Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1F
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1F
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetic acid (I55) (1.11 g, 4.12 mmol) in THF (50 ml), were added N,N′-methanediylidenedicyclohexanamine (1.02 g, 4.95 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.67 g, 4.95 mmol), and (R)-quinuclidin-3-ol (0.63 g, 4.95 mmol). The reaction was stirred at RT for hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetate (1.56 g; quantitative yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[C:28]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:18](=[O:20])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:12]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 2.5 g (E)-3-[1-(4-Iodo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid is dissolved in 140 ml DMF. To this mixture are added 0.949 g HOBtxH2O, and 6.27 g Et3N. After 30 min 3.57 g EDCxHCl are added and the resulting mixture is stirred for 30 min. Now 1.29 g of N-boc-o-phenylenediamine are added and the reaction mixture is stirred overnight. The solvent is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is dried and evaporated and the crude product is purified by silica gel flash chromatography.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:9][C:10]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)c(O)c1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C=O)c(OCc2ccccc2)c1OC
Yield: 91.5 %

Procedure:
Benzyl bromide (12.9 ml, 0.108 mol) was added to a suspension of 2-hydroxy-3,4-dimethoxybenzaldehyde (19 g, 0.104 mol) and potassium carbonate (14.41 g, 0.104 mol) in acetone (200 ml) and the reaction stirred at reflux for 3 hours. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between water (150 ml) and dichloromethane (150 ml). The organic layer was filtered through silica, washing through with hexane and then ethyl acetate. Evaporation of the filtrate under reduced pressure gave a yellow gum. The crude product was purified on silica gel eluting with ethyl acetate:hexane (30:70 v/v) to give the subtitle compound (25.9 g, 88%). Rf 0.82 (ethyl acetate:hexane 1:1, v/v). MS m/z 273 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6](Cl)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Fc1cc2c(cc1Cl)C(Cl)Cc1ccccc1S2
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2Cc3ccccc3Sc3cc(F)c(Cl)cc32)CC1
Yield: 74 %

Procedure:
A mixture of 7-fluoro-8,10-dichloro-10,11-dihydrodibenzo(b,f)thiepine (7.48 g), 1-methylpiperazine (5.2 ml) and chloroform (7 ml) was refluxed for 7 hours. The chloroform was evaporated and the residue taken up in water (20 ml) and benzene (80 ml). The benzene solution was washed with water and shaken with 3 N-HCl (100 ml). The separated hydrochloride was filtered and added to the aqueous layer of the filtrate. The resulting suspension was made alkaline with ammonium hydroxide and the liberated base taken up in benzene. The desired product, m.p. 105°-107° C. (acetone), was obtained in 74% yield (6.66 g). Its neutralization with maleic acid in ethanol, followed by addition of ether, yielded the crystalline maleate, m.p. 168°-169° C. (ethanol).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[C:17](=[O:29])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[C:21]([C:26](O)=[O:27])[CH:20]=4)[N:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.C(Cl)(=O)C(C)(C)C.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O>[C:1]1([S:7]([CH2:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[C:17](=[O:29])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[C:21]([C:26]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[O:27])[CH:20]=4)[N:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Reactant: C1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-(2-benzenesulfonylmethyl-thiazol-4-yl)-1H-quinolin-2-one-7-carboxylic acid (Example 8733 step (h), 0.1 g, 0.2 mmol) and 5 mL of anhydrous CH2Cl2 was added TEA (0.2 mL, 1.4 mmol) and pivaloyl chloride (0.1 mL, 0.8 mmol). The solution was stirred overnight at RT. The reaction was now homogenous and piperidine (0.5 mL, 5.1 mmol) was added. After 6 h, the reaction was diluted with H2O. The aqueous solution was extracted with EtOAc (6×). The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The solid was suspended in a minimum of EtOAc and filtered to give a solid. MS m/z: 494.1 (M+1). Anal. Calc'd for C25H23N3O4S2.0.5H2O: C, 59.74; H, 4.81; N, 8.36. Found: C, 59.64; H, 4.82; N, 8.30.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Br:9][C:10]1[CH:40]=[C:39](F)[C:13]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[N:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:27]([O:37][CH3:38])=[CH:26][N:25]=3)=[N:16]2)=[C:12]([F:42])[CH:11]=1.O>CN(C=O)C>[Br:9][C:10]1[CH:40]=[C:39]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:13]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[N:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:27]([O:37][CH3:38])=[CH:26][N:25]=3)=[N:16]2)=[C:12]([F:42])[CH:11]=1
Reactant: OCC(F)(F)F
Reactant: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3F)c3ccccc23)nc1Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3OCC(F)(F)F)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
38.2 mg of 2,2,2-trifluoroethanol (0.382 mmol, 2 eq.) were dissolved in 1.5 ml of dry DMF under nitrogen atmosphere. 16.8 mg of 60% sodium hydrid in paraffin oil (0.42 mmol, 2.2 eq.) were added. The suspension was stirred at room temperature for 15 minutes. 100 mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-12-1, 0.191 mmol, 1 eq.) were added. The reaction mixture was stirred at room temperature for 18 hours. Water was added dropwise. The suspension was filtered off. The precipitate was dried at 50° C. under vacuo. The precipitate was purified by preparative HPLC to yield 34 mg (0.05 mmol, 28%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][N:43]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:42][CH2:41]1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3cccc(C(F)(F)F)c3)noc2C)CC1
Yield: 64.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (524 mg, 1.18 mmol, 64%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].Cl[C:27]([O:29][CH3:30])=[O:28]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([C:27]([O:29][CH3:30])=[O:28])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Cl
Reactant: COC(=O)Cl
Product: COC(=O)n1c2c(c(=O)n(-c3cc(C(=O)OC(C)C)c(Cl)cc3F)c1=O)CCC2

