Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[O:15][CH2:16][CH3:17])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:16]([O:15]/[C:9](=[CH:8]\[C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][CH3:24])[CH:27]=2)=[CH:3][CH:4]=1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)/C(=C/c1ccc(Br)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)OCC
Yield: 89.4 %

Procedure:
To a solution of 10.8 g (36.1 mmol) of ethyl (Z)-3-(4-bromophenyl)-2-ethoxyacrylate, 108 mL (217 mmol) in 120 mL of toluene, aqueous 2 M sodium carbonate solution and 1.5 g (1.8 mmol) of dichloro[11′-bis(diphenylphosphino)ferrocene]palladium are added. The reaction medium is stirred and 9.25 g (39.7 mmol) of methyl[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]amine are then added. After stirring at 80° C. for 2 hours, the reaction medium is hydrolyzed and diluted with ethyl acetate. After separation of the phases by settling, the ethyl acetate phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 90/10 and then 80/20 heptane/ethyl acetate mixture. 10.5 g (94%) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a yellow oil. After taking up the product in pentane, 9.5 g (85%) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a pale yellow solid with a melting point of 52° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:5]=1[OH:19])[CH:2]=[CH2:3]>C(Cl)Cl.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[C:5]([OH:19])=[C:4]([CH:1]=[CH:2][CH3:3])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: C=CCc1ccc(F)c(-c2ccc(Cl)cc2Cl)c1O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Product: CC=Cc1ccc(F)c(-c2ccc(Cl)cc2Cl)c1O
Yield: 72.8 %

Procedure:
Treatment of 3-allyl-2′,4′-dichloro-6-fluorobiphenyl-2-ol (1.1 g, 3.70 mmol) with dichlorobis(acetonitrile)palladium (II) (0.15 g, 0.58 mmol) in methylene chloride (50 mL) according to the procedure described for Example 69, Step 5 provided 0.8 g (73%) of 2′,4′-dichloro-6-fluoro-3-(prop-1-enyl)biphenyl-2-ol as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[C:9](I)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.CN([CH:28]=[O:29])C>C1COCC1>[CH2:1]([C:8]1[C:9]([CH:28]=[O:29])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc(Cc3ccccc3)c(I)nc2c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=Cc1nc2cc(Cl)ccc2cc1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 110.5 %

Procedure:
To a solution of 3-benzyl-7-chloro-2 iodo-quinoline (1.5 g, 3.95 mmol) in 15 mL of anhydrous THF at −78° C., was added isopropylmagnesium chloride (5.93 ml, 11.85 mmol). After stirring at −78° C. for 30 minutes, DMF (1.53 ml, 19.8 mmol) was added. The reaction mixture was allowed to slowly warm to ambient temperature over two hours. It was then quenched with saturated NH4Cl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed in vacuo yielding 1.23 g of 3-benzyl-7-chloroquinoline-2-carbaldehyde 24 as brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:11])[F:10].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([F:11])[F:10])=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=1
Reactant: FC(F)c1ccc(Cl)cc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cc(Cl)ccc1C(F)F
Temperature: 90 °C
Reaction time: 5 h
Yield: 22.1 %

