Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[F:28])([C:15]([F:18])([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[F:28])([C:15]([F:17])([F:16])[F:18])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc([N+](=O)[O-])ccc2F)(C(F)(F)F)CCOC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)(F)F)CCOC1
Reaction time: 6 h
Yield: 87.9 %

Procedure:
A solution of [5-(2-fluoro-5-nitro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamic acid tert-butyl ester (1.69 g, 4.01 mmol) in 10 mL ethanol and 10 mL THF was brought under nitrogen atmosphere and 500 mg of 5% Pd on charcoal was added. The reaction mixture was then stirred under a hydrogen atmosphere (balloon) for 6 hours. Then it was filtered over celite and evaporated. The crude product was crystallized from hexane/TBME to give 1.38 g of the title compound as white crystals.
Reaction SMILES: C(OC([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)([CH3:13])[CH2:11][O:10][S:9]1(=[O:22])=[O:21])=O)(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[Br:20][C:16]1[CH:15]=[C:14]([C:12]2([CH3:13])[CH2:11][O:10][S:9](=[O:22])(=[O:21])[NH:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)c2)COS1(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2cccc(Br)c2)COS(=O)(=O)N1
Reaction time: 3 h
Yield: 91 %

Procedure:
3-(tert-Butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC4; R6=Me) (10.8 g, 28 mmol) was dissolved in 25% TFA in DCM (40 mL, 5 eq) and the mixture was left standing at RT for 3 h. The mixture was concentrated in vacuo to give 7.3 g (91%) of 4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide as a yellow oil. 1H NMR (CDCl3) 7.59 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.39-7.42 (m, 1H), 7.30 (t, J=8.1 Hz, 1H), 4.59 (m, 2H), 1.82 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1.C1C(=O)N([Br:32])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:24][Br:32])=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1-c1cccc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccc(-c2cc(-c3nc4ccccc4o3)ccc2CBr)c1

Procedure:
A mixture of 5′-(1,3-benzoxazol-2-yl)-2′-methyl-1,1′-biphenyl-3-carbonitrile (229 mg, 0.74 mmol), n-bromosuccinimide (145 mg, 0.81 mmol), and benzoyl peroxide (9 mg, 0.037 mmol) in carbon tetrachloride (15 mL) was refluxed for 5 h. The solvent was evaporated to dryness and the crude was purified by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 30 min: 0 to 20% EtOAc, 30 to 40 min: 50% EtOAc) to afford 5′-(1,3-benzoxazol-2-yl)-2′-(bromomethyl)-1,1′-biphenyl-3-carbonitrile as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: O=C(O)c1cnc(-c2ccc(F)cc2)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-pyrimidine-5-carboxylic acid (107 mg, 0.49 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and PS-DCC (511 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (30.4 mg, 0.33 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (392 mg, 3.75 mmol/g, 1.47 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(4-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide (83.4 mg, 86%) as a solid. MS: 294 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[CH:6]1([CH2:5][CH:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)[C:3]([OH:30])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C(CC1CCCCC1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CC1CCCCC1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 88.3 %

Procedure:
To a solution of 3-cyclohexyl-2-[4-(quinolin-2-yl-methoxy)phenyl]propionic acid methyl ester (650 mg; 1.6 mmol) in methanol (20 ml) was added 1N sodium hydroxide (3 ml) and the mixture was stirred at 50° C. for 10 h. The methanol was removed in vacuo, to the residue was added 10 ml of water and the resulting mixture was acidified to pH 4. The precipitated solid was filtered, washed with water and dried in vacuo to provide 550 mg of 3-cyclohexyl-2-[4-(quinolin-2-yl-methoxy)phenyl]propionic acid, mp. 148°-150° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[CH:8]=2)([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[CH:8]=2
Reactant: CCc1ccc(COc2ccc3cc([N+](=O)[O-])cnc3c2)nc1
Agent: O=[Pt]
Solvent: CCO
Product: CCc1ccc(COc2ccc3cc(N)cnc3c2)nc1
Reaction time: 3 h