Procedure:
using isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and methyl chloroformate there is obtained isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methoxycarbonyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.84 ppm (d, 1H), 7.35 ppm (d, 1H), 5.24 ppm (m, 1H), 4.03 ppm (s, 3H), 3.02 ppm (m, 2H), 2.79 ppm (m, 2H), 2.16 ppm, (m, 2H), 1.36 ppm (d, 6H),
Reaction SMILES: [OH-].[Li+].[CH2:3]([NH:7][C:8](=[O:33])[N:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[O:30][CH2:31][CH3:32])/[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:10])[CH2:4][CH2:5][CH3:6].C(O)(=O)C>O1CCCC1>[CH2:3]([NH:7][C:8](=[O:33])[N:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[CH:19][C:20](/[CH:23]=[C:24](\[O:30][CH2:31][CH3:32])/[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:10])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)O)cc2)c1
Yield: 100.9 %

Procedure:
2.9 mL (2.9 mmol) of aqueous 1 M lithium hydroxide solution are added to a solution of 0.8 g (1.9 mmol) of ethyl (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-ethoxyacrylate in 10 mL of tetrahydrofuran. The reaction medium is heated at reflux for 20 hours. After cooling, 3 mL (2.9 mmol) of 1 N acetic acid are added and the reaction medium is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, filtered and evaporated. 760 mg (100%) of (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-ethoxyacrylic acid are obtained in the form of a white solid with a melting point of 126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH2:21]([N:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1)[C:22]#[CH:23]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:23]#[C:22][CH2:21][N:24]3[CH2:25][CH2:26][S:27](=[O:31])(=[O:30])[CH2:28][CH2:29]3)=[CH:14][C:6]1=2
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: C#CCN1CCS(=O)(=O)CC1
Product: O=S1(=O)CCN(CC#Cc2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)CC1
Yield: 34 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (108 mg) was coupled with 4-prop-2-ynyl-thiomorpholine 1,1-dioxide as in General Procedure 5 to give the title compound as an off-white solid (34% yield). M.p.>200° C., LCMS: m/z=467.33 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.11 (8H, s), 3.40 (2H, t, J=4.8 Hz), 3.56 (2H, s), 3.61 (2H, t, J=4.7 Hz), 4.41 (2H, s), 6.42 (1H, dt, J=1.5 Hz), 7.22 (2H, m), 7.35 (1H, d, J=8.3 Hz), 7.58 (1H, d, J=1.5 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([O:10][CH3:11])=[O:9].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cccn1C
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
Methyl 1-methylpyrrole-2-acetate (5.0 g, 32.0 mmol) and 4-chloronitrobenzene (10.3 g, 65.0 mmol) were dissolved in DMF (30 ml) and the mixture was cooled in an ice bath under argon. Sodium hydride, 50% in mineral oil, (3.1 g, 64.0 mmol) was added in portions. After stirring for 1 h at room temperature the reaction mixture was poured into 1M HCl/ice and the product was extracted into ethyl acetate. The organic extracts were washed with water, dried over sodium sulfate, and concentrated to dryness. Purification on a Florisil® column (methylene chloride) gave methyl 2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (4.13 g, 46%) as a solid. ##STR39##
