Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[C:5]([NH:20][CH:21]2[CH:27]3[CH2:28][CH2:29][CH:23]([CH2:24][CH2:25][CH2:26]3)[CH:22]2[C:30]([O:32]C)=[O:31])=[N:6][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[NH:12][N:11]=2)=[N:8][CH:9]=1>C1COCC1>[F:3][C:4]1[C:5]([NH:20][CH:21]2[CH:27]3[CH2:28][CH2:29][CH:23]([CH2:24][CH2:25][CH2:26]3)[CH:22]2[C:30]([OH:32])=[O:31])=[N:6][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[NH:12][N:11]=2)=[N:8][CH:9]=1
Reactant: COC(=O)C1C2CCCC(CC2)C1Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1C2CCCC(CC2)C1Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1F
Temperature: 85 °C

Procedure:
A solution of lithium hydroxide (2.10 mL of 2N solution, 4.15 mmol) was added to a stirred solution of racemic methyl 7-(5-fluoro-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-ylamino)bicyclo[3.2.2]nonane-6-carboxylate, I-36, (0.18 g, 0.42 mmol) in THF (7 mL). The solution was heated at 85° C. for 6 hr and cooled to room temperature. The solution was concentrated in vacuo and water (5 mL) was added. The solution was slowly neutralized with 1N HCl to produce a white precipitate. The precipitate was filtered and washed with water (10 mL). The wet solid was lyophilized for 2 days to 112 mg of the desired product as a white powder: 1H NMR (400 MHz, CD3OD) δ 8.77 (s, 1H), 8.52 (s, 1H), 8.10 (s, 1H), 5.29 (m, 1H), 2.82 (m, 1H), 2.53 (m, 1H), 2.11-1.54 (brm, 10H), 1.29 (m, 1H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.33 minutes (M+H) 415.44.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1
Yield: 66.7 %

Procedure:
A mixture of 2.05 g of 2-(R)-hydroxy-4-methylpentanoic acid, 2.01 g of benzyl alcohol and 0.251 g of p-toluenesulfonic acid monohydrate in 40 ml of benzene was heated to reflux for 1.5 hours. The reaction mixture, after being allowed to cool, was washed with a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure to yield the title compound as a colorless oil (2.30 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=CC=2F)=NOC=1C)=O)C>>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2cccc(F)c2F)noc1C
Agent: CCOC(=O)c1c(-c2ccccc2F)noc1C
Product: Cc1onc(-c2cccc(F)c2F)c1CO
Yield: 34.8 %

Procedure:
As described for example 84d, 3-(2,3-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (16.0 g, 59.9 mmol) was converted, instead of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (4.7 g, 35%) which was obtained as a yellow oil. MS: m/e=226.2 [M+H]+.
Reaction SMILES: O.C(O)C.[CH3:5][C@@H:6]1[C@H:40]([OH:41])[C@@H:39]([CH3:42])[C@@H:38]([OH:43])[C@@H:37]([CH3:44])[C@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@H:35]([CH3:49])[C@@H:34]([O:50][CH3:51])[CH:33]=[CH:32][O:31][C@:28]2([CH3:52])[C:29](=[O:30])[C:18]3[C:19]([O:27]2)=[C:20]([CH3:26])[C:21]([OH:25])=[C:22]2[C:23](=[O:24])[C:14](=[CH:15][C:16]4(OC(=O)CO4)[C:17]=32)[NH:13][C:11](=[O:12])[C:10]([CH3:58])=[CH:9][CH:8]=[CH:7]1.[NH2:59][C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[CH:62][N:61]=1>CC(C)=O>[CH3:66][C:64]1[CH:63]=[CH:62][N:61]2[C:15]3[C:14]4[NH:13][C:11](=[O:12])[C:10]([CH3:58])=[CH:9][CH:8]=[CH:7][C@H:6]([CH3:5])[C@H:40]([OH:41])[C@@H:39]([CH3:42])[C@@H:38]([OH:43])[C@@H:37]([CH3:44])[C@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@H:35]([CH3:49])[C@@H:34]([O:50][CH3:51])[CH:33]=[CH:32][O:31][C@:28]5([CH3:52])[C:29](=[O:30])[C:18]6=[C:19]([O:27]5)[C:20]([CH3:26])=[C:21]([OH:25])[C:22](=[C:17]6[C:16]=3[N:59]=[C:60]2[CH:65]=1)[C:23]=4[OH:24]
Reactant: Cc1ccnc(N)c1
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C2(C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O)OCC(=O)O2
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c5c(nc6cc(C)ccn65)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C2(C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O)OCC(=O)O2
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c5c(nc6cc(C)ccn65)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In flask equipped with a mechanic stirrer, 200 ml of demineralized water, 150 ml of ethyl alcohol, 50 ml of acetone, 100 g of Rifamycin O and 43.3 g of 2-amino-4-methylpyridine are loaded in succession at room temperature. After loading, the mixture is kept under stirring at room temperature for 24 hours, then is cooled to 10° C. for 60 minutes. Then the precipitate is filtered and washed by means of a mixture of 100 ml of demineralized water and 100 ml of ethyl alcohol and at least with two washing of 100 ml of demineralized water. The product is dried under vacuum at 70° C. until the water content is between 2.0 and 4.5%.
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57]>C1COCC1>[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27]([NH:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: C[C@H](N)C(=O)CCl
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)CCl
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Boc-Ala-CH2Cl (2 g) in 5 equiv of HCl in dioxane was stirred at room temp for 1 h. After removal of solvent, the residue was triturated with diethyl ether to give crude H-Ala-CH2Cl (1.41 g). The Z-Leu-Asp(OtBu)-Leu-OH (2.68 g) and N-methylmorpholine (0.54 mL) were dissolved in THF (25 mL), the cooled to -20° C. Isobutyl chloroformate (0.64 mL) was added to generate the mixed anhydride, which was transferred to the H-Ala-CH2Cl (1.41 g in 10 mL of DMF) solution at -20° C. The resulting mixture was allowed to come to room temp and reaction was completed in 3 h. The salt was removed by filtration. The filtrate was concentrated, redissolved in ethyl acetate (100 mL). The solution was washed with 0.2N HCl, 5% NaHCO3, sat. NaCl; dried over Na2SO4, filtered, and concentrated to yield crude solid of 3.19 g. The crude Z-Leu-Asp(OtBu)-Leu-Ala-CH2Cl was purified by Sephadex LH20 column chromatography.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>C1COCC1>[C:19]1([S:25]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)c1ccc2c(c1)CCN2
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1

