Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[CH2:16](Br)[C:17]#[CH:18]>C1COCC1>[CH2:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:15][CH2:18][C:17]#[CH:16]
Reactant: C#CCBr
Reactant: OCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 740 mg, 18.5 mmol) in THF (50 mL) at 0° C. was added tetraethylene glycol (4.0 g, 20.6 mmol). After stirring for 15 minutes, propargyl bromide (80% in toluene, 2.00 mL, 18.0 mmol) was added slowly. The reaction was allowed to warm to RT and stirred 16 hours. Solids were removed by filtration and rinsed with MTBE (3×20 mL). The combined filtrates were concentrated and purified by flash chromatography on silica gel (EtOAc) to give 3,6,9,12-tetraoxapentadec-14-yn-1-ol (2.14 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[C:8]([NH2:38])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCCCC1

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (7.58 g, 22.0 mmol). 3-Chloroperoxybenzoic acid (9.1 g of 50% pure material, 26.4 mmol) was added in five portions during the oxidation step, and the amination with ammonium hydroxide (55 mL) and p-toluenesulfonyl chloride (6.3 g, 33 mmol) proceeded overnight. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration and washed with a small amount of acetonitrile. A portion of the brown solid was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 85:15) to provide 7-bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a brown solid, mp 215-216° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(N(CC1C=CC(OC)=C(Cl)C=1)C1NC2C=C([O:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])C=CC=2N=1)=O)(C)(C)C.C(=O)(O)[O-].[Na+].O>ClCCl>[F:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([OH:28])(=[O:25])=[O:27])=[CH:34][CH:33]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3[nH]2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(F)cc1

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 4-fluoro-benzenesulfonic acid 2-[tert-butoxycarbonyl-(3-chloro-4-methoxy-benzyl)-amino]-3H-benzoimidazol-5-yl ester (67 mg) in dichloromethane (4 ml). After cooling, the mixture was neutralised by addition of saturated sodium bicarbonate solution. Water (10 ml) was added and the solution extracted three times with dichloromethane (10 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-fluoro-benzenesulfonic acid 2-(3-(chloro-4-methoxy-benzylamino)-3H-benzoimidazol-5-yl ester (53 mg) as an off-white solid. Mass spectrum: 462 [M+H]+; retention time=7.69 minutes.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(=O)NCCCCC1.C(=O)([O-])[O-].[K+].[K+].[NH2:24][C:25]1[C:38]2[C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([Cl:40])=[CH:34][CH:35]=3)[C:30](=[O:41])[C:29]=2[C:28]([OH:42])=[CH:27][C:26]=1[O:43]C1C=CC=CC=1>CO>[NH2:24][C:25]1[C:38]2[C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([Cl:40])=[CH:34][CH:35]=3)[C:30](=[O:41])[C:29]=2[C:28]([OH:42])=[CH:27][C:26]=1[O:43][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1c(Oc2ccccc2)cc(O)c2c1C(=O)c1ccc(Cl)cc1C2=O
Reactant: OCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCCCCN1
Agent: [K+]
Solvent: CO
Product: Nc1c(OCCc2ccccc2)cc(O)c2c1C(=O)c1ccc(Cl)cc1C2=O
Temperature: 140 °C