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[H-].[Na+].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14]>O1CCCC1>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:7]=1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(trifluoromethyl)-1H-imidazole (compound 216.1, 5 g, 36.74 mmol) in tetrahydrofuran (100 mL). This was followed by the addition of sodium hydride (1.6 g, 40.00 mmol, 60%) in portions at 0° C. and stirred for 1 h at 0° C. To this was added SEMCl (7.1 mL, 40.36 mmol) dropwise at 0° C. The resulting solution was stirred for 4 h at 0° C., then carefully quenched with 100 mL of brine. The pH of the solution was adjusted to 7-8 with hydrogen chloride (1 M). The aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:5) as eluent to furnish 6 g (61%) of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:10]3[CH2:12][CH2:13][N:14](C(=O)C(F)(F)F)[CH2:15][CH2:16][C:9]=3[CH:8]=[CH:7][C:6]=2[O:5][CH2:4]1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:1]([CH:3]1[C:11]2[C:10]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:9]=3[CH:8]=[CH:7][C:6]=2[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1COc2ccc3c(c21)CCN(C(=O)C(F)(F)F)CC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC1COc2ccc3c(c21)CCNCC3
Temperature: 25 °C
Yield: 50.8 %

Procedure:
The product of step (i) (45 mg, 0.143 mmol) was dissolved in an appropriately sized flask in MeOH (3 ml). To this mixture water (1 ml) and K2CO3 (500 mg, 3.62 mmol) were added. The reaction mixture was stirred at room temperature until the product formation was complete by LCMS. The reaction mixture was diluted with water (>10× total volume) and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to provide the title compound (15.8 mg). 1H NMR (300 MHz, CDCl3) δ 6.86 (d, J=7.8 Hz, 1H); 6.52 (d, J=8.1 Hz, 1H); 4.49-4.44 (m, 1H); 4.39-4.35 (m, 1H); 3.31-3.21 (m, 1H); 2.99-2.85 (m, 8H); 2.07 (bs, 1H); 1.58-1.52 (m, 2H); 0.92 (t, J=7.5 Hz, 3H). MS: ESI (positive): 218 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]3=[O:20])=[CH:10][C:9]=2[F:21])=[C:5]([O:24][CH3:25])[CH:4]=1)[CH3:2].CO.[BH4-].[Na+]>C(#N)C>[CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][C:9]=2[F:21])=[C:5]([O:24][CH3:25])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(N3C(=O)CCC3=O)cc2F)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CCc1ccc(Oc2ccc(NC(=O)CCCO)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-dione (169.8 mg, 0.49 mmol) was added methanol (2 mL). The reaction mixture was stirred for 1 h 30 at room temperature under argon. Acetonitrile (2 mL) and NaBH4 (190.7 mg, 4.9 mmol) were added to the reaction. The reaction mixture was stirred at 50° C. for 17 h. Then it was concentrated, dissolved in dichloromethane, washed with a saturated solution of NH4Cl and extracted with dichloromethane. Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give the title product as a white solid used without further purification (169.5 mg; 100%).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[CH:3]\[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[F:12][C:13]([F:23])([F:22])[C:14]1[C:15](=[O:21])[CH:16]=[CH:17][C:18](=O)[CH:19]=1.C(Cl)Cl>CCO>[OH:21][C:15]1[C:14]([C:13]([F:12])([F:22])[F:23])=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:1][C:2]([CH3:11])=[C:3]2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Reactant: O=C1C=CC(=O)C(C(F)(F)F)=C1
Solvent: CCO
Solvent: ClCCl
Product: Cc1[nH]c2ccc(O)c(C(F)(F)F)c2c1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 66 %

