Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:41]=[CH:40][C:14]([CH2:15][NH:16][C:17](=[O:39])[CH2:18][N:19]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[C:20]2=[O:38])=[CH:13][CH:12]=1.Cl>C(Cl)Cl.C(O)(=O)C.O.O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17](=[O:39])[CH2:18][N:19]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[C:20]2=[O:38])=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)NCc2ccc(Nc3nc4ccccc4[nH]3)cc2)C(=O)c2ccccc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)CC1CCN(CC(=O)NCc2ccc(Nc3nc4ccccc4[nH]3)cc2)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.53 g (10 mmol) of the t-butyl ester from Example I was dissolved in a mixture of 10 ml of CH2Cl2, 5 ml of glacial acetic acid and 0.25 ml of water, and the solution was treated with 7 ml of 4 N HCl in dioxane and stirred at room temperature overnight. Toward the end, the solvent was distilled off in vacuo with addition of toluene and the residue was purified by column chromatography (eluent: CH2Cl2/MeOH/50% strength acetic acid, 45/5/1). After stripping off the solvent and digesting with ether, 0.42 g (84%) of amorphous powder remained; FAB-MS [M−H+]: 498.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:44]1([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.C(#N)C>[F:28][C:4]1[CH:3]=[C:2]([NH:1][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[S:55])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCC4)CC3)ncn2)c(F)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h
Yield: 57.4 %

Procedure:
After dissolving 4-(azetidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (40 mg) in ethanol (1 ml) under a nitrogen atmosphere, D-10-camphorsulfonic acid (22.3 mg) was added and the mixture was stirred for 5 minutes. Phenylacetyl isothiocyanate (34.1 mg)-acetonitrile (0.5 ml×3) was added thereto, and the mixture was stirred for 30 minutes. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (1.5 ml) and hexane (1.5 ml) were added to the resultant residue to produce a suspension. After filtering the solid, it was subjected to aeration drying to provide the title compound (33.5 mg, 61.8%) as white powder.
Reaction SMILES: CS(O[CH2:6][C:7]1([C:10]#[N:11])[CH2:9][CH2:8]1)(=O)=O.[N-:12]=[N+:13]=[N-:14].[Na+]>C(N)=O.O.C(OCC)(=O)C.CCOCC>[N:12]([CH2:6][C:7]1([C:10]#[N:11])[CH2:9][CH2:8]1)=[N+:13]=[N-:14]
Reactant: CS(=O)(=O)OCC1(C#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: NC=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N#CC1(CN=[N+]=[N-])CC1
Temperature: 120 °C
Yield: 68.5 %

Procedure:
A stirred mixture of (1-cyanocyclopropyl)methyl methanesulfonate (21.52 mmol, 3.77 g) and sodium azide (43.0 mmol, 2.80 g) in N,N-diemethyl formamide (40 mL) was heated to 120° C. for ˜18 hours. The mixture was allowed to cool and was diluted with water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to give an oil. This oil was taken up in ether and washed with water, dried and concentrated under reduced pressure to give the intermediate 1-(azidomethyl)cyclopropanecarbonitrile (1.8 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[N:9][OH:10])[NH2:8])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:29])[CH2:24]C(OC)=O)=[CH:18][CH:17]=1.C1(C)C=CC=CC=1>CCCCCCC>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([C:24]2[O:10][N:9]=[C:7]([C:6]3[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:8]=2)=[O:29])=[CH:18][CH:17]=1
Reactant: NC(=NO)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)Cc1ccc(OC)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: COc1ccc(CC(=O)c2nc(-c3cccc([N+](=O)[O-])c3)no2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
In a 100 ml flask, place 5 g (0.0276 m) of 3-nitrobenzamidoxime (9a), 8.6 g (0.0414 m) of methyl p-methoxyphenyacetoacetate (10c; R1=p-methoxyphenyl), and 50 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 14 hrs. Cool the reaction mixture to room temperature, add 40 ml of heptane and stir for 30 min. Collect solid, wash with heptane, and dry in air to give 8.4 g (85%) of 5-(p-methoxyphenyl)acetyl-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula II: R1=p-methoxyphenyl and R2=3-nitrophenyl].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([OH:26])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-])=O)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.O.O.[Sn](Cl)(Cl)(Cl)Cl.[C:34](=O)(O)[O-].[Na+]>CO>[NH2:20][C:11]1[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:23][C:24]([O:26][CH3:34])=[O:25])=[CH:4][C:3]=2[O:2][CH3:1])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:19])[NH:15]2
Reactant: O=C([O-])O
Reactant: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C)cc2c1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2N)c(OC)c1
Temperature: 65 °C