Procedure:
To a solution of Intermediate 14A (0.88 g, 3.64 mmol) in DMF (10 mL) was added tert-butyl acrylate (1.401 g, 10.93 mmol), TEA (1.270 mL, 9.11 mmol) and Pd(OAc)2 (0.082 g, 0.364 mmol). The reaction was warmed to 90° C. After 5 h, the reaction was cooled to rt and then filtered to remove the solid. The filtrate was diluted with EtOAc, washed with 1M HCl, saturated NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and concentrated. Purification by normal phase chromatography gave Intermediate 14B (232 mg, 22% yield) as a tan oil. MS (ESI) m/z: 233.1 (M-tBu)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:16]=2)[NH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][NH:55][CH3:56]>CN(C=O)C.CS(C)=O>[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][N:55]([CH3:56])[C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)[CH:19]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Reactant: CNCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N(C)CCN(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
To a solution of 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (21 mg, 0.06 mmol) in anhydrous DMF (1 mL) was added HATU (23 mg, 0.06 mmol) and N,N,N′-trimethylethylenediamine (7.9 μL, 0.06 mmol). The reaction solution was stirred 16 hours at ambient temperature then diluted with DMSO (1 mL), filtered through a 0.45 um syringe filter, and purified by reverse phase chromatography in a mobile phase of H2O and acetonitrile (with 0.1% formic acid as the modifier). Clean fractions were combined and lyophilized, affording the title compound as a white powder (14.0 mg, 54% yield). 1H NMR (500 MHz, CD3OD) δ8.51 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.83 (br s, 1H), 7.81 (bs, 1H), 7.69 (s, 1H), 7.60 (m, 2H), 7.49 (m, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.13 (d, 8.5 Hz, 1H), 7.07 (t, J=6.5 Hz, 1H), 3.90 (t J=6.0 Hz, 2H), 3.86 (s, 3H), 3.33 (s, 3H), 3.17 (s, 3H), 2.91 (s, 3H), 2.80 (br s, 2H). MS: m/e 429.1 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][O:6][C:7]=1[C:8]([OH:10])=O.O/[N:19]=[C:20](/[C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)=[CH:24][CH:23]=1)\[NH2:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:17][CH:2]([F:1])[C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][O:6][C:7]=1[C:8]1[O:10][N:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:27]3[CH2:28][CH:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]3)=[CH:38][CH:39]=2)[N:19]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)F)n3)cc2)C1
Temperature: 55 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
A mixture of 4-(difluoromethyl)-3-phenylisoxazole-5-carboxylic acid (28 mg, 0.117 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (35.7 mg, 0.117 mmol), HOBT (28.7 mg, 0.187 mmol), EDC (52.7 mg, 0.275 mmol) and diisopropylethylamine (82 μL, 0.468 mmol) in DMF was stirred at rt for 3 hr and at 55° C. for 18 hr. The reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2×30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-50% EtOAc/Hex gradient. The essentially pure fractions containing the product were concentrated to afford tert-butyl 1-(4-(5-(4-(difluoromethyl)-3-phenylisoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (23 mg, 0.045 mmol, 38.6% yield) as a white solid. HPLC retention time=1.80 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=509.14.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:9])[CH3:8].[Cl-].[CH3:11][NH2+]C.C=O>>[CH:2]([C:3](=[CH2:11])[CH2:4][CH2:5][O:6][C:7](=[O:9])[CH3:8])=[O:1]
Reactant: CC(=O)OCCCC=O
Reactant: C[NH2+]C
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCOC(C)=O

Procedure:
13.0 g (100 mmol) of acetic acid (4-oxo)butyl ester, 92.0 g (112.6 mmol) of dimethylammonium chloride and 10.8 ml (117 mmol) of 37% formaldehyde solution are heated at 100° for one hour with stirring. The mixture is allowed to cool and is extracted 3 times with 30 ml of diethyl ether each time. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. Acetic acid (3-formyl)but-3-enyl ester is obtained in the form of a colourless oil which can be reacted further without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16][Cl:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C(C2C=CC=CC=2)(CCBr)C#N)C=CC=CC=1>>[ClH:17].[C:8]1([CH:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:15][CH2:16][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: ClCCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: N#CC(CCBr)(c1ccccc1)c1ccccc1
Product: c1ccc(C(CCN2CCCCC2)c2ccccc2)cc1

