m, 4H) 2.17 (s, 3H) 2.71-2.95 (m, 2H) 3.29 (s, 3H) 3.67-3.87 (m, 3H) 3.94 (s, 3H) 4.89 (d, J=8.59 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.49, 12.69, 10.74 Hz, 1H) 7.41-7.54 (m, 2H) 7.82 (s, 1H) 8.12 (s, 2H) 8.30 (d, J=8.34 Hz, 1H). [M+H] calc'd for C29H38FN7O3, 552. found 552.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[C:11]([O:18][CH3:19])[C:12]([O:16][CH3:17])=[N:13]2)=[C:8]([CH2:20]Br)[CH:7]=1.O>CN(C)C=O>[N:1]([CH2:20][C:8]1[CH:7]=[C:6]([Br:5])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:18][CH3:19])[C:12]([O:16][CH3:17])=[N:13]2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2cc(Br)cc(CN=[N+]=[N-])c2nc1OC
Reaction time: 3 h

Procedure:
743 mg (2 eq.) of sodium azide are added at 20° to 2.07 g (5.72 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxyquinoxaline in 25 ml of dimethylformamide. After 3 hours, the mixture is poured into water, extracted with diethyl ether, and the extract is washed with water and brine and dried using magnesium sulfate. The solvent is evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27])[CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1.[CH3:29][C:30]1[C:35]([C:36](O)=[O:37])=[C:34]([CH3:39])[N:33]=[CH:32][N:31]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:36]([C:35]4[C:30]([CH3:29])=[N:31][CH:32]=[N:33][C:34]=4[CH3:39])=[O:37])[CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C3CCN(C(C)CCN)CC3)Oc3ccccc3O2)cc1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: COc1ccc(C2(C3CCN(C(C)CCNC(=O)c4c(C)ncnc4C)CC3)Oc3ccccc3O2)cc1
Yield: 62.5 %

Procedure:
Using general procedure E, 3-{4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 284) (50 mg, 0.13 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (24 mg, 0.16 mmol) afforded COMPOUND 285 as a white solid (42 mg, 63%). 1H NMR (CDCl3) δ 0.70-0.84 (m, 1H), 0.94 (d, 3H, J=6.6 Hz), 0.95-1.08 (m, 1H), 1.45-1.63 (m, 3H), 1.66-1.80 (m, 1H), 1.86-1.98 (m, 2H), 2.38 (t, 1H, J=11.4 Hz), 2.52 (s, 6H), 2.66-2.84 (m, 3H), 3.22-3.31 (m, 1H), 3.79 (s, 3H), 3.87-3.97 (m, 1H), 6.74-6.79 (m, 2H), 6.83-6.88 (m, 3H), 6.91-6.94 (m, 1H), 7.29 (d, 2H, J=9.0 Hz), 8.86-8.88 (m, 1H), 9.08 (s, 1H). 13C NMR (CDCl3) δ 13.37, 22.07, 25.89, 26.55, 30.77, 40.43, 43.83, 45.63, 52.47, 55.45, 60.96, 108.65, 108.73, 113.61, 118.42, 121.44, 126.99, 131.00, 131.96, 147.38, 147.50, 157.84, 159.96, 163.05, 166.71. ES-MS m/z 517 (M+H). Anal. Calcd. for C30H36N4O4.0.1CH2Cl2: C, 68.85; H, 6.95; N, 10.67. Found: C, 69.00; H, 7.03; N, 10.76.