Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([O:20][CH2:21][CH:22]=O)[CH2:15]2)[C:3]=1[C:4]([O:6]C)=[O:5].[C:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([O:20][CH2:21][CH2:22][NH:33][CH2:32][CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](OCC=O)C1
Reactant: NCCCc1ccccc1
Solvent: CO
Product: Cc1cccc(CO[C@@H]2CCC[C@H](OCCNCCCc3ccccc3)C2)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg of methyl 2-methyl-6-[(1R,3S)-3-(2-oxoethoxy)cyclohexyloxy-methyl]benzoate and 90 μl of 3-phenylpropylamine are dissolved in 5 ml of methanol. 300 mg of 4 Å molecular sieve, which had been dried by heating, are added, and the mixture is stirred at room temperature for two hours. 25 mg of sodium borohydride are then added to the reaction mixture. After 30 minutes, 50 ml of ethyl acetate are added and the molecular sieve is removed from the mixture by filtration through celite. The filtrate is concentrated under reduced pressure, the residue is dissolved in 5 ml of tert-butanol and 0.5 ml of 10 N potassium hydroxide solution are added. The mixture is refluxed for 1 day. After addition of 2 ml of water, the organic phase is removed and the aqueous phase is extracted three times with in each case 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvents are then removed under reduced pressure. This gives 160 mg of 2-methyl-6-{(1R,3S)-3-[2-(3-phenylpropylamino)ethoxy]cyclohexyloxymethyl}benzoic acid as a yellow oil. C26H25NO4 (425.57), MS(ESI): 426 (M+H+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[NH2:23][CH:24]1[C:46](=[O:47])[N:26]2[CH:27]([C:36]([O:38]CC3C=CC=CC=3)=[O:37])[C:28]3([S:35][C@H:25]12)[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3.[H][H]>C(O)C.[Pd]>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[NH2:23][CH:24]1[C:46](=[O:47])[N:26]2[CH:27]([C:36]([OH:38])=[O:37])[C:28]3([S:35][C@H:25]12)[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3
Reactant: [H][H]
Reactant: CN1CCC2(CC1)S[C@@H]1C(N)C(=O)N1C2C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CN1CCC2(CC1)S[C@@H]1C(N)C(=O)N1C2C(=O)O
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
A solution of 2.5 g (0.00354 mole) of benzyl 6-amino-1'-methyl-spiro[penam-2,4'-piperidine]-3-carboxylate di-p-toluenesulfonate (obtained in 8.1) in 1.5 liter of ethanol is subjected to hydrogenolysis in a Parr's apparatus under 3.2 kg/cm2 of hydrogen in the presence of 2 g of palladium on carbon (10% Pd). After 90 minutes, the reaction mixture is filtered and the filtrate is evaporated to dryness and lyophilized in 600 ml of water. 1.8 g of 6-amino-1'-methyl-spiro[penam-2,4'-piperidine]-3-carboxylic acid di-p-toluenesulfonate is obtained; yield: 83%; M.P. approx 155°-160° C. (start of decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([CH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([CH2:38][N:39]([CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:35]=1[O:36][CH3:37])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1)=[O:23])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22](=[O:23])[C:21]2[CH:33]=[C:34]([CH2:38][N:39]([CH2:40][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:35]([O:36][CH3:37])=[C:19]([CH2:18][N:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:20]=2)=[CH:25][CH:26]=1
Reactant: COc1c(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1c(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc(C(=O)c2ccc(N)cc2)cc1CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C