Procedure:
In ethanol (20 mL) was suspended 3-nitro-7-(5-ethyl-2-pyridylmethoxy)quinoline (700 mg, 2.26 mmol.), and to the suspension was added platinum oxide (80 mg). Then, catalytic reduction was performed for 3 hours. After the completion of reaction was confirmed, the reaction mixture was filtered over Celite®, and the filtrate was placed under reduced pressure to give the desired compound as residual oil in a quantitative yield.
Reaction SMILES: [C:1]1(=[O:14])[N:9]2[CH:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[CH2:3][NH:2]1.[H-].[Na+].Cl[CH2:18][C:19]1[N:20]=[CH:21][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]=1[CH3:24].O>CN(C)C=O>[CH3:24][C:23]1[N:22]([C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:21]=[N:20][C:19]=1[CH2:18][N:2]1[CH2:3][CH:4]2[CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]2[C:1]1=[O:14]
Reactant: O=C1NCC2COc3ccccc3N12
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN2CC3COc4ccccc4N3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,3,3a,4-tetrahydro-1H-imidazo [5,1-c][1,4]benzoxazin-1-one (0.89 g; 0.0047 moles) in 20 ml of anhydrous dimethylformamide kept under nitrogen atmosphere, 50% NaH (0.22 g; 0.0047 moles) is added. The solution is stirred for 1 hour at 60° C.; then, at room temperature, 4-chloromethyl-5-methyl-1-triphenylmethyl-1H-imidazole (1.75 g; 0.0047 moles) is added. The mixture is stirred for 6 hours at 70° C., then cooled, poured into water and extracted with methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[NH:7][C:6]=1[CH3:18].C(O)C.[OH-].[Na+].Cl>O>[C:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:18])=[C:5]2[CH2:4][C:3]1[CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:22][C:2]=1[Cl:1])([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2[nH]c(C)c(Cc3ccc(-c4ccccc4)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1[nH]c2ccc(C(=O)O)cc2c1Cc1ccc(-c2ccccc2)cc1Cl
Yield: 76.5 %

Procedure:
To 3-(2-chloro-4-phenylbenzyl)-5-methoxycarbonyl-2-methylindole (0.95 g), added are ethanol (5 ml), water (5 ml) and aqueous sodium hydroxide (0.29 g), and refluxed for 3 hours. The reaction mixture is cooled, and neutralized with HCl. This is extracted with ethyl acetate and water, and the organic layer is dried and concentrated. The resulting residue is crystallized from a small amount of a mixed solution of chloroform and ether. The crystal is taken out through filtration and dried to obtain 5-carboxy-3-(2-chloro-4-phenylbenzyl)-2-methylindole (145) (0.701 g)
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]([CH2:13][CH3:14])[C:6]2[N:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>C1(C)C=CC=CC=1>[CH2:13]([N:5]1[C:4]2[N:15]=[CH:16][CH:17]=[CH:18][C:3]=2[C:2]([NH:22][CH2:19][CH2:20][CH3:21])=[N:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]1=2)[CH3:14]
Reactant: CCN1c2ncccc2N=C(Cl)c2cccnc21
Reactant: CCCN
Solvent: Cc1ccccc1
Product: CCCNC1=Nc2cccnc2N(CC)c2ncccc21

Procedure:
A mixture of 6-chloro-11-ethyl-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.7 g, n-propylamine (0.8 g), and toluene (25 mL) was heated at reflux for ten days. At two day intervals during the ten day period, additional 1.6 g portions of n-propylamine was added to the refluxing mixture. The mixture was then concentrated in vacuo and the residue chromatographed over silica gel (eluted with 20% ethyl acetate/hexane) to give 0.15 g of the title compound, m.p. 114°-116° C.
Reaction SMILES: C[Mg]Br.Br[C:5]1[CH:6]=[C:7]2[C:11](=[N:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.C(Cl)Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH2:22]Br>[Cl-].[Cl-].[Zn+2]>[CH3:28][O:27][C:25]1[CH:24]=[C:21]([CH:20]=[C:19]([O:18][CH3:17])[CH:26]=1)[CH2:22][C:9]1[NH:10][C:11]2=[N:12][CH:13]=[CH:5][CH:6]=[C:7]2[CH:8]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: COc1cc(CBr)cc(OC)c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COc1cc(Cc2cc3cccnc3[nH]2)cc(OC)c1
Yield: 4.4 %

