Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.C[O:14][C:15](=O)[C:16]([CH3:22])([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)C>C1COCC1.O>[CH3:21][C:16]([CH3:22])([CH2:17][CH2:18][CH2:19][CH3:20])[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)(C)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Yield: 59.4 %

Procedure:
Dimethyl methylphosphonate (9.92 g, 0.08 mol) was dissolved in 60 ml anhydrous THF under argon atmosphere. To the mixture stirred at -78° C. was added drowise n-butyl lithium 1.62N, 49.5 ml, 0.08 mol) over a period of 30 minutes, and then a solution of 2,2-dimethylhexanoic acid methyl ester (5.0 g, 0.032 mol) in 10 ml anhydrous THF was added over a period of 30 minutes. The reaction mixture was warmed to room temperature. Acetic acid (5 ml) and water (10 ml) were added to the reaction mixture cooled with ice bath. After concentration, 20 ml water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue gave dimethyl 3,3-dimethyl-2-oxoheptylphosphonate (4.74 g, 0.019 mol, yield 59.3%, b.p.=108°-111° C./0.2 mmHg) as a colorless clear oil. The structure of this product was confirmed by the following data.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][CH2:38][OH:39])=[CH:29][N:28]=1.[C:40]1([P:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6](=[O:26])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:38][CH2:37][C:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[N:28][CH:29]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3].[C:53]1([P:46](=[O:39])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: OCCc1cncc2ccccc12
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1cncc2ccccc12
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To (S)-3-(2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (194 mg, 0.50 mmol), 2-isoquinolin-4-yl-ethanol (108 mg, 0.625 mmol), triphenyl phosphine (197 mg, 0.75 mmol) in THF(5 mL) was added diethyl azodicarboxylate (133 μL, 0.85 mmol). After 16 h the solvent was removed under reduced pressure, the residue was chromatographed on silica gel 20% THF in dichloromethane to give (S)-3-[2-(2-isoquinolin-4-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a colorless foam (394 mg, contaminated with triphenyl phosphine oxide). MS (APCI) m/z 544.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH:28]=O)([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([NH2:33])[CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH2:28][NH:33][CH2:30][CH2:31][CH3:32])([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:26])([CH3:27])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCN
Reactant: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCNCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.4 %

Procedure:
A slurry of ethyl 2-(tert-butoxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (172 mg, 0.42 mmol) and propylamine (40 μL, 0.49 mmol, 1.3 equiv) in 1,2-dichloroethane (3 mL) was treated with sodium triacetoxyborohydride (352 mg, 1.66 mmol, 4 equiv). Acetic acid (2 drops, ca 3-5 equiv) was added and the mixture stirred at room temperature for 17 hours then 60° C. for 1 hour. Once the reaction was complete, saturated aqueous sodium bicarbonate was added and the solution was extracted with dichloromethane. The organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by flash chromatography (0-60% ethyl acetate in hexane) gave ethyl 2-(tert-butoxycarbonylamino)-2-((propylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as an oil (66 mg, 34%). 1H NMR (CDCl3, 400 MHz) δ 4.16 (m, 2H), 3.5-3.3 (m, 2H), 3.2 (br m, 2H), 2.9 (m, 1H), 1.8-1.6 (m, 4H), 1.5-1.4 (m, 2H), 1.38 (s, 9H), 1.36-1.3 (m, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.18 (s, 12H), 1.05 (m, 1H), 0.75 (t, J=7.4 Hz, 3H), 0.68 (t, J=7.5 Hz, 2H). ESI+ MS: obsd m/z 457 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].[C:18](Cl)(Cl)=[O:19].[CH2:22]([N:24](CC)CC)[CH3:23].C(N)C>C1COCC1.CCOC(C)=O>[CH2:22]([NH:24][C:18](=[O:19])[NH:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH3:23]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Cl
Reactant: C=CCOC(=O)c1cc(C(F)(F)F)ccc1N
Agent: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1cc(C(F)(F)F)ccc1NC(=O)NCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.2 %