Procedure:
Nitrotetraester 4 (3.0 g, 3.9 mmol) was reduced in 50 mL CH3OH with 100 mg 10% Pd/C in a Parr shaker with an initial hydrogen pressure of 50 psi for 2.5 hours. TLC indicated quantitative reduction. The mixture was filtered through diatomaceous earth and evaporated to leave a yellow oil which was purified by gel permeation chromatography by the method used for compound 4. The yellow glass thus obtained had the correct NMR, IR and field desorption mass spectroscopic behavior.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:24]([O:26][C:27](=[O:28])[C:19]=12)=[O:25]>O1CCCC1>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:27]([C:19]2[C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH:22]=[CH:23][N:18]=2)=[O:28])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=C1OC(=O)c2ncccc21
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NC(=O)c3ncccc3C(=O)O)cc2Cl)C1=O
Yield: 34.1 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 4.0 grams (0.016 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 2.3 grams (0.016 mole) of 2,3-pyridinedicarboxylic anhydride in 175 mL of tetrahydrofuran. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil. The oil was crystallized by dissolving it in ethanol and adding diethyl ether until precipitation occurred. The solid was recrystallized in the same manner to yield 2.2 grams of 2-[[2-chloro-4-[(3-carboxy-2-pyridinyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 94°-96° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([S:11][CH3:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[NH2:13][C:9]1[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]=1[S:11][CH3:12]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(Cl)ccc(-c2nc(N)c(SC)c(C(=O)O)n2)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methylsulfanyl-pyrimidine-4-carboxylic acid methyl ester (100 mg, 0.28 mmol) was dissolved in 2 mL methanol and 0.5 mL of 2N sodium hydroxide (1 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then acidified with a slight excess of 2N HCl. The resulting solution was concentrated and partitioned between ethyl acetate and water. The organic phase was dried and concentrated to yield the title compound (68 mg, 70% yield): mp 153° C. (dec.): 1H NMR (CDCl3): δ 7.63 (m, 1H), 7.2 (m, 1H), 6.4 (br s, 2H), 3.98 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([CH:20]=1)[CH:18]=[O:19].[H-].[Na+].Cl>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[C:17]([CH:18]=[O:19])[CH:20]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
3-Hydroxyphenylacetic acid (3 g, 19.7 mmol) and 5-bromo-2-fluorobenzaldehyde (2.34 mL, 19.7 mmol) were combined in DMF (60 mL). Sodium hydride (60% in mineral oil; 1.58 g, 39.4 mmol) was added portionwise, and the reaction was stirred at 70° C. for 3 hours. Additional 5-bromo-2-fluorobenzaldehyde (2.34 mL, 19.7 mmol) and sodium hydride (60% in mineral oil; 0.79 g, 19.7 mmol) were added, and the reaction was stirred at 70° C. for 3 hours. The mixture was acidified with 1N aqueous HCl to pH 3-4 and extracted with EtOAc, and the combined organic layers were washed three times with H2O, dried and concentrated. The residue was purified by silica gel chromatography (20-40% EtOAc in hexanes) to give the desired product (2.7 g).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28]C=CC=1)[C:13](N[C@H](C(OC)=O)CO)=[O:14].Cl.O.[CH2:32]([O:34]CC)C>>[CH3:32][O:34][C:13](=[O:14])[CH:12]([CH2:23][CH2:24][CH:29]=[CH2:28])[NH2:3]
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: CCOCC
Agent: Cl
Solvent: O
Product: C=CCCC(N)C(=O)OC
Reaction time: 2 h

Procedure:
Dissolve N-(phenylmethylene)-2-(3-butenyl)glycine methyl ester (25g) in ethyl ether (400mL) and stir with 1N hydrochloric acid (150mL) and water (150mL). Place under an argon atmosphere and stir for 2 hours. Separate the aqueous phase and adjust to pH 9, extract into chloroform, dry and evaporate the solvent in vacuo to give the title compound as a light oil (4.5g).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:23]([NH2:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24].[CH3:33][O:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:40](O)=[O:41]>CN(C=O)C>[CH3:33][O:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:40]([NH:32][C:23]([CH3:25])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24])=[O:41]
Reactant: CC(C)(N)c1ccccc1
Reactant: COCOc1cc(C(=O)O)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C
Yield: 79.6 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-methoxymethoxy-4-methylbenzoic acid (2.69 g) was dissolved in DMF (53 mL), and the solution was treated with EDCI (5.04 g, 26.3 mmol), HOBT monohydrate (2.01 g, 13.1 mmol) and cumylamine (3.80 mL, 26.4 mmol), followed by purification by slurry using hexane to obtain 3-methoxymethoxy-4-methyl-N-(1-methyl-1-phenylethyl)benzamide (3.42 g, yield 83%, 2 steps).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[CH3:11]>CC(N(C)C)=O>[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)[CH2:21][CH2:22]1)[CH3:11]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3cc(C)nc(N)n3)CC2)ccc1OC
Yield: 11 %