Procedure:
1-(2,3-Dihydro-1H-indol-5-yl)-ethanone (0.200 g, 1.24 mmol) was dissolved in THF (2 ml) before pyridine (0.303 ml, 3.75 mmol) was added, leaving a yellow solution. The benzenesulfonyl chloride (0.220 g, 1.24 mmol) was then added, as a solid, with stirring. The reaction mixture was stirred at 40 C for 5 h. The mixture was cooled and the THF and pyridine were removed in vacuo. The desired sulfonamide (0.310 g, 1.02 mmol, 82%) was recrystallized from ethyl acetate and hexanes. It had LC-MS (ES+): 302 [MH]+ m/e
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12](C(=O)CC)[CH2:11]2)[CH:5]=1.[OH-].[Na+].CO>O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=1
Reactant: CCC(=O)N1CCCC(c2cccc(C(=O)OC)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(-c2cccnc2)c1
Yield: 69 %

Procedure:
A mixture of methyl-3-(1-propionylpiperidin-3-yl)benzoate (4.8 g, 0.17 mol), sodium hydroxide pellets (5 g), methanol (80 ml) and water (20 ml) was stirred until TLC indicated that no starting material remained (4 hours). The methanol was evaporated and the alkaline water layer was washed with ether, acidified with hydrochloride acid and extracted with chloroform. Evaporation gave the product (4.0 g, 69% yield from methyl-3-(3-pyridyl)-benzoate) as an oil which crystallized after several weeks on standing. (Mp. 125°-126° C.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])=[C:4]2[N:9]([C:10]=1[C:11](OCC)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:35]1(C)[CH:40]=CC=C[CH:36]=1>COC(OC)(C)C>[OH:12][C:11]1[C:10]2[N:9]3[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]3)=[C:3]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])[C:2]=2[N:1]=[C:35]([CH3:40])[CH:36]=1
Reactant: CCOC(=O)c1c(N)c(-c2c(C)cc(C)cc2C)c2ccccn12
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COC(C)(C)OC
Product: Cc1cc(C)c(-c2c3nc(C)cc(O)c3n3ccccc23)c(C)c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of 2-amino-3-ethoxycarbonyl-1-(2,4,6-trimethylphenyl)-indolizine (19.2 g; 59.6 mmol) in 2,2-dimethoxypropane (100 mL) is added di-camphorsulfonic acid (0.2 g). The mixture is stirred at reflux for 30 minutes and then distilled slowly to remove ca. 60 mL of volatiles over a 30-minute period. The solution is cooled to ambient temperature under an inert atmosphere, diluted with anhydrous toluene (50 mL), and concentrated in vacuo. The residue is dissolved in toluene (50 mL) and to the stirred solution is then added a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (250 mL; 125 mmol) dropwise over a 1-hour period. After the addition is complete, the mixture is further stirred for 2 hours at room temperature before being concentrated in vacuo to a small volume and then diluted with aqueous ammonium chloride. The resulting emulsion-like biphasic mixture is suction-filtered and washed succesively with water, methanol, and ethyl ether. Air- and vacuum drying provides 10.1 g of the title compound as a pale yellow solid (54%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[S:24][C:25]5[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=5[CH:27]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-])=O>[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[S:24][C:25]5[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=5[CH:27]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3cc4ccccc4s3)ccc2o1
Agent: [Zn]
Product: CCCNc1ccc(N)cc1-c1nc2cc(-c3cc4ccccc4s3)ccc2o1