Procedure:
Preparation B1, Step 2: The allyl 2-amino-5-(trifluoromethyl)benzoate from step 1 (ca. 15.7 mmol) was dissolved in THF (60 mL) and phosgene (24.9 mL, 47 mmol) was added at 0° C. dropwise. The reaction was stirred for 15 minutes at 0° C. Triethylamine (13.1 mL, 94 mmol) was slowly added and stirring was continued for 2 hours. The reaction was concentrated in vacuo to afford a yellow solid. A portion (2.4 g, ca. 7.7 mmol) of the yellow solid was dissolved in THF (40 mL) and the solution was charged with ethylamine (20 mL of a 2.0 M solution in THF). The reaction was stirred for 14 h at RT and then diluted with EtOAc. The organic phase was washed successively with 1N HCl (2×) and brine (1×) before being dried (Na2SO4), filtered, and concentrated in vacuo to give allyl 2-(3-ethylureido)-5-(trifluoromethyl)benzoate as a white solid (1.8 g). MS found: (M+Na)+=339.29.
Reaction SMILES: [Cl:1]C1C=CC(C(C(Cl)=C(Cl)Cl)O)=CC=1.Cl.[CH3:16][O:17][C:18](=[O:30])/[C:19](/[Cl:29])=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24](OC)=[CH:23][CH:22]=1>>[CH3:16][O:17][C:18](=[O:30])/[C:19](/[Cl:29])=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([Cl:1])=[CH:23][CH:22]=1
Reactant: COC(=O)/C(Cl)=C/c1ccc(OC)cc1
Reactant: OC(C(Cl)=C(Cl)Cl)c1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)/C(Cl)=C/c1ccc(Cl)cc1
Yield: 93 %

Procedure:
p-Chlorophenyltrichlorovinyl carbinol (6.0 g, 22.0 millimoles) is added to a refluxing solution of methanolic sulfuric acid (30 ml as noted in Example 4). Hydrogen chloride evolution is noted during the stirring procedure for 45 minutes. The mixture is cooled and has a workup as in Example 4, which affords z-methyl-2-chloro-3-(4'-chlorophenyl)propenoate (4.7 g, 20.4 millimoles) in 93 percent yield (M.P.=78° C.-80° C.): 'H NMR (CDCl3) δ 7.77 (1H, s), 7.45 (4H, ab quartet), 3.81 (3H, s); 13C NMR (CDCl3) δ 163.5, 136.1, 135.8, 131.6, 131.3, 128.8, 122.3, 53.4. Analysis calculated for: C, 52.01; H, 3.50. Found: C, 51.85; H, 3.42.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>C(Cl)Cl.CCOC(C)=O>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CN(C)CCN
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 3-nitrobenzenesulfonyl chloride (1, 1.0 g, 4.51 mmol) in anhydrous CH2Cl2 (9.0 mL) was added N,N-dimethyl-ethylenediamine (2, 0.5 mL, 4.55 mmol) dropwise. The resulting solution was stirred at room temperature overnight before it was diluted with EtOAc (80 mL). The organic mixture was washed with saturated NaHCO3 (90 mL), brine (90 mL), and dried over MgSO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 3 as a foam (0.8 g) which was used in the next step without further purification.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]O)[CH2:31][CH2:30]1>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][C:14]([O:17][CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:13][CH:12]=3)[N:19]=1
Reactant: CN1CCN(CCO)CC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(O)cc12
Product: CN1CCN(CCOc2ccc3oc(-c4cc5ccccc5cn4)cc(=NO)c3c2)CC1