Procedure:
A solution of 1.2 (1.00 g, 2.81 mmol) and tin chloride dihydrate (5.07 g, 22.5 mmol) dissolved in methanol (10 mL) was heated to 65° C. (external temperature, oil bath) overnight. The reaction solution was poured into aqueous 5% sodium bicarbonate solution and the resulting bi-phase passed through a pad of Celite, rinsing with water and ethyl acetate. The filtrate was separated and the organic layer washed with water and brine then stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a yellow-green foamy solid. The product was isolated by chromatography on silica gel, eluting with ethyl acetate/hexane gradient, to afford a yellow foamy solid. LC-MS ESI (pos.) m/z: 341.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31]Cl)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:31][CH2:30][CH2:29][CH2:28][C:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)=[O:33])[CH2:16][CH2:15]1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Product: O=C(CCCCN1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1)c1ccc(F)cc1
Yield: 34.1 %

Procedure:
According to Procedure B above, 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one (0.025 g, 0.05 mmol) and 1-(4-fluorophenyl)-5-chloro-1-oxopentane (0.024 g, 0.11 mmol) were allowed to react to give the title compound (0.0078 g, 27.4%, mono-TFA salt) as a off-white solid. 1H NMR (300 MHz, MeOH) δ ppm 8.05-8.15 (m, 3H), 7.62 (dd, J=3, 9, 1H), 7.35 (d, J=9, 1H), 7.20-7.28 (m, 2H), 5.47 (s, 1H), 3.82-3.92 (m, 1H), 3.67-3.75 (m, 2H), 3.11-3.25 (m, 5H), 2.32-2.43 (m, 2H), 2.15-2.25 (m, 1H), 1.87-2.03 (m, 2H), 1.79-1.87 (m, 4H); MS (ESI+Q1MS) m/z 457 [M]+
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][S:8]([C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13])(=[O:10])=[O:9])=[O:5])C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:15][C:11]([S:8]([CH2:7][C@@H:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]([OH:3])=[O:5])(=[O:10])=[O:9])([C:12]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)Cl
Reactant: C1COCCN1
Product: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In an analogous manner to that described in Example 1, paragraphs (d) and (e), starting from 2-mercaptoisobutyric acid and ethyl 2-benzylacrylate there was obtained (RS)-2-[[2-[(ethoxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride, reaction of which with morpholine analogously to Example 2, paragraph (a), and subsequent enzymatic hydrolysis analogously to Example 6, paragraph (c), yielded (S)-α-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamic acid, MS: 383 (M)+, as a colourless solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1.O1CCCC1.[F:35][C:36]1[CH:37]=[C:38](O)[CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:35][C:36]1[CH:41]=[C:40]([CH:39]=[CH:38][CH:37]=1)[O:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: Oc1cccc(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2cccc(F)c2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C