Procedure:
Prepared by the method of Example 47b), from 2-(3-nitro-6-propylaminophenyl)-5-(2-benzothiophenyl)benzoxazole (386 mg, 0.90 mmol) and zinc (589 mg, 9.0 mmol) the subtitle compound was obtained (154 mg, 100%). MS 400.3 m/z (M+H)+.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[C:9]1([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25]>>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25].[C:9]1([N:15]2[CH2:20][CH2:19][N:18]([CH2:2][CH:3]3[O:7][C:6](=[O:8])[NH:5][CH2:4]3)[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1NCC(CCl)O1
Agent: O=C(O)/C=C\C(=O)O
Product: O=C1NCC(CN2CCN(c3ccccc3)CC2)O1

Procedure:
Following the procedure of Example 35, the free base was prepared from 5-chloromethyl-2-oxazolidinone and 1-phenylpiperazine. The product was converted to the maleic acid salt, mp 166°-168° C.
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]2[C:34]([C:38]#[N:39])=[C:35]([NH2:37])[S:36][C:30]=2[CH2:29]1)=[O:27])[CH3:24].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]2[C:34]([C:38]#[N:39])=[C:35]([NH:37][C:1](=[O:11])[CH2:2][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[S:36][C:30]=2[CH2:29]1)=[O:27])[CH3:24]
Reactant: O=C(O)CCc1ccccc1
Reactant: CCOC(=O)N1CCc2c(sc(N)c2C#N)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N1CCc2c(sc(NC(=O)CCc3ccccc3)c2C#N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a sealed test tube hydrocinnamic acid (1.5 mmol) is suspended in a mixture of DMF (0.15 mmol) and dichloromethane (7.5 mL). A solution of oxalyl chloride (3.0 mmol) in dichloromethane (7.5 mL) is then added and the mixture stirred for 1 h at room temperature. After that, the solvents and excess of oxalyl chloride are removed in vacuo, the residue is dissolved in toulene (7.5 mL) and added to 2-amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid ethyl ester (1 mmol) in a vial suitable for microwave technology. Diisopropyl ethyl amine (1.5 mmol) is added, the vial is capped and the mixture heated for 30 min at 150° C. using microwave technology. Purification is achieved by filtration followed by washing (water) and crystallization (ethanol).
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[CH3:30][CH:31]1[CH2:35][C:34]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:33]=2[O:32]1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([C:37]3[CH:38]=[CH:39][C:33]4[O:32][CH:31]([CH3:30])[CH2:35][C:34]=4[CH:36]=3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc3c(c2)CC(C)O3)c2nc(C)nn12
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a suspension (5 mL) of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.15 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.13 g), triethylamine (0.15 mL), pyridine (0.3 mL) and molecular sieves 4A (0.3 g) in dichloromethane was added copper(II) acetate (0.14 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]([OH:18])=[O:17])[CH2:11][C:10]([O:14]C)(OC)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH3:20]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:16]([O:18][CH3:20])=[O:17])[CH2:9][C:10](=[O:14])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: COC1(OC)CC(C(=O)O)(c2ccc(F)cc2)C1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(c2ccc(F)cc2)CC(=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a stirred solution of Intermediate 308B (1.0 g, 3.93 mmol) in MeOH (15 mL) was added a concentrated aq. solution of HCl (5 mL) and the solution was stirred at RT for 12 h. The volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography (24 g REDISEP® column, eluting with 20% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 308C as a colorless oil (700 mg, 80%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.45 (dd, J=8.94, 5.05 Hz, 2H), 7.09 (t, J=8.66 Hz, 2H), 3.89 (m, 2H), 3.71 (s, 3H), 3.57-3.72 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[O:14])[C:11](=[C:15]([CH3:17])[CH3:16])[CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1>CO.C(OCC)(=O)C.[C].[Pd]>[CH:15]([CH:11]1[C:12](=[O:14])[C:13]2[C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=[CH:8][C:9]=2[CH2:10]1)([CH3:17])[CH3:16]
Reactant: CC(C)=C1Cc2ccc3nc(C)oc3c2C1=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2o1)C(=O)C(C(C)C)C3
Temperature: 25 °C
Reaction time: 40 h
Yield: 96.9 %