Procedure:
2-isoquinolin-3-yl-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-chromen-4-one oxime was prepared in 49% overall yield using the method described in examples 44 and 44A, starting from 6-hydroxy-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 41A) and 2-(4-methyl-piperazin-1-yl)-ethanol. The title compound was isolated as a yellow solid and as a 90/10 mixture of Z/E oxime isomers.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([NH2:25])[CH2:23][NH2:24])=[CH:17][CH:16]=1>C(Cl)Cl>[NH2:25][C@@H:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=1)[CH2:23][NH:24][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:11]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC[C@@H](N)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: N[C@H](CNC(=S)NC(=O)c1ccccc1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of benzoyl isothiocyanate (2.94 mL, 21.9 mmol) in DCM (50 mL) was added dropwise via an addition funnel to the mixture of (S)-3-(4-chlorophenyl)propane-1,2-diamine dihydrochloride (5.63 g, 21.9 mmol) and TEA (7.60 mL, 54.6 mmol) in DCM (200 mL) at −10° C. under nitrogen. The addition took 30 minutes. The mixture was then gradually warmed to ambient temperature and stirred overnight. The solvent was removed in vacuo. The residue was partitioned between EtOAc and water. The combined organic portions were washed with brine. The crude product was purified by flash column chromatography (20 to 100% of EtOAc in hexanes, Biotage Si 40M). The product was obtained as an off-white foamy solid, 5.53 g, 73%. 1H NMR (300 MHz, CDCl3) δ 1.84 (broad, NH2), 2.57-2.71 (m, 1H), 2.82-2.94 (m, 1H), 3.34-3.48 (m, 1H), 3.51-3.65 (m, 1H), 3.82-3.99 (m, 1H), 7.13-7.21 (m, 2H), 7.28-7.34 (m, 2H), 7.49-7.58 (m, 2H), 7.59-7.68 (m, 1H), 7.80-7.91 (m, 2H), 9.00 (broad, NH), 11.07 (broad, NH). LCMS (API-ES): 348.1/350.1 (M++H), chloro pattern.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl.[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1([CH2:65][CH2:66]O)[CH:64]=[CH:63][N:62]=[CH:61]1.C(O)(=O)C>C(Cl)Cl>[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:66][CH2:65][N:60]3[CH:64]=[CH:63][N:62]=[CH:61]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: OCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCCn4ccnc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Diethyl azodicarboxylate (160 mg, 1.4 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(imidazol-1-yl)ethanol (94 mg, 0.84 mmol), (J. Med. Chem. 1993, 25, 4052-4060), in methylene chloride (5 ml) and the mixture stirred for 1 hour at ambient temperature. Acetic acid (42 mg, 0.7 mmol) was added and the solvent was removed by evaporation. The residue was triturated with ether, the solid collected by filtration, dried under vacuum and purified by chromatography eluting with methylene chloride/methanol (9/1 followed by 8/2) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (250 mg, 76%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc(CCc2cc(-c3ccccc3)n(-c3ccccc3)n2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc(CCc2cc(-c3ccccc3)n(-c3ccccc3)n2)c1
Yield: 90.1 %

Procedure:
A mixture of 3-[2-(1,5-diphenyl-1H-pyrazol-3-yl)ethyl]phenol (4.50 g, 13 mmol), methyl bromoacetate (2.23 g, 1.375 mL, 14.5 mmol), potassium carbonate (2.19 g, 16 mmol), potassium iodide (catalytic amount) and acetonitrile (80 mL) was stirred at reflux for 3 hours. The mixture was filtered, concentrated and the residue chromatographed on a column of silica gel prepared in a mixture of hexanes and diethyl ether (9:1). Subsequent elution with a mixture of hexanes and diethyl ether (1:1) furnished methyl [3-[2-(1,5-diphenyl-1H-pyrazol-3-yl)ethyl]phenoxy]acetate (4.83 g, 85% ) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:11][N:12]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:23]2[CH2:22][CH2:21][CH:20]([N:12]([CH3:11])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:25][CH2:24]2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Cc1c(Cl)nnc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(Cl)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Yield: 64.9 %

Procedure:
Heat a mixture of 3,6-dichloro-4,5-dimethylpyridazine (11.0 g, 62.1 mmol), tert-butyl methyl(piperidin-4-yl)carbamate (23.3 g, 109 mmol), and powdered K2CO3 (17.2 g, 124 mmol) in DMSO (310 mL) at 120° C. for 2 d. Cool the reaction mixture, dilute with H2O, and filter off the solid. Rinse the solid with H2O, and dry under vacuum at 45° C. Dissolve the solid in CH2Cl2, and pass the solution through a pad of silica gel, eluting with CH2Cl2. Concentrate the organic layer under reduced pressure to obtain the title compound as a yellow solid (14.3 g, 65%). ES/MS m/z (35Cl) 355.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[C:17]([Cl:20])([Cl:19])=[CH2:18]>C(Cl)Cl>[Cl:19][C:17]([Cl:20])=[CH:18][C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[C:8]([F:12])[CH:7]=1)=[O:5]
Reactant: O=C(Cl)c1cc(F)c(Cl)nc1Cl
Reactant: C=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1cc(F)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the 2,6-dichloro-5-fluoronicotinoyl chloride from the previous reaction in CH2Cl2 (25 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (7.9 g, 59.5 mmol) in CH2Cl2 (25 mL). After 15 min, vinylidene chloride (4.75 mL, 59.5 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2Cl2. The organic layer was collected and cooled to 0° C. before TEA (8.3 mL, 59.5 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HCl, NaHCO3, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one: (6.1 g, 90%) as a brown oil: 1H-NMR (d6-DMSO, 300 MHz)δ8.43 (d, 1H, J=8.4 Hz), 7.56 (s, 1H), Rf=0.76 (3:1 Hex:EtOAc).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:3](=O)[CH2:2]1.[NH3:11].[H][H]>>[NH2:11][CH:3]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCc2ccccc21
Reactant: N
Product: NC1CCc2ccccc21
Yield: 91.8 %