Procedure:
To a solution of dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (50.0 mg, 0.000123 mol) in tetrahydrofuran (0.50 mL, 0.00617 mol) was added 3-fluoro-phenol (0.0134 mL, 0.000148 mol), triphenylphosphine (38.8 mg, 0.000148 mol), followed by diethyl azodicarboxylate (0.0233 mL, 0.000148 mol). The mixture was heated at 70 Celsius overnight. After concentrated to dry, the mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to generate the phenyl ether compound (27 mg, 44%). MS (ESI): (M+H)+=500.05.
Reaction SMILES: [CH:1]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:11])[CH:2]=1.[CH2:12]([NH2:14])[CH3:13].C(N(CC)CC)C>ClCCl.C1COCC1>[CH2:12]([NH:14][S:7]([C:6]1[CH:5]=[CH:4][C:3]([I:11])=[CH:2][CH:1]=1)(=[O:9])=[O:8])[CH3:13]
Reactant: CCN
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pipsyl chloride 25 g was dissolved in dichloromethane 250 ml to which was added a solution of ethyl amine 2M, in THF 42 ml and triethylamine 9 g in dichloromethane 100 ml over 30 min. The mixture was stirred a further 1 h at room temperature and then washed with water and 1N hydrochloric acid, dried (MgSO4) and evaporated in vacuo to give N-ethyl-4-iodo-benzenesulfonamide as a white solid, 26.2 g. 1H NMR 7.88 (2H, d), 7.59 (2H, d), 4.65 (1H, m), 3.01 (2H, m), 1.11 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:37])[CH2:33][CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][OH:37])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCCCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-pentyn-1-ol (0.056 mL). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (5L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 117.5 mg (43%) of the desired product as a creme solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:21]1[O:29][C@H:22]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(OC(C)C)(=O)C.[OH-].[Na+]>O1CCCC1.CN1CCCN(C)C1=O>[NH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:21][C@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:29])=[CH:3][CH:4]=1
Reactant: c1ccc([C@H]2CO2)cc1
Reactant: NCCc1ccc(N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(=O)OC(C)C
Product: NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a 1000 mL 3-neck flask was added 20 g (147 mmol) of 2-(4-aminophenyl)ethylamine and 30 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU). The reaction flask was fitted with an overhead stirrer and a thermometer. The reaction flask was purged with nitrogen and placed in a cold water bath. The reaction mixture was charged with 165 mL (165 mmol) of 1.0 M sodium bis(trimethylsilyl)amide in tetrahydrofuran (the temperature remained below 30° C.). The sodium bis(trimethylsilyl)amide solution was added in one portion with vigorous stirring. The reaction mixture was cooled to −10° C. and (S)-styrene oxide (17 mL, 150 mmol) was added. The rate of addition was controlled to maintain a temperature below −10° C. The reaction was allowed to warm to 20° C. within 15 minutes after the addition of (S)-styrene oxide, reaching 28° C. within 30 minutes. The reaction was cooled to 25° C., and was quenched by dropwise addition of 90 mL water. The reaction mixture was transferred to a separatory funnel, diluted with 100 mL isopropyl acetate and washed with 90 mL saturated aqueous sodium chloride. The organic layer was washed three times with a mixture of 90 mL water and 90 mL saturated aqueous sodium chloride and finally with 180 mL saturated aqueous sodium chloride. The organic layer was concentrated under vacuum. The residue was twice reconcentrated from isopropanol (100 mL portions) and then redissolved in isopropanol (500 mL) and heated to 70° C. with stirring. Concentrated hydrochloric acid (27 mL, 327 mmol) was added over two minutes. The mixture was allowed to cool to room temperature and stirred for 14 h. The precipitated product was isolated by filtration and washed with isopropanol and isopropyl acetate. The product was dried under vacuum over a 50° C. water bath for 1 h and then dissolved in 80 mL water and transferred to a separatory funnel. Isopropyl acetate (80 mL) and 10 N aqueous sodium hydroxide (40 mL, 400 mmol) were added. The separatory funnel was shaken and the phases separated. The organic layer was washed once with 40 mL saturated NaCl and dried over magnesium sulfate. The solids were collected and the filtrate was concentrated. The residue was twice reconcentrated from toluene to afford the title intermediate as an oil (14.7 g, 59 mmol, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[C:6]([CH3:24])=[N:7][CH:8]([NH:13]C(=O)OCC3C=CC=CC=3)[C:9](=[O:12])[N:10]([CH3:11])[C:4]=2[CH:3]=1.CS(O)(=O)=O.[OH-].[NH4+]>C1(OC)C=CC=CC=1>[NH2:13][CH:8]1[N:7]=[C:6]([CH3:24])[C:5]2[CH:25]=[CH:26][C:2]([Br:1])=[CH:3][C:4]=2[N:10]([CH3:11])[C:9]1=[O:12]
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)N(C)c2cc(Br)ccc21
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: COc1ccccc1
Product: CC1=NC(N)C(=O)N(C)c2cc(Br)ccc21
Temperature: 40 °C