Procedure:
To a solution of 2-methyl-7-(1-methylethylidene)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-one (677 mg, 2.98 mmol) in methanol/ethyl acetate (5/15 mL) was added a palladium-carbon powder (68 mg), and the mixture was stirred at room temperature for 40 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (662 mg, yield 97%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNCCN
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 11.2 %

Procedure:
To a solution of 5 g (67.45 mmol) N1-methyl-ethane-1,2-diamine in 50 mL DMF a solution of 16.72 g (60 mmol) trityl-chloride in 50 mL DMF was added slowly over a period of 10 minutes at room temperature. The mixture was stirred overnight then it was evaporated to dryness, the oil was dissolved in 100 mL ethylacetate, was washed three times with water, dried with sodium sulfate then was evaporated. The components of the oil were separated on a silicagel column using chloroform-methanol gradient elution to give 2.13 g (10%) 197.). 1H-NMR (CDCl3) 7.48–7.44 (m, 6H), 7.27–7.21 (m, 6H), 7.18–7.12 (m, 3H), 3.44 (s, 1H), 2.78–2.74 (m, 2H), 2.42–2.38 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl>CCO>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[Cl:1])(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2c(Cl)ccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)Nc1cccc2c(Cl)ccnc12
Yield: 64 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(4-chloro-quinolin-8-yl)-2-nitro-benzenesulfonamide (Intermediate 246) (2.3 g, 6.32 mmol), SnCl2 (5.99 g, 31.6 mmol) and 6N HCl (cat.) in EtOH (30 ml) at 90° C. for 22 h gave the title compound (1.35 g, 64%) which was used in the next step without further purification.
Reaction SMILES: C[O:2][CH2:3][C:4]1([C:21]([N:23]2[CH2:32][CH2:31][C:30]3[N:29]=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=3[CH2:24]2)=[O:22])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]=3[CH:20]=2)[CH2:5]1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][CH2:3][C:4]1([C:21]([N:23]2[CH2:32][CH2:31][C:30]3[N:29]=[CH:28][C:27]([C:33]([F:35])([F:36])[F:34])=[CH:26][C:25]=3[CH2:24]2)=[O:22])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]=3[CH:20]=2)[CH2:5]1
Reactant: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCN(Cc2ccc3oc(=O)n(C)c3c2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(=O)oc2ccc(CN3CCC(CO)(C(=O)N4CCc5ncc(C(F)(F)F)cc5C4)C3)cc21
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a stirred solution of compound from Example 39 (770 mg, 1.52 mmol) in 14 mL of DCM at −78° C. was added a solution of BBr3 (4.58 mmol) in DCM. After 1 hour, the reaction mixture was warned up to −25° C. and the reaction was monitored by TLC. After completion, the mixture was quenched with sat. NaHCO3. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combinated organic layer were washed with brine, dried over MgSO4 and concentrated to gave the crude product, which was purified by a flash column chromatography give 172 mg of the title compound (0.351 mmol, 23%): 1H NMR (400 MHz, CD3OD): δ 8.63 (s, 1H), 7.89 (s, 1H), 7.20-7.15 (m, 3H), 4.83-4.79 (m, 2H), 4.15-3.85 (m, 2H), 3.81-3.60 (m, 2H), 3.40 (s, 2H), 3.35 (s, 3H), 3.30-3.00 (m, 3H), 2.80-2.60 (m, 3H), 2.32-2.20 (m, 1H), 2.10-1.99 (m, 1H); MS (ESI) m/z: Calculated for C24H25F3N4O4: 490.47. found 491.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][C:8]=1[NH:17][C:18](=[O:35])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[O:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[NH:17][C:18](=[O:35])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[O:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C)cc1OC

Procedure:
3.0 ml (6.0 mmol) of a 2N aqueous aqueous solution of sodium hydroxide were added to a solution of 1.11 g (2.34 mmol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(2-methoxy-4-methylphenyl)octanamide [prepared as described in step (ii) above] in 30 ml of methanol, and the resulting mixture was heated under reflux for 1 hour, after which the solvent was removed by distillation under reduced pressure. The resulting residue was acidified with 1N aqueous hydrochloric acid, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, afterwhich it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, giving 1.02 g (a quantitative yield) of the title compound as crystals, melting at 163.5°-165° C.