Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15].N1C=CN=C1.S(=O)(=O)(O)O>CN(C)C=O.CCOCC>[Si:1]([O:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(CO)c1
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.7 %

Procedure:
33.3 g of tert-butyldimethylsilyl chloride is added to a solution of 30 g of 3-hydroxymethylbenzyl alcohol and 30 g of imidazole in 250 ml of dimethylformamide at 0° C. under argon and stirred for 20 hours at 25° C. It is diluted with 1.5 1 of ether, shaken twice with 100 ml of 10% sulfuric acid each, washed neutral with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/0-80% ether, 23.4 g of 3-tert-butyldimethylsilyloxymethyl-benzyl alcohol is obtained as colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[CH:3]=[CH:4]/[C:5]#[N:6].[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl>[C:5](/[CH:4]=[CH:3]/[C@H:2]([NH:1][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:15]([F:14])([F:27])[F:28])(=[O:25])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:6]
Reactant: N#C/C=C/[C@H](N)Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: N#C/C=C/[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To a solution of compound 31f (2.5 g, 14.5 mmol) in DCM (100 mL) was added 2-(trifluoromethoxy)benzene-1-sulfonyl chloride (4.2 g, 16.0 mmol) and TEA (4.4 g, 3.5 mmol). The mixture was stirred at rt for 12 h, then DCM (50 mL) and 2N HCl (20 mL) were added to the mixture. The organic layer was separated and washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA=5:1) to give compound 31g (4.2 g, 74% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[OH:17])=O)=[CH:4][CH:3]=1.Cl.[NH2:19]O.C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[O:17][N:19]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2c(-c3ccc(Br)cc3)noc2c1
Temperature: 85 °C
Yield: 95.1 %

Procedure:
A mixture of 4.25 g of (4-bromo-phenyl)-(2,4-dihydroxyphenyl)-methanone, 3.22 g of hydroxylamine.hydrochloride and 2.85 g of sodium acetate in 100 ml of ethanol is heated under reflux. The reaction mixture is concentrated, treated with 100 ml of saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic extracts are washed with saturated sodium chloride solution, dried and evaporated. The residue is treated with 200 ml of ethanol. After the addition of 1.1 g of p-toluenesulphonic acid the mixture is heated to 85° C. for 24 hrs. For the working-up, the reaction mixture is concentrated and the residue is taken up in 250 ml of ethyl acetate and washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution. The organic phase is dried and evaporated. There are obtained 4.0 g of 3-(4-bromo-phenyl)-benzo[d]isoxazol-6-ol, MS: m/e 289 (M+H+, 1 Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[F:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(F)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(F)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-fluorobenzoxazole (114 mg, 0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the title compound was obtained (107 mg, 58%). 1H NMR (DMSO) δ 8.40(m, 2H), 8.30(s, 1H), 8.08(m, 2H), 7.79(m, 1H), 7.70(dd, 1H), 7.48(dd, 1H), 7.28(m, 1H), 7.05(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS 457.6 m/z (M−H)−.
Reaction SMILES: COC1C=C2C(=CC=1)C(=O)CCC2.C1(NC2N=CC=CC=2C(OC)=O)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39](=O)[CH:38]([C:44]([C:46]1[C:47]([NH:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[N:48][CH:49]=[CH:50][CH:51]=1)=[O:45])[CH2:37][CH2:36]2.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:42]=[CH:41][C:40]2[C:39]3[N:52]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:47]4[C:46]([C:44](=[O:45])[C:38]=3[CH2:37][CH2:36][C:35]=2[CH:34]=1)=[CH:51][CH:50]=[CH:49][N:48]=4
Reactant: COc1ccc2c(c1)CCC(C(=O)c1cccnc1Nc1ccccc1)C2=O
Agent: COC(=O)c1cccnc1Nc1ccccc1
Agent: COc1ccc2c(c1)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCc1c-2n(-c2ccccc2)c2ncccc2c1=O
Reaction time: 8 h