Procedure:
Repetition of the procedure detailed in Example 12 using piperidine hydrochloride and 1,1-diphenyl-3-chloropropane in place of the 2-azabicyclo[2.2.2]octane hydrochloride and 2,2-diphenyl-4-bromobutyronitrile affords 1-(3,3-diphenylpropyl)piperidine hydrocloride, melting at about 216° - 217° C., and represented by the following structural formula. ##STR13##
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH2:37])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:38](Cl)(=[O:46])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C.Cl>ClCCl.C(OCC)(=O)C>[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH:37][C:38]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:46])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@@H](N)CCCC(=O)OCc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-aminopentanoyl]oxyhexadecanamide hydrochloride (2.17 g) in dichloromethane (8 ml) were added phenyl chlorocarbonate (0.65 ml) and triethylamine (1.68 ml). This mixture was stirred at room temperature overnight, and then poured into a mixture of ethyl acetate (80 ml) and 1N hydrochloric acid (80 ml). The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine successively. This solution was dried and evaporated to dryness. The residue was chromatographed on silica gel (200 cc) eluting with a mixture of dichloromethane and methanol (20:1) to give (3S)-3-[(2S)-5-benzyloxycarbonyl-2-(phenoxycarbonylamino)-pentanoyl]oxyhexadecanamide (1.73 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:20](=[O:21])[C:19]2[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:18]=2[O:17][CH3:16])=[CH:11][CH:10]=1)[CH3:2]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: c1ccncc1
Product: CCN(CC)CCOc1ccc(NC(=O)c2c(OC)cccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
N,N-diethyl-2-(4-aminophenoxy)ethylamine (4.00 g) was added into 2,6-dimethoxybenzoic acid chloride (4.20 g) in pyridine (40 ml) in an ice bath. After stirred for one hour at room temperature, the reaction mixture was concentrated under vacuum and residue was dissolved into chloroform (50 ml). The solution was washed with 1N sodium hydroxide aqueous solution followed by water and then saturated sodium chloride (50 ml, each). Solvent was distilled out and residue was purified by silica-gel column chromatography (chloroform:methanol=25:1) to obtain 4′-[2-(diethylamino)ethoxy]-2,6-dimethoxybenzanilide (5.01 g) as color-less crystal.
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][O:6][C:7](=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:25])[CH2:16][CH2:17][C:18](=O)[CH:19]([O:22][CH3:23])[O:20][CH3:21]>CO>[CH3:5][O:6][C:7](=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:15](=[O:25])[CH2:16][CH2:17][C:18]=1[CH:19]([O:22][CH3:23])[O:20][CH3:21]
Reactant: COC(=O)CCCCCCCC(=O)CCC(=O)C(OC)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCCCCC1=C(C(OC)OC)CCC1=O

Procedure:
To a solution of sodium methoxide in methanol, prepared from 0.52 g of sodium and 90 ml of methanol, were added 5.68 g of a mixture containing about 5.28 g of 13,13-dimethoxy-9,12-dioxotridecanoic acid methyl ester.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9]([S:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[O:10])[N:6]([C:28]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])=[C:29]([CH3:31])[CH3:30])[C:5]1=[O:45])[CH3:3].[N+:46]([C:49]1[CH:59]=[CH:58][C:52]([CH2:53][O:54][C:55](Cl)=[O:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:15]([NH:14][CH2:13][CH2:12][S:11][C:9]([CH2:8][C@H:7]2[N:6]([C:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])=[C:29]([CH3:30])[CH3:31])[C:5](=[O:45])[C@@H:4]2[C@H:2]([O:1][C:55]([O:54][CH2:53][C:52]2[CH:51]=[CH:50][C:49]([N+:46]([O-:48])=[O:47])=[CH:59][CH:58]=2)=[O:56])[CH3:3])=[O:10])=[O:16])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)O)[C@H]1CC(=O)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1CC(=O)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 51.3 %

Procedure:
125 mg (0.194 mmole) of (3S, 4R)-3-[(R)-1-hydroxyethyl]-4-([2-(p-nitrobenzyloxycarbonylamino)ethylthio]-carbonylmethyl)-1-[2-methyl-1-(p-nitrobenzyloxycarbonyl)-prop-1-enyl]-2-azetidinone were dissolved in 4 ml of methylene chloride. To the solution were added, in turn, 71 mg (0.58 mmole) of 4-(N,N-dimethylamino)-pyridine and 126 mg (0.58 mmole) of p-nitrobenzyloxy-carbonyl chloride, with stirring at 0° C. The reaction mixture was then stirred at room temperature for 1 hour, after which it was diluted with methylene chloride and washed with a saturated aqueous solution of sodium chloride. The solvent was distilled off and the residue was subjected to chromatography using a Lobar column B eluted with a 2:3 by volume mixture of hexane and ethyl acetate, to afford 82 mg (yield 51%) of the title product as an oily substance. Infra-red and nuclear magnetic resonance spectra of the product agreed with those of the product of Preparation 7.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[CH:10]=2)[N:5]([CH2:20][CH2:21][CH2:22][C:23](=[O:32])[NH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:4]=1[CH2:33][O:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)=[O:2].C([OH:49])(C)(C)C.CC(=CC)C>O>[CH:15]1([C:13]([NH:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]([CH2:20][CH2:21][CH2:22][C:23](=[O:32])[NH:24][S:25]([C:28]([F:29])([F:30])[F:31])(=[O:27])=[O:26])[C:4]([CH2:33][O:34][C:35]2[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=2)=[C:3]3[C:1]([OH:49])=[O:2])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)O
Reactant: O=Cc1c(COc2ccc3ccccc3c2)n(CCCC(=O)NS(=O)(=O)C(F)(F)F)c2ccc(NC(=O)C3CCCC3)cc12
Agent: CC=C(C)C
Solvent: O
Product: O=C(CCCn1c(COc2ccc3ccccc3c2)c(C(=O)O)c2cc(NC(=O)C3CCCC3)ccc21)NS(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
The product of Step 1, Example 53B (1 eq) was weighed into a flask along with NaH2PO4 (12 eq), t-butyl alcohol (0.12 M), water (0.12 M), 2-methyl-2-butene (50 eq) and to this mixture was added NaO2Cl (11.8 eq) at 25° C. Reaction mixture was then heated at 60° C., 3 h and left overnight at 25° C. Workup with ethyl acetate/water followed by chromatographic purification and triturations with CH2Cl2/hexane (1:1) afforded the desired product in 57% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2)([O-:3])=[O:2].FC(F)(F)C(O[C:21]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=1[F:31])=O>>[F:27][C:26]1[C:21]([O:14][C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)=[O:15])=[C:22]([F:31])[C:23]([F:30])=[C:24]([F:29])[C:25]=1[F:28]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 57 %