Procedure:
Into a round bottom flask, under an atmosphere of nitrogen, methylmagnesium bromide (0.16 mL, 1.4 mmol) was added to a solution of 7-azaindole (1) (0.150 g, 1.27 mmol) in anhydrous methylene chloride (12 mL, 0.19 mol), at room temperature. The resulting mixture was stirred at room temperature for one hour before zinc dichloride (0.21 g, 1.5 mmol) was added. After stirring for an additional hour, 3,5-dimethoxybenzyl bromide (4) (0.35 g, 1.5 mmol) was added into the reaction mixture. The reaction was stirred overnight at room temperature before it was quenched with methanol. The mixture was evaporated to dryness, dissolved into ethyl acetate and washed with water. The aqueous portion was neutralized with sodium bicarbonate (s.s.) and extracted with ethyl acetate (3×). Organic portions were combined and washed with 0.1N HCl, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Purification by preparative TLC with 50% ethyl acetate/hexane gave Compound 29 as a yellow powder (15 mg; M+H=269.2, M−H=267.2).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[CH2:47]I>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:47][C:46]2[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:44]([O:43][CH3:42])[CH:45]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(CI)cc1OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1OC

Procedure:
In analogy with Example 44c), 1 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] in 4 ml of abs. THF is deprotonated (-75° C.) with 6.42 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, with the addition of 0.66 ml of DMPU, and alkylated with 911 mg of 3,4-dimethoxybenzyl iodide. Chromatography on silica gel (eluents D, C and J) gives the pure title compound. TLC Rf (C)=0.42. MS M+ =455.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[O:41]1[CH2:42][CH2:43][N:38]([C:2]2[CH:7]=[C:6]([N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:15])([CH3:14])[CH3:16])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[N:5]3[N:25]=[CH:26][C:27]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:4]3[N:3]=2)[CH2:39][CH2:40]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 130 °C
Yield: 82.4 %

Procedure:
A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (77.9 mg, 0.14 mmoL), morpholine (36.7 mg, 0.42 mmoL), NaHCO3 (53 mg, 0.63 mmoL) in NMP (3 mL) was heated at 130° C. overnight. The mixture was cooled to room temperature and diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude displacement compound. Purification by column chromatography afforded 5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (70 mg, 82%). LCMS tR=2.72 Min (5 min run, UV254nm). Mass calculated for, M+ 606.3, observed LC/MS m/z 607.2 (M+H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([C:47]([F:49])([F:50])[F:48])=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1c(F)cccc1C(F)(F)F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-(trifluoromethyl)phenyl)boronic acid gave 278. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.85-7.69 (m, 4H), 7.47 (s, 2H), 5.03-4.74 (m, 2H), 4.00-3.86 (m, 2H), 3.74 (s, 3H), 2.13 (ddt, J=14.4, 6.1, 2.8 Hz, 1H), 2.01-1.61 (m, 3H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)(O)[CH2:9][O:10]C)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(O)(c1cccc(F)c1)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CC(c1cccc(F)c1)c1cccc(F)c1
Yield: 104.9 %