Procedure:
For example, with 3,4-dihydro-6-methoxy-1-naphthalenone as the ketone and methyl 2-phenylaminonicotinate as the arylaminonicotinate, the 1,3-diketone, 3,4-dihydro-6-methoxy-2-[[2-(phenylamino)-3-pyridinyl]carbonyl]-1(2H)-napthalenone, results from the process of Example 8. To cyclize, reflux 9 g of the diketone in 400 ml of toluene containing a catalytic amount of p-toluenesulfonic acid. Collect the evolved water in a Dean-Stark trap. Remove the heat after 21/2 hours and allow the mixture to stand overnight. Distill the toluene under vacuum on a steam bath and crystallize the residue from acetonitrile, to provide the product 5,6-dihydro-3-methoxy-12-phenylnaphtho[1,2-b][1,8]naphthyridin-7(12H)-one, m.p. 234°-237.5° C., after crystallization from CH3CN.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]1=[CH:13][C:14](=[C:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[OH:15])[CH3:2].[Br:27]Br>C(Cl)Cl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]1=[C:13]([Br:27])[C:14](=[C:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])[OH:15])[CH3:2]
Reactant: CCN1C(=CC(O)=C2C(=O)c3ccccc3C2=O)C=Cc2ccccc21
Reactant: BrBr
Solvent: ClCCl
Product: CCN1C(=C(Br)C(O)=C2C(=O)c3ccccc3C2=O)C=Cc2ccccc21

Procedure:
A suspension of 2-[(1-ethyl-2(1H)-quinolylidene)-1-hydroxyethylidene]indan-1,3-dione (1.72 g, 0.005 mol) in methylene chloride (25ml) is stirred as bromine (1.76 g, 0.011 mol) in methylene chloride is added in one lot. The solid dissolves initially, and a new solid precipitates. After 5 minutes the product is collected and washed with methylene chloride. Yield 3.25 g (98%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][O:21][CH3:22].C(OCC)(=O)C>CN(C=O)C>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:19][CH2:20][O:21][CH3:22]
Reactant: COc1ccc(C=O)cc1O
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(C=O)ccc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 3-hydroxy-4-methoxybenzaldehyde (8.0 g) in DMF (60 mL) was added K2CO3 (8.0 g) and 1-chloro-2-methoxyethane (5.1 g). The resulting mixture was stirred at 80° C. overnight. After reaction finished, ethyl acetate (200 ml) was added, and washed with 2 N aqueous HCl solution, brine, dried over Na2SO4, filtered, concentrated. The residue was washed with petrol ether to give 4-methoxy-3-(2-methoxyethoxy)benzaldehyde (11 g) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ: 9.84 (s, 1H); 7.49-7.43 (m, 2H); 6.98 (d, J=8.0, 1 H); 4.25-4.22 (m, 2H); 3.95 (s, 3H); 3.83-3.81 (m, 2H); 3.46 (s, 3H).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:18](=[O:20])[CH3:19])[CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[ClH:21]>O>[Cl:21][C:6]1[CH:7]=[C:8]([C:18](=[O:20])[CH3:19])[CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(=O)c1ccc(C2CCCCC2)c(N)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(C2CCCCC2)c(Cl)c1
Reaction time: 0.25 h