Procedure:
The product of Step 3 (0.831 g, 2.00 mmol) was dissolved in anhydrous anisole (16 ml) and then methanesulfonic acid (3.84 g, 40 mmol) was added in one portion. The reaction mixture was heated to 40° C. for 30 minutes with stirring, then cooled to 0° C. in an ice bath and made basic (pH=10) with concentrated ammonium hydroxide. The aqueous solution was then extracted with chloroform (3×50 ml) and the organic layers combined, dried over magnesium sulfate, filtered and concentrated to give the crude product. Purification on silica gel, eluting with 10% methyl alcohol in chloroform, providing the title compound as an XXXX (0.463 g, 82%). 1H NMR (CDCl3, 300 MHz): δ 7.32-7.23 (m, 3H), 4.12 (d, 1H, J=1.1 Hz), 3.27 (s, 3H), 2.30 (d, 3H, J=1.5 Hz) ppm.
Reaction SMILES: NC(C(O)=O)CS.[Cl:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]3[N:20]4[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:19]4=[CH:18][C:17]=3[CH:16]=2)=[CH:11][C:10]=1[C:37]([F:40])([F:39])[F:38]>C(O)(C(F)(F)F)=O>[Cl:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]3[N:20]4[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([OH:30])=[O:29])[C:19]4=[CH:18][C:17]=3[CH:16]=2)=[CH:11][C:10]=1[C:37]([F:40])([F:38])[F:39]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(Cl)c(C(F)(F)F)c3)ccc12
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(Cl)c(C(F)(F)F)c3)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of D,L-cysteine (0.056 g, 0.460 mmol) in TFA (0.9 mL) was added tert-butyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.079 g, 0.153 mmol). The reaction was stirred for 2 h and poured into ice water. The resulting precipitate was collected by vacuum filtration to give the title compound as a solid. LCMS m/z=424.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14-2.27 (m, 1H), 2.55 (dd, J=16.29, 7.96 Hz, 1H), 2.64-2.72 (m, 1H), 2.72-2.82 (m, 1H), 3.51-3.64 (m, 1H), 3.90-4.01 (m, 1H), 4.05-4.17 (m, 1H), 5.18 (s, 2H), 6.01 (s, 1H), 6.78 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.20 (d, J=8.72 Hz, 1H), 7.69-7.81 (m, 2H), 7.92 (s, 1H), 12.24 (bs, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[ClH:9].[Mg+2].[Cl-].[Cl-].[Na+].[Cl-].[As](C)(C)(=O)[O-].[Na+].SC[C@H]([C@@H](CS)O)O.[OH:29][P:30](=[O:57])([O:40][CH2:41][C@H:42]1[O:56][C@@H:46]([N:47]2[CH:53]=[C:51]([CH3:52])[C:50](=[O:54])[NH:49][C:48]2=[O:55])[CH2:45][C@@H:43]1[OH:44])[O:31]P(=O)(OP(=O)(O)O)O>>[CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[ClH:9].[CH3:52][C:51]1[C:50](=[O:54])[NH:49][C:48](=[O:55])[N:47]([C@@H:46]2[O:56][C@H:42]([CH2:41][O:40][P:30]([OH:31])([OH:57])=[O:29])[C@@H:43]([OH:44])[CH2:45]2)[CH:53]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: C[As](C)(=O)[O-]
Agent: Cl
Agent: NC(CO)(CO)CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O

Procedure:
First, a vector primer is synthesized. A vector, e.g. pcDV1, is treated with KpnI in an adequate solution such as a solution consisting of Tris-HCl buffer (e.g. pH 7.5, 10 mM), MgCl2 (e.g. 6 mM) and NaCl (e.g. 10 mM) to cut pcDV1 at KpnI site. The DNA is incubated with terminal deoxynacleotidyltransferase at an appropriate temperature (e.g. 37° C.) for an appropriate period (e.g. 20 minutes) in a solution consisting of Tris-HCl buffer (e.g. pH 6.8, 30 mM), sodium cacodylate (e.g. 140 mM), CoCl2 (e.g. 1 mM), dithiothreitol (e.g. 0.1 mM) and dTTP (e.g. 0.25 mM) to add about 60 thymidyl residues to the both 3' ends of the vector DNA. Then, the DNA is cut with EcoRI in a solution consisting of Tris-HCl buffer (e.g. pH 7.5, 10 mM), MgCl2 (e.g. 6 mM) and NaCl (e.g. 100 mM) The digested solution is fractionated by low-gelling-temperature agarose gel electrophoresis [Lars Wieslahder: Analytical Biochemistry, 98, 305 (1979), referred to as LGT method hereinafter] to recover a DNA fragment of about 3.1 Kb. Then, the DNA is dissolved in an NaCl or KCl hypertonic solution (e.g. 0.5M) and passed through a poly(dA) cellulose column to allow only vector primer molecules having poly(T) to be adsorbed on the column. Elution is carried out with water or a hypotonic salt solution such as 10 mM Tris-HCl buffer to isolate only the vector primer molecule with poly(T).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: Cc1cc(Cl)ccc1N1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
To a solution of 1-(4-chloro-2-methyl-phenyl)-piperazine (0.13 g, 0.6 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (95 uL, 0.802 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 12 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound (0.11 g, 54%). 1H-NMR (DMSO) δ: 1.45 (6H, s), 2.30–2.65 (8H, m), 2.75–2.85 (4H, m), 3.30 (3H, d), 5.30 (2H, br s), 6.20 (1H, t), 6.75 (1H, d), 7.00–7.47 (6H, m), 7.80 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 504 (M+1), UV retention time: 1.65 min.