Procedure:
A solution of 1,1-bis-(3-fluorophenyl)-2-methoxyethanol (156.7 g) (obtained by reaction of (3-fluorophenyl)magnesium bromide on methyl 2-methoxyacetate in THF) in formic acid (160 cc) is refluxed for 16 hours, cooled and poured into a mixture of saturated sodium carbonate solution (800 cc) and ethyl acetate (500 cc). The organic phase is washed with water (2×500 cc) and with saturated sodium chloride solution (500 cc) and then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis-(3-fluorophenyl)acetaldehyde (144.5 g) in the form of a yellow oil.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]2[O:29][CH:30]=[C:31]([CH2:33]Cl)[N:32]=2)=[C:22]([F:35])[CH:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2[O:29][CH:30]=[C:31]([CH2:33][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:32]=2)=[C:22]([F:35])[CH:21]=1
Reactant: Fc1cc(Cl)ccc1C=Cc1nc(CCl)co1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Cl)ccc1/C=C/c1nc(COc2ccc(CCCCn3ccnn3)cc2)co1
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
1H-NMR(400 MHz, D6-DMSO): δ=6.72(d, 1H, 1′-H), 7.35(d, 1H, 5″-H), 7.44(d, 1H, 2′-H), 7.50(d, 1H, 3″-H), 7.95(dd, 1H, 6″-H), 8.21(s, 1H, 5-H-oxazole). 26 mg (1.0 mmol) of 95% sodium hydride were given at 0° C. to a solution of 217 mg (1.00 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 2.0 ml N,N-dimethyl formamide and stirred for 30 min. 272 mg (1.00 mmol) 2-[2-(4-Chloro-2-fluoro-phenyl)-vinyl]-4-chloromethyl-oxazole dissolved in 1.0 ml N,N-dimethyl formamide were added at 0° C., stirring continued at 0° C. for 1 h and 12 h at room temperature thereafter. The mixture was quenched by 6 ml water, stirred for 1 h and the precipitate isolated by filtration. After washing with water, three times with cold ether and drying at 40° C. in vacuo, 350 mg (77%) 1-[4-(4-{2-[2-(E)-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole were obtained.
Reaction SMILES: S(=O)(=O)(O)O.O.[Cl:7][C:8]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([SH:17])=[CH:11][C:9]=1[NH2:10].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)([CH3:28])[CH3:27]>O1CCCC1>[Cl:7][C:8]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([S:17][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])([CH3:28])[CH3:27])=[CH:11][C:9]=1[NH2:10]
Reactant: COc1ccccc1C(C)(C)O
Reactant: COc1cc(Cl)c(N)cc1S
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(N)cc1SC(C)(C)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To concentrated sulfuric acid (6 mL) was added water (6 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of 2-chloro-5-mercapto-4-methoxyaniline (0.5 g) and 2-(2-methoxyphenyl)-2-propanol (0.88 g) in tetrahydrofuran (6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=4/1) to give the title compound (0.3 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.[CH2:17]([S:23](Cl)(=[O:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1.CN(C=O)C>[CH3:15][C:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:4][NH:3][S:23]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:25])=[O:24]
Reactant: CCCCCCS(=O)(=O)Cl
Reactant: Cc1c(CN)[nH]c2ccccc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCS(=O)(=O)NCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.5 %

Procedure:
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (212 mg) in pyridine-DMF (8:1, 9 mL) was added hexanesulfonyl chloride (180 mg) under ice-cooling, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]hexane-1-sulfonamide (56 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:13]2)[O:9][N:8]=1.O>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[O:29])[CH2:13]2)[O:9][N:8]=1
Reactant: COCCO
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: C1COCCO1
Solvent: O
Product: COCCOc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 684 mg (8.99 mmol) of ethylene glycol monomethyl ether in 8.00 ml of 1,4-dioxane were added, at RT, 4 Å molecular sieve and 0.90 ml (0.90 mmol; 1 M solution in n-hexane) of phosphazene P4 base. Subsequently, 200 mg (0.450 mmol) of the oxadiazole from Example 23A in 2.0 ml of 1,4-dioxane were added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was admixed with water, filtered and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 89.8 mg (41% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH:24]([C:28](=O)[CH3:29])[CH2:25][C:26]#[N:27]>C(#N)C>[CH2:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:24]([CH2:25][C:26]#[N:27])=[C:28]([CH3:29])[N:1]=2)[CH:4]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(NCc2ccccc2)cn1
Reactant: CC(=O)C(Cl)CC#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(NCc3ccccc3)cn2c1CC#N

Procedure:
A mixture of 2-amino-5-benzylamino pyridine (4.0 g), triethylamine (2.1 g),3-chloro-4-oxopentanenitrile (2.7 g) and acetonitrile (50 ml) is stirred and heated under reflux for 18 hr. The solvent is removed in vacuo, and the residue is dissolved in chloroform (200 ml). The solution is washed with water (4×100 ml), dried over anhydrous potassium carbonate and the chloroform is removed in vacuo. The residue is chromatographed on silica gel (200 g) using chloroform as the eluant. The product is obtainedand crystallized from acetonitrile.