Procedure:
Solution of sodium nitrite (1.2 g, 0.017 mol) in demineralized water (7 mL) is added to a solution of 1-(3-amino-4-cyclohexylphenyl)ethanone (3.4 g, 0.016 mol) in concentrated hydrochloric acid (34 mL) at 0-5° C. & is allowed to stir for 15 minutes at this temperature. It is then poured into a slurry of cuprous chloride (3.1 g, 0.03 mol) in demineralized water (10 mL) at 60-65° C. & stirred for 30 minutes. The reaction mixture is extracted in ethyl acetate (2×30 mL). Combined organic layer is dried over sodium sulfate and concentrated to get the crude, which is purified using column chromatography (230-400 mesh; toluene:n-hexane, 3:2) to yield 1-(3-chloro-4-cyclohexyl-phenyl)ethanone.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][C:11]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:36]=3[F:42])=[C:12]([C:33]#[N:34])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[C:8]2[C:7]([CH3:43])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:51](Cl)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl>[C:51]([O:41][C:38]1[CH:39]=[CH:40][C:35]([C:11]2[N:10]=[C:9]3[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:6]=[C:7]([CH3:43])[C:8]3=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[C:12]=2[C:33]#[N:34])=[C:36]([F:42])[CH:37]=1)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: Cc1nn(C(C)(C)C)c2nc(-c3ccc(O)cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)(C)C)c2nc(-c3ccc(OC(=O)c4ccccc4)cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
To a solution of 0.33 g (0.56 mmol) of tert-butyl 4-(4-(1-tert-butyl-5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate and 325 μL (0.24 g, 2.3 mmol) of triethylamine in 17 ml of anhydrous dichloromethane are added dropwise 78 μL (0.09 g, 0.67 mmol) of benzoyl chloride. The mixture is stirred at room temperature for 24 h. The mixture is diluted with dichloromethane and washed with water. The aqueous phase is then extracted with dichloromethane. The organic phases are combined, dried over sodium sulfate, and concentrated to give 0.38 g (quantitative) of tert-butyl 4-(4-(6-(4-(benzoyloxy)-2-fluorophenyl)-1-tert-butyl-5-cyano-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate which is used in the following step without purification.
Reaction SMILES: C[C:2]([Si:5](Cl)([CH3:7])[CH3:6])(C)C.C1CCN2C(=NCCC2)CC1.[OH:20][CH:21]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH3:2][Si:5]([CH3:7])([CH3:6])[O:20][CH:21]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCC(O)c1nccs1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCC(O[Si](C)(C)C)c1nccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
TBDMSCl (1.37 g, 9.07 mmol) and DBU (1.4 mL, 9.07 mmol) were added to a solution of 2-(1-hydroxyhexyl)thiazole (0.7 g, 3.8 mmol) in dry THF (8 mL). The mixture was stirred at rt for 3 h, then quenched with water and the layers separated. The aqueous portion was extracted with EtOAc, the combined extracts dried (MgSO4) and concentrated. The material was purified by flash chromatography to give 1.03 g (91%) of 2-(1-trimethylsiloxyhexyl)thiazole as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].C(N(CC)CC)C.[Br:21][CH2:22][C:23](Br)=[O:24].Cl>C(Cl)Cl>[Br:21][CH2:22][C:23]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12])=[O:24]
Reactant: O=C(Br)CBr
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reaction time: 3 h
Yield: 94 %