Procedure:
A mixture of 48.8 g of β-phenylethanol, 45.2 g of ε-caprolactam, 5.2 g of dry potassium carbonate and 18.3 g of 1-amino-2-phenoxy-4-hydroxy-6-chloroanthraquinone (preparation see Example 467c) is heated at 140° C. until, after about 4 hours, the reaction is complete. The mixture at 70° C. is diluted with 100 ccm of methanol, allowed to cool down, filtered with suction, washed with methanol and hot water and dried at 60° C. 14 g, corresponding to 71% of theory, of 1-amino-2-(2-phenylethoxy)-4-hydroxy-6-chloroanthraquinone are obtained, the colour shade of which on silica gel is a pink tinged with blue between Indicator Numbers 50 and 51 (Colour Index Hue Indication Chart).
Reaction SMILES: [C:1]([N:9]1[CH:22]([C:23](O)=[O:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:45][O:46][C:47](=[O:63])[C@@H:48]([NH2:62])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:63])[C@@H:48]([NH:62][C:23]([CH:22]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=2)=[CH:54][CH:55]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccncc2)cc1
Reactant: O=C(O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester (61 m g, LC/MS: m/z 842) was prepared from Intermediate D (100 mg) and (S)-2-amino-3-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester bis hydrochloride according to general procedure A.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21]CC2C=CC(OC)=CC=2)[CH:20]=1)[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14]C(=O)C)=[N:11][CH:12]=1)=[O:6].[CH3:31][C:32]1[N:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1.[CH:40]1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[OH:21][C:19]1[CH:18]=[C:4]([C:5]([C:7]2[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[O:6])[CH:3]=[C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:36]3[C:35]=2[CH:38]=[CH:40][NH:37]3)[CH:20]=1
Reactant: COc1ccc(COc2cc(Br)cc(C(=O)c3ccc(COC(C)=O)nc3)c2)cc1
Reactant: Cc1ccc(C=O)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1ccc(CO)nc1)c1cc(O)cc(-c2cccc3[nH]ccc23)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Acetic acid 5-[3-bromo-5-(4-methoxy-benzyloxy)-benzoyl]-pyridin-2-ylmethyl ester. To a stirred solution of 3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-(6-methyl-pyridin-3-yl)-methanone (388 mg, 0.94 mmol) in dry methylene chloride (20 mL) at 0° C. was added dropwise a solution of MCPBA (0.371 mg, 1.50 mmol) in methylene chloride (10 mL). The resulting solution was stirred overnight. TLC indicated that the completion of the reaction. The organic phase was washed with sat. NaHCO3, dried, and concentrated. The crude product was then dissolved in Ac2O (2 mL) and the resulting solution was stirred at 150° C. for 30 min. TLC indicated that the completion of the reaction. The reaction mixture was then poured into an ice cold sat. NaHCO3 solution and stirred for 20 min. The aqueous phase was the extracted with EtOAc for three times. After removal of the solvents, the crude product was purified by flash chromatography (4:1 Hexane/EtOAc) to afford the titled product (0.140 mg, 31% over two steps).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CO.C(N(CC)CC)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 2-bromomethyl-benzoic acid methyl ester (1.50 g, 6.55 mmol, 1.0 equiv; [CAS RN 2417-73-4]) in methanol (12.5 mL) and triethylamine (1.10 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.38 g, 6.88 mmol, 1.05 equiv; commercially available) and the reaction stirred at rt overnight. The reaction mixture was poured on crashed ice, extracted with ethyl acetate, the combined organic phases washed with water and a sat. solution of NaCl, dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with hexane/ethyl acetate (1:1) followed by crystallization from hexane/ethyl acetate to obtain 1.12 g (54%) of the title compound as white crystals. MS (ISP): 261.0 [M-tert-Bu+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+]>CO>[CH2:11]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CNCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 2-amino-1-phenyl-ethanol (12.0 g, 87.48 mmol) in methanol (60 mL) was added benzaldehyde (9.3 g, 8.9 mL, 87.48 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then cooled to 0° C. and sodium borohydride (3.3 g, 87.48 mmol) was added. The reaction mixture was gradually allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo, diluted with water, and filtered. The residue was rinsed with cold isopropanol (3×), then dried in vacuo to give 2-(benzylamino)-1-phenylethanol as white crystals (14.0 g, 70%). ESI-MS m/z calc. 227.1. found 228.2 (M+1)+; Retention time: 0.8 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 7.37-7.27 (m, 8H), 7.27-7.19 (m, 2H), 4.78 (dd, J=8.5, 4.5 Hz, 1H), 3.77 (q, J=13.0 Hz, 2H), 2.82-2.68 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1nc2ccccc2o1