Procedure:
A solution of 4-chloro-6-methyl-pyrimidin-2-ylamine (21.5 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 180° C. for 40 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 6.1 mg (11%) of the title compound. MS (ISP): 372.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][N:11]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:11]=1
Reactant: C1=COCCC1
Reactant: Brc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccccc1C=Cc1nn(C2CCCCO2)c2ccccc12
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A solution of (E)-3-[2-(2-bromophenyl)vinyl]-1H-indazole (0.35 g, 1.2 mmol) obtained in Step 1 of Example 133, 3,4-dihydro-2H-pyrane (0.21 mL, 2.3 mmol) and p-toluenesulfonic acid monohydrate (22 mg, 0.12 mmol) in THF was stirred at 80° C. for 8 hours. After cooling to room temperature, the reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was reslurried with diisopropylether to obtain 3-[2-(2-bromophenyl)vinyl]-1-(tetrahydropyran-2-yl)-1H-indazole (0.39 g, 86%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([NH:12][C:25]([C:15]34[CH2:24][CH:19]5[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]5)[CH2:22]3)[CH2:16]4)=[O:26])[S:11][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CS(=O)(=O)c1ccc2nc(N)sc2c1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2nc(NC(=O)C34CC5CC(CC(C5)C3)C4)sc2c1

Procedure:
Commercially available 6-methanesulfonyl-benzothiazol-2-ylamine, triethylamine, and adamantane-1-carbonyl chloride were processed as described for Example 17A to afford the title compound. MS (ESI+) m/z 391 (M+H)+;
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[O:12]=[C:13]1[NH:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[S:31][CH3:32])[C:20]2[C:19](=[O:33])[CH2:18][CH2:17][CH2:16][C:15]=2[N:14]1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1>ClCCl>[O:12]=[C:13]1[NH:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[S:31]([CH3:32])=[O:6])[C:20]2[C:19](=[O:33])[CH2:18][CH2:17][CH2:16][C:15]=2[N:14]1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Solvent: ClCCl
Product: CS(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reaction time: 0.17 h

Procedure:
3-chloroperoxybenzoic acid (77%, 111 mg, 0.495 mmol) is added at room temperature to a solution of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methylsulfanyl-benzonitrile (INTERMEDIATE 6, 340 mg, purity 70%, 0.520 mmol) in dichloromethane (2 mL) and the mixture is stirred for 10 min. The reaction mixture is concentrated under reduced pressure and purified by reversed phase HPLC (X-Bridge C18, gradient of acetonitrile in water, 0.1% NH4OH) yielding the two diasteromers of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][C:13]([OH:15])=O)=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].[CH2:24]([O:26][C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[C:28]=1[NH2:29])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][C:13]([NH:29][C:28]1[C:30]([O:34][CH2:35][CH3:36])=[CH:31][CH:32]=[CH:33][C:27]=1[O:26][CH2:24][CH3:25])=[O:15])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23]
Reactant: CCOc1cccc(OCC)c1N
Reactant: COc1ccccc1-c1c(CC(=O)O)n(C)c2ccc(Cl)cc12
Product: CCOc1cccc(OCC)c1NC(=O)Cc1c(-c2ccccc2OC)c2cc(Cl)ccc2n1C

Procedure:
5-Chloro-3-(2-methoxyphenyl)-1-methylindole-2-acetic acid was reacted with 2,6-diethoxyaniline by a method similar to Example 6 to give the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].[CH:11]1([C:14](=O)[CH2:15][C:16](OCC)=[O:17])[CH2:13][CH2:12]1.C[O-].[Na+].CO>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:16](=[O:17])[CH:15]=[C:14]([CH:11]3[CH2:13][CH2:12]3)[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=c1cc(C2CC2)nc(-c2cccc(Cl)c2)[nH]1
Temperature: 0 °C
Yield: 33.1 %