Procedure:
A continuously operated high-pressure reactor was packed with 250 cm3 of catalyst A and, at 130° C. and 100 bar, charged hourly from the base with 32 g of a methanolic α-indanone solution (80% by weight indanone), 55 ml of liquid ammonia and 15 1 (Stp) of hydrogen. Excess ammonia and methanol were then distilled off. The collected discharges from the reaction were analyzed by gas chromatography: 1-aminoindane was obtained in a yield of 91.8%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[C:18]1([CH2:21][CH2:22][NH:23][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl-4-oxo-1-piperidinecarboxylate in methylene chloride was added 2-phenethylamine, NaBH(OAc)3 and HOAc. The mixture was stirred at ambient temperature for 16 hours and quenched by addition of H2O. The aqueous layer was neutralized with NaHCO3 and extracted with CH2Cl2. The combined organic layer was washed with saturated NaHCO3 and brine and dried over MgSO4. Evaporation of solvent gave an off-white solid. This material was used without further purification. ESI-MS 305 (M+H); HPLC A: 2.54 min.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[CH:17]1([C:20](=O)[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:19][CH2:18]1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[CH:17]1([C:20]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:1]=2)[CH2:19][CH2:18]1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: COC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the solution of 2-amino-4′-fluorobenzophenone (100 g) in acetic acid (500 ml) added methyl 3-cyclopropyl-3-oxopropanoate (132 g), sulfuric acid (5 ml) and stirred for 15 minutes at 25° C. Heated the reaction mixture to 100° C. for 10 hrs. Cooled the reaction mixture to 0-5° C. and pH adjusted to neutral conditions with 40% sodium hydroxide solution. Filtered the solid formed and washed with water. The wet solid was dissolved in methylene chloride and separated the water from it. Silica slurry was given to the reaction mixture and filtered it. Methylene chloride was distilled off and the compound was co-distilled with methanol. To the compound added methanol (150 ml) and stirred for 1 hr at 25° C. Filtered the solid and washed with methanol (50 ml). Dried the obtained solid to get the title compound.
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:44])=[O:3])=[C:10]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(CCc2ccccc2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionic acid ethyl ester (0.54 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH 1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-phenethylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ8.06 (d, J=1.5 Hz, 2H), 8.05 (d, J=2.0 Hz, 2H), 7.69 (d, J=2.0 Hz, 2H), 7.67-7.36 (m, 3H), 7.28-7.15 (m, 5H), 6.77-6.73 (m, 2H), 6.62 (dd, J=8.8, 2.9 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.86 (s, 4H, 2.41 (s, 3H), 1.55 (s, 6H), MS (ES) m/e 562 M+1).
Reaction SMILES: ICI.[CH2:4]([N:11]([C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[C@@H:12]1[C@H:17]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:16][CH:15]=[CH:14][CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:37]([Zn]CC)C.C(=O)([O-])O.[Na+]>CO.C(Cl)Cl>[CH2:4]([N:11]([C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[C@H:12]1[CH2:13][CH:14]2[CH:15]([CH2:37]2)[CH2:16][C@H:17]1[N:18]1[C:19](=[O:28])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]1=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@H]1CC=CC[C@H]1N1C(=O)c2ccccc2C1=O
Reactant: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ICI
Solvent: ClCCl
Solvent: CO
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@H]1CC2CC2C[C@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 15 h

Procedure:
A methylene chloride (3 ml) solution containing diiodomethane (0.2 ml) and a methylene chloride solution (3 ml) containing 2-((1R,6S)-6-(benzyl ((R)-1-phenylethyl)amino)-3-cyclohexen-1-yl)isoindolin-1,3-dione (0.36 g) obtained in the 1st step were added to a methylene chloride solution (10 ml) containing diethyl zinc (1M in hexane) (2.47 ml), followed by stirring for 15 hours. Methanol and sodium hydrogen carbonate were added to the reaction solution. The reaction solution was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layers were washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:0.2). A 2-((3R,4S)-4-(benzyl ((R)-1-phenylethyl)amino)bicyclo[4.1.0]heptan-3-yl)isoindolin-1,3-dione (0.20 g) was thus obtained.