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloro-1,3-benzooxazole as starting materials and by operations similar to those of Example 303-3 and 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: Cl[S:2]([OH:4])=[O:3].[CH2:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:9])[CH3:6].[OH2:17]>CCOC(C)=O>[CH2:5]([NH:7][C:8](=[S:9])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:2]([OH:4])(=[O:17])=[O:3])=[CH:13][CH:12]=1)[CH3:6]
Reactant: CCNC(=S)Nc1ccccc1
Reactant: O
Reactant: O=S(O)Cl
Solvent: CCOC(C)=O
Product: CCNC(=S)Nc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of chlorosulfanic acid (3 mL) is cooled to 0° C. and 1-ethyl-3-phenylthiourea (360 mg, 2.0 mmol) is then added over a period of 5 minutes and the resulting mixture is stirred at 0° C. for 2 hour followed by addition of water (10 mL) which results in the formation of a precipitate. EtOAc is added to dissolve the precipitate and the mixture is extracted (5×15 mL). The combined organic layers are concentrated and dissolved in a mixture of dioxane and water (12 mL, 1:1). The resulted mixture is heated to 80° C. for 2 hr. and concentrated to provide 4-(3-ethylthioureido)benzenesulfonic acid (1-4) as an off white solid. HPLC-MS calculated for C9H12N2O3S2 (M+H+) 261.0. found 261.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](C)=[CH:4][N:3]=1.[Cl:9]Cl.[C:11]([Cl:15])(Cl)([Cl:13])[Cl:12]>>[Cl:9][C:2]1[CH:7]=[CH:6][C:5]([C:11]([Cl:15])([Cl:13])[Cl:12])=[CH:4][N:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(Br)nc1
Reactant: ClCl
Product: Clc1ccc(C(Cl)(Cl)Cl)cn1

Procedure:
172 g of thus obtained 2-bromo-5-methylpyridine was dissolved in 1.3 l of carbon tetrachloride, and the system was then heated. At the time refluxing begain (at 77° C.), chlorine gas was bubbled into the system with ultraviolet light irradiation. After a lapse of 5 hours, the completion of the reaction was confirmed by gas chromatography, and the system was cooled and air was bubbled into the system to expel the unreacted chlorine. The system was washed with water several times and dried over anhydrous sodium sulfate. Then, the carbon tetrachloride was distilled off, and the system was allowed to cool. The solid crystals thus-obtained were washed with n-hexane to obtain 152 g of 2-chloro-5-trichloromethylpyridine with a melting point of 51° to 54° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:25]=[C:26](Br)[CH:27]=[CH:28][C:29]=1[Cl:30].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:13]=3)[CH2:22][CH2:21]2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: c1cc(N2CCNCC2)ccc1OCCCN1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccc(N2CCN(c3ccc(OCCCN4CCCCC4)cc3)CC2)cc1Cl
Temperature: 25 °C

Procedure:
Tris(dibenzylidineacetone) di palladium (0) (5 mol %; 23 mg) was added to a mixture of 1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D11) (150 mg; 0.49 mmol), 3,4-dichloro bromo benzene (160 mg; 1.2 eq), sodium tert-butoxide (71 mg; 1.1 eq) and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (7.5 mol %; 24 mg) in dry toluene (3 ml). The resulting mixture was heated at reflux under argon for 18 hours. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (10 ml). The resulting solids were removed by filtration and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica eluting with 3% methanol in dichloromethane to afford the title compound as a buff solid (45 mg)
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:34]Br>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:34][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(Cl)c2)C(=O)C1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) suspension of tert-butyl 3-oxopiperazine-1-carboxylate (2.0 g, 9.99 mmol) in DMF (20 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (10.69 mL, 10.69 mmol) was added and stirred at the temperature for 30 min. The resultant clear red brown solution was treated with 3-chloro-4-fluorobenzyl bromide (2.34 mL, 10.49 mmol), and stirred at 0° C. for 2 hours. The product mixture was concentrated under vacuum, and the residue partitioned between water and ethyl acetate. The organic extract was washed successively with 5% aq KHSO4, sat. NaHCO3, and brine. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0-100% gradient of ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the benzylated product.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH:4]=[CH:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])[CH3:2].N1CC[CH:26]([CH2:29][OH:30])CC1.C(OC1C=CC(C2C=CC=CC=2)=CC=1)(=O)C#C>>[OH:30][CH2:29][CH:26]1[CH2:2][CH2:1][N:3](/[CH:4]=[CH:5]/[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[O:7])[CH2:21][CH2:22]1
Reactant: CCN(C=CC(=O)Oc1ccc(-c2ccccc2)cc1)CC
Reactant: OCC1CCNCC1
Agent: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Product: O=C(/C=C/N1CCC(CO)CC1)Oc1ccc(-c2ccccc2)cc1
Yield: 84 %