Procedure:
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (500 mg, 2.55 mmol) and triethylamine (0.35 mL, 2.55 mmol) were stirred in DCM (10 mL). Bromoacetylbromide was added dropwise under a nitrogen atmosphere. Stirring was continued for 3 h. 2 M HCl (20 mL) was added and the reaction mixture extracted into DCM (3×50 mL). The combined DCM layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to give the desired product as a cream solid (760 mg, 2.40 mmol, 94%).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:28][CH2:27][CH2:26][C@H:11]2[C:12]([NH:14][C@H:15]([C:23]([OH:25])=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:31][O:32][NH2:33]>>[CH3:31][O:32][NH:33][C:23](=[O:25])[C@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:14][C:12](=[O:13])[C@@H:11]1[CH2:26][CH2:27][CH2:28][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:29])=[CH:6][CH:5]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: CON
Agent: Cl
Product: CONC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-prolyl-L-phenylalanine was coupled to O-methylhydroxylamine hydrochloride using the mixed anhydride procedure (as described in Greenstein, J. P. and Milton Wenitz, “Chemistry of the Amino Acids,” volume 2, pp. 978-979, Robert E. Krieger Publishing Co., Malabar, Fla. (1961)) to give the title compound as an oil.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:18])[NH:9]2)[CH:2]=[CH2:3].Cl.[C:20](=[O:23])(O)[O-].[Na+]>O1C=CCCC1>[CH2:1]([C:4]1[C:13]([O:14][CH:3]2[CH2:2][CH2:1][CH2:4][CH2:20][O:23]2)=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:18])[NH:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2
Reactant: O=C([O-])O
Agent: C1=COCCC1
Agent: Cl
Agent: [Na+]
Product: C=CCc1cc2c(c(CC=C)c1OC1CCCCO1)CCC(=O)N2
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
5,7-Diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone (24.3 g) obtained in Example 26 was dissolved in 100 ml of 3,4-dihydro-2H-pyran, then 1 ml of concentrated hydrochloric acid was added thereto and stirred at 60° C. for 8 hours. The reaction mixture was cooled, and neutralized with 10% sodium bicarbonate solution, then extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium bicarbonate, and concentrated under reduced pressure. Recrystallized from ethyl acetate-n-hexane, there was obtained 14 g (58%) of 5,7-diallyl-3,4-dihydro-6-(2-tetrahydropyranyloxy)-2(1H)-quinolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]3[CH2:24][O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[F:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(CC)CC>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]([OH:23])[CH2:24][N:30]3[CH2:31][CH2:32][CH:27]([F:26])[CH2:28][CH2:29]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC2CO2)CC1
Reactant: FC1CCNCC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC(O)CN2CCC(F)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
A solution of 0.080 g (0.22 mmol) of (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one (example 166A) in 0.5 ml of MeOH was treated with 0.038 (0.26 mmol) of 4-fluoropiperidine hydrochloride and 0.15 ml (1.08 mmol) of Et3N in 0.5 ml of MeOH. The reaction was stirred for 24 h at RT, partitioned between aqueous saturated NaHCO3 and extracted with Et2O (3×). The organic phase was dried over Na2SO4 and evaporated to give after flash silica gel column (CH2Cl2/MeOH 98:2) 0.0099 g (10%) of the title compound as white foam. MS: 471.9 (MH+, 2Cl).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.Cl.[CH3:21][C:22]1[C:26]([CH2:27][CH2:28][NH2:29])=[C:25]([CH3:30])[NH:24][N:23]=1>>[CH3:21][C:22]1[C:26]([CH2:27][CH2:28][NH:29][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:25]([CH3:30])[NH:24][N:23]=1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1n[nH]c(C)c1CCN
Agent: Cl
Product: Cc1n[nH]c(C)c1CCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)C)C1=O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and [2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]amine dihydrochloride in a similar manner as described for Example 24 with TEA as base. 1H NMR (500 MHz, CDCl3): δ 7.53-7.48 (m, 2H), 7.47-7.43 (m, 3H), 5.34 (t, 1H), 4.41 (sept, 1H), 3.01 (q, 2H), 2.41 (t, 2H), 2.05 (s, 6H), 1.58 (d, 6H); 13C NMR (125 MHz CDCl3): δ 158.8, 135.3, 131.5, 129.9, 129.0, 125.3, 111.2, 107.2, 47.8, 43.9, 23.7, 20.4, 10.9; Mass Spectrum: M+H+ 389
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]#[N:5].[N:21]([Sn](CCCC)(CCCC)CCCC)=[N+:22]=[N-:23].[ClH:37]>C(OCC)C>[ClH:37].[CH3:1][N:2]([CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4]1[NH:23][N:22]=[N:21][N:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CN(CC#N)CCC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CN(CCC(c1ccccc1)c1ccccc1)Cc1nnn[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A mixture of 0.132 g (0.5 mmol) N-methyl-N-cyanomethyl-3,3-diphenylpropylamine (from step 2) and 0.183 g (0.55 mmol) azidotributyltin (Aldrich) was stirred at 80° C. under argon for 16 hours. The reaction mixture was suspended with 1 M solution of hydrogen chloride in diethyl ether (Aldrich) and the precipitated yellow wax was purified by preparative TLC with 10% methanol in ethyl acetate to give 0.06 g (yield 35%) N-methyl-N-[(1H-tetrazol-5-yl)methyl]-3,3-diphenylpropylamine hydrochloride (Compound A146)as a white powder. 1H NMR (DMSO-d6, 300 MHz) 7.30-7.16(m, 10H),4.11 (s, 2H), 3.97 (t, I H), 2.60 (br. s, 2 H), 2.45 (s, 3H), 2.36 (br. s, 2H).
Reaction SMILES: C(O)C.[OH-].[K+].[NH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([OH:25])=[C:17]([C:26](OC2C=CC=CC=2)=[O:27])[CH:16]=1)([O-:14])=[O:13]>O>[C:9]([CH2:8][CH2:7][NH:6][C:26]([C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[OH:25])=[O:27])([OH:11])=[O:10]
Reactant: O=C(Oc1ccccc1)c1cc([N+](=O)[O-])c2ccccc2c1O
Reactant: NCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCNC(=O)c1cc([N+](=O)[O-])c2ccccc2c1O
Yield: 70 %