Procedure:
A 500-mL round bottomed flask was charged with 3-chlorobenzimidamide (5.75 g, 30.1 mmol), ethyl 3-cyclopropyl-3-oxopropanoate (5.00 g, 32.0 mmol), and ethanol (100 mL) and the mixture cooled to 0° C. To the stirred mixture was added 25% sodium methoxide in methanol (15.0 mL, 64.0 mmol). The resulting mixture was stirred at reflux for 20 h. After cooling to room temperature, the mixture was evaporated under reduced pressure to 25 mL. The residual slurry was cautiously treated with 2N HCl (50 mL) forming a solid. The solid was collected by filtration and washed with water followed by ether to afford the title compound (2.46 g, 31%) as a white solid, which was carried forward into the next step without further purification. MW=246.69. 1H NMR (DMSO-d6, 500 MHz) δ 12.55 (s, 1H), 8.13 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.64-7.60 (m, 1H), 7.54 (t, J=8.0 Hz, 1H), 6.34 (s, 1H), 2.00-1.93 (m, 1H), 1.08-1.02 (m, 2H), 0.99-0.91 (m, 2H).
Reaction SMILES: C(OC([NH:8][C@:9]([CH3:37])([C:14]([N:16]1[CH2:36][CH2:35][CH2:34][C@H:17]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH:33]=[N:32][N:31]=[N:30]1)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:37][C@@:9]([C:14]([N:16]1[CH2:36][CH2:35][CH2:34][C@H:17]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH:33]=[N:32][N:31]=[N:30]1)=[O:19])=[O:15])([CH2:10][CH:11]([CH3:13])[CH3:12])[NH2:8]
Reactant: CC(C)C[C@](C)(NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@](C)(N)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Reaction time: 1 h