Procedure:
A stirred solution of 1,1-dimethylethyl (2Z)-3-amino-2-butenoate (47.6 g, 0.3 mol) in EtOH (100 mL) was treated dropwise at ambient temperature with a 1.2 M solution of 2-(trifluoromethyl)-2,5-cyclohexadiene-1,4-dione in CH2Cl2 (300 mL, 0.35 mol) (internal temperature rose to +35° C. during the addition). The reaction was stirred 1 h and concentrated at reduced pressure. Stirring the resulting material with CHCl3 at ice-bath temperature afforded 1,1-dimethylethyl 5-hydroxy-2-methyl-4-(trifluoromethyl)-1H-indole-3-carboxylate as an off-white solid which was collected by filtration (62 g, 66% yield): 1H NMR (DMSO-d6) δ 11.55 (s, 1H), 9.68 (bs, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 2.37 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[I:17]I>C(O)C.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:17])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: II
Reactant: CCOC(=O)CCc1ccc(OC)cc1F
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(I)c(OC)cc1F
Temperature: 25 °C

Procedure:
Ethyl 3-(2-fluoro-4-methoxyphenyl)propanoate (1480 mg, 6.54 mmol) was dissolved in ethanol (60 mL). Iodine (1660 mg, 6.54 mmol) and silver sulfate (2040 mg, 6.54 mmol) were added and the reaction was stirred vigorously at room temperature, protected from light, for 1 hr. The reaction was then diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with sodium bisulfite (2×60 mL), water (70 mL), and brine (70 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 50% ethyl acetate/hexanes to afford ethyl 3-(2-fluoro-5-iodo-4-methoxyphenyl)propanoate. 1H NMR (CDCl3, 500 MHz) δ 7.59 (d, J=8.4 Hz, 1H), 6.55 (d, J=11.6 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 2.87 (t, J=7.6 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10](=[CH2:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].[CH2:17]([N:24]([CH2:28][Si](C)(C)C)[CH2:25]OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([N:24]1[CH2:25][CH2:16][C:10]([C:8]#[N:9])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:28]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C(C#N)C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C#N)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
TFA (4.31 mmol, 0.49 g) was added to a solution of ethyl 2-cyanoacrylate (17.58 mmol, 2.20 g) in DCM (100 mL) under nitrogen atmosphere. Subsequently, a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (21.49 mmol, 5.10 g) in DCM (50 mL) was added dropwise while cooling with an ice-bath in order to keep the reaction temperature at room temperature (exothermic reaction). The reaction mixture was stirred overnight at room temperature. Then the mixture was washed with saturated aqueous NaHCO3 (100 mL). The aqueous phase was extracted with DCM (100 mL). The combined organic phase was dried over MgSO4 and evaporated in vacuo. The crude product was purified by flash silicagel chromatography (100% heptane to 50% EtOAc) yielding 4.27 g of a colorless oil (94%). 1H-NMR (400 MHz, CDCl3, 300K): δ=1.32 (3H, t, J=7.1 Hz), 2.44 (1H, m), 2.59 (1H, m), 2.69 (1H, m), 2.89 (1H, m), 2.99 (1H, d, J=9.8 Hz), 3.17 (1H, d, J=9.8 Hz), 3.69 (2H, s), 4.27 (2H, q, J=7.1 Hz), 7.29 (5H, m).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCc1ccccc1
Reactant: ClCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CCCNCCOc2ccc3ccccc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.47 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 6 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(2-(naphthalen-2-yloxy)ethyl)amine, solid, m.p. 104° C., (yield 0.65 gm, 87.6%).