Procedure:
1,500 ml of ethanol was added to a solution of 56.8 g of potassium hydroxide dissolved in 100 cc of water. 47 g of β-alanine was dissolved into this mixture, and then 132 g of 4-nitro-2-phenoxycarbonyl-1-naphthol was suspended, followed by reflux for 4 hours. After the reaction was completed, the solution was cooled, followed, by filtration of crystal. The obtained crystal was dissolved in 4,000 ml of water. After the insolubles were filtered off, the aqueous solution was neutralized with hydrochloric acid to give yellow crystals. Recrystallization from 5,000 ml of ethanol gave the desired product at a yield of 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH:38]1([CH2:43][CH2:44][C:45](Cl)=[O:46])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:45](=[O:46])[CH2:44][CH2:43][CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)(Cc1c(C(=O)CCC2CCCC2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using 3-cyclopentylpropanoyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[Cl:22].BrC1C=CC(C(NC2C=CC=C(C(C)(C)C)C=2)=O)=CC=1F>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[CH:15][C:14]=1[Cl:22]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(Cl)c2)c1

Procedure:
4-Bromo-N-(3-tert-butyl-phenyl)-3-chloro-benzamide was synthesized from 3-tert-butyl-phenylamine and 4-bromo-3-chloro-benzoic acid in a manner similar to the one described in the synthesis of 4-bromo-N-(3-tert-butyl-phenyl)-3-fluoro-benzamide above. LCMS calcd for C17H17BrClNO (m/e) 367, obsd 368 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:14][CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:7]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: N[C@H](CO)Cc1ccccc1
Product: Cc1cc(C(=O)NC(CO)Cc2ccccc2)ccc1[N+](=O)[O-]
Yield: 82 %

Procedure:
5 g (27.6 mmol) of 3-methyl-4-nitrobenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.1 g (82%) of the product were obtained.
Reaction SMILES: [Cu][C:2]#[N:3].[CH3:4][O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br>CN(C)C=O.O.[Fe](Cl)(Cl)Cl>[CH3:4][O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:2]#[N:3]
Reactant: N#C[Cu]
Reactant: COC(=O)Cc1ccccc1Br
Agent: Cl[Fe](Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1C#N
Temperature: 25 °C

Procedure:
To a stirring solution of copper (I) cyanide (1.2 eq) in dimethylformamide (2.1 M) at room temperature was added slowly a solution of 2a in dimethylformamide (8.7 M). The reaction was heated to reflux overnight then cooled to room temperature. A solution of iron (III) chloride (1.2 eq) in H2O (0.3 M) was added slowly to the vigorously stirred solution. The resulting solution was extracted with ethyl acetate (3×). The organic phases were combined then washed with brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (15% ethyl acetate/hexanes) to afford the product as a clear oil. (70%) 1H NMR (300 MHz, CDCl3) δ 6.09 (m, 1H), 5.98 (m, 1H), 5.79 (m, 2H), 2.29 (s, 2H), 2.11 (s, 3H).