Procedure:
The compound 39 was prepared according to the method described for compound 2 employing piperidin-4-ylmethanol (900 mg, 4.05 mmol) and compound 1 (466 mg, 4.05 mmol) to give white solid compound 39 (1.15 g, 84%). 1H NMR (300 MHz, CD2Cl2) δ 1.29 (m, 1H), 1.80 (m, 2H), 3.08 (br s, 1H), 3.51 (s, 2H), 3.62 (d, J=9.9 Hz, 2H), 4.82 (d, J=13.0 Hz, 1H), 7.15 (d, J=8.2 Hz, 2H), 7.35 (m, 1H), 7.45 (t, J=7.0 Hz, 2H), 7.60 (br s, 5H). HRMS ESI (m/z): Calculated for C21H23NO3 ([M+Na]+): 338.1678. found: 338.1751.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[C:11]([F:39])[CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=1>ClCCCl>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=4[F:39])[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:66][CH:67]=1)#[N:70]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Yield: 51.2 %

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 71 (0.4 g, 0.67 mmol), was reacted with diisopropylethylamine (0.69 g, 5.4 mmol), diphenylphosphinic chloride (0.63 g, 2.7 mmol) in 1,2-dichloroethane at room temperature, then reacted with 4-aminobenzonitrile (Aldrich) (0.24 g, 2.1 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield 0.2 g, 51%).
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:15][CH:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:13]1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C([O-])(O)=O.[Na+]>C1COCC1>[O:1]=[C:2]([N:12]1[CH2:13][CH:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:15]1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:24](=[O:26])[CH3:25])=[N:9][CH:10]=1
Reactant: Nc1ccc(/C=C/C(=O)N2CC(OCc3ccncc3)C2)cn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N2CC(OCc3ccncc3)C2)cn1
Temperature: 60 °C
Reaction time: 40 h
Yield: 13.1 %

Procedure:
To a solution of 5-{(1E)-3-oxo-3-[3-(pyridin-4-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}pyridin-2-amine (16 mg, 0.05 mmol) and acetic anhydride (6 μL, 0.06 mmol) in THF (2.4 mL) was added NaHCO3 (5.5 mg, 0.065 mmol). The reaction mixture was warmed at 60° C. and stirred for 40 h. LCMS showed that some starting material was remaining. Another portion of acetic anhydride (6 μL) and NaHCO3 (5.5 mg) were added and the mixture was stirred at 60° C. for 24 h. These additions were repeated twice over 48 h. The mixture was then concentrated, partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give an oil. The crude was purified on preparative TLC (eluent: 90/10 DCM/MeOH) to give the title compound (2.3 mg, 12%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[CH:15]=[O:16])[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:14])[CH3:13]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)c1cc(Br)c2ncccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-c2cccc(C=O)c2)c2ncccc2c1
Temperature: 70 °C

Procedure:
A mixture of 8-bromo-6-isopropyl-quinoline (9.79 g, 39 mmol, described in International Patent Publication WO 94/22852), 3-(formyl)-phenyl-boronic acid (11.7 g, 78 mmol), sodium carbonate (78 mL, 2M, H2O), Pd(Ph3P)4 (2.7 g, 2.3 mmol) in DME (200 mL) was heated at 70° C. for 18 h. The reaction mixture was cooled to 21° C. then diluted with water and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 80:20) provided the title compound.