Procedure:
Compound 105 was prepared from compound 104 with pentafluorophenyl trifluoroacetate according to the procedure for 3, and purified by chromatography (toluene-EtOAc 35:1). Yield: 57%.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][NH:9][CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1>>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:23])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6]
Reactant: CON=C(C#N)C1=CCCNC1
Reactant: COc1ccc(OC(=O)Cl)cc1
Product: CON=C(C#N)C1=CCCN(C(=O)Oc2ccc(OC)cc2)C1
Yield: 85.6 %

Procedure:
α-(Methoxyimino)-α-(1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (D8) (0.5 g, 0.003 moles) was treated with 4-methoxyphenylchloroformate (0.5 ml, 0.0033 moles) as in the method of Example 1. The crude produce was triturated with pentane to give the title compound (E4) as a white crystalline solid (0.81 g, 85%) m.p. 75°-76° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[N:17]=[C:18]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[S:19][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:20]1[S:19][C:18]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[N:17][C:16]=1[CH3:15])=[O:22]
Reactant: Cc1nc(-c2cnccn2)sc1C(=O)Cl
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cnccn2)sc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 56.5 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0486 g, 0.190 mmol), 4-methyl-2-(pyrazin-2-yl)thiazole-5-carbonyl chloride (0.047 g; 0.190 mmol), and triethylamine (0.067 mL; 0.475 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 3 to 30% of ethyl acetate in dichloromethane gave 0.0427 g (56%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-methyl-2-(pyrazin-2-yl)thiazole-5-carboxamide as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2
Reactant: O=C(O)C1CC1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)C4CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172) and cyclopropyl carboxylic acid; MS: m/e=374.4 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([N:18]=[CH:19][N:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[Br-].[CH2:24]([Zn+])[CH2:25][CH3:26].O.Cl>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][N:20]([CH3:22])[CH:19]=[N:18][S:15]([C:8]1[N:6]2[N:7]=[C:2]([CH2:24][CH2:25][CH3:26])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]([F:14])([F:13])[F:12])(=[O:17])=[O:16]
Reactant: CCC[Zn+]
Reactant: CN(C)C=NS(=O)(=O)c1c(C(F)(F)F)nc2ccc(Cl)nn12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc2nc(C(F)(F)F)c(S(=O)(=O)N=CN(C)C)n2n1
Temperature: 25 °C

Procedure:
To a suspension of N′-(6-chloro-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-dimethylformamidine (1.00 g, 2.81 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) dichloride (0.076 g, 0.14 mmol) in tetrahydrofuran (8.0 ml) was added dropwise a solution of n-propylzinc bromide in tetrahydrofuran (0.5 M, 8.43 ml, 4.22 mmol) with stirring under ice-cooling and nitrogen stream. The reaction mixture was stirred for 30 minutes under ice-cooling and 4.5 hours at room temperature, then poured into cold water and made acid with dilute hydrochloric acid. The precipitated solid was collected by filtration, washed with dilute hydrochloric acid, then water, and purified by silica gel column chromatography (ethyl acetate:chloroform=2:5) to give the title compound as white crystals. The yield was 0.62 g (60.7%).