Procedure:
Each diastereomer of N-(tert-butoxycarbonyl)-2-methylleucyl-N-[5-chloro-2(1H-tetraazol-1-yl)benzyl]-L-prolinamide (A: 86 mg, 0.161 mmol; B: 84 mg, 0.158 mmol) was dissolved in a 2:1 solution of CH2Cl2/TFA (3 mL) and stirred for 1 h. Both reactions were then concentrated to oils. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded each diastereomer as a clear oil. Diastereomer A: 1H NMR (300 MHz, CDCl3): δ0 9.32 (s, 1 H), 8.08 (br s, 2 H), 7.78 (t, J=5.1 Hz, 1 H), 7.64 (d, J=2.4Hz, 1 H), 7.44 (dd, J=2.1, 8.7 Hz, 1 H), 7.29 (d, J=8.7 Hz, 1 H), 4.44–4.41 (m, 1 H), 4.23 (m, 2 H), 3.67–3.63 (m, 2 H), 2.28–2.24 (m, 1 H), 2.08–1.85 (m, 5 H), 1.78–1.71 (m, 1 H), 1.68 (s, 3 H), 0.86 (d, J=6.3 Hz, 3 H), 0.78 (d, J=6.6 Hz, 3 H). LCMS (M+H): 434.0. Diastereomer B: 1H NMR (300 MHz, CDCl3): δ 9.17 (s, 1 H), 8.30 (br s, 2 H), 8.08–8.04 (m, 1 H), 7.55 (d, J=2.1 Hz, 1 H), 7.44 (dd, J=2.1, 8.7 Hz, 1 H), 7.30 (d, J=8.7 Hz, 1 H), 4.49–4.45 (m, 1 H), 4.26–4.21 (m, 2 H), 3.77–3.66 (m, 2 H), 2.16–1.80 (m, 6 H), 1.77 (s, 3 H), 1.72–1.66 (m, 1 H), 0.92 (d, J=6.6 Hz, 3 H), 0.79 (d, J=6.3 Hz, 3 H). LCMS (M+H): 434.0.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.[Br:19][C:20]1[C:21]([O:32][CH2:33][CH3:34])=[N:22][CH:23]=[C:24]([CH:31]=1)[C:25](N(OC)C)=[O:26]>C(OCC)C.CCCCCC>[Br:19][C:20]1[CH:31]=[C:24]([C:25]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=2)=[O:26])[CH:23]=[N:22][C:21]=1[O:32][CH2:33][CH3:34]
Reactant: CC(C)n1cc(I)c2cncnc21
Reactant: CCOc1ncc(C(=O)N(C)OC)cc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 5-Iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 93, 530 mg, 1.85 mmol) in anhydrous diethyl ether (8 mL) was cooled to −78° C. under nitrogen and n-BuLi (1 mL of a 2.03M solution in Hexane, 2.03 mmol) was added drop wise over a period of 10 min. Just after the completion of addition of n-BuLi, a solution of 5-Bromo-6-ethoxy-N-methoxy-N-methyl-nicotinamide (Preparation 240) in anhydrous diethyl ether (7 mL) was added slowly to the mixture and it was stirred at the same temperature for another 1 hour. The reaction mixture was warmed to room temperature and allowed to stir for another hour before being quenched with sat. aq. NH4Cl (15 mL). The mixture was extracted with EtOAc (3×15 mL), washed with water (20 mL), brine (15 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:petroleum ether 2:10) to afford the title compound as a yellow gum in 49% yield, 350 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of 3-(3-nitro-phenyl)-acrylic acid ethyl ester (16.5 g, 74.6 mmol) and Pd/C (1.65 g) in methanol (200 mL) was stirred under 40 psi of H2 at RT for 2 h then filtered over celite. After removal the solvent, 14 g of 3-(3-amino-phenyl)-propionic acid ethyl ester was obtained and used directly without further purification. 1H-NMR (400 MHz, CDCl3): 7.11 (t, J=5.6 Hz, 1H), 6.67 (d, J=7.2 Hz, 1H), 6.63–6.61 (m, 2H), 4.13 (q, J=7.2 Hz, 2H), 2.87 (t, J=8.0 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.34 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2([CH:18]3[CH2:20][CH2:19]3)[C:9]3[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:8]=3[NH:7][C:6](=[O:17])[O:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24](Br)[CH:23]=1>>[Br:21][C:22]1[CH:23]=[C:24]([C:11]2[CH:12]=[CH:13][C:8]3[NH:7][C:6](=[O:17])[O:5][C:4]([CH:18]4[CH2:20][CH2:19]4)([CH:1]4[CH2:3][CH2:2]4)[C:9]=3[CH:10]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C1Nc2ccc(B(O)O)cc2C(C2CC2)(C2CC2)O1
Reactant: Fc1cc(Br)cc(Br)c1
Product: O=C1Nc2ccc(-c3cc(F)cc(Br)c3)cc2C(C2CC2)(C2CC2)O1

Procedure:
Prepared according to Procedure B from (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-fluorobenzene. A white solid: mp 228-229° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.76-7.72 (m, 2H), 7.65 (dd, 1H, J=8.32, 1.74 Hz), 7.60 (d, 1H, J=10.36 Hz), 7.51 (d, 1H, J=8.3 Hz), 6.93 (d, 1H, J=8.31 Hz), 1.63-1.54 (m, 2H), 0.58-0.41 (m, 6H), 0.30-0.28 (m, 2H); MS (APCI) m/z 402/404 ([M−H]−, 100%); Anal. Calc. For C20H17BrFNO2: C, 58.48; H, 4.17; N, 3.41. Found: C, 58.77; H, 4.23; N, 3.32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[N:21][N:20]=[C:19]1[CH2:24]Br.[NH3:27]>CO>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:18]3[C:22]([CH3:23])=[N:21][N:20]=[C:19]3[CH2:24][N:27]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: N
Reactant: Cc1nnc(CBr)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Solvent: CO
Product: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 8, 2'-chloro-5nitro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with a saturated solution of ammonia in methanol to give 8-nitro-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo- [4,3-a][1,4]benzodiazepine of melting point 231°-233° C.