Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and methyl iodide (2 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (80 mg, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]([C:18]([O:20]C)=[O:19])=[C:5]2[OH:22].Br[CH2:24][C:25]([O:27]C)=[O:26].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:18]([C:6]1[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[C:4]([C:5]=1[O:22][CH2:24][C:25]([OH:27])=[O:26])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)([OH:20])=[O:19]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1c(O)c2cc(Cl)ccc2n1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1c(C(=O)O)n(-c2ccc(F)cc2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 106.4 %

Procedure:
A mixture of methyl 5-chloro-1-(4-fluorophenyl)-3-hydroxy-1H-indol-2-carboxylate (200 g, 0.62 mol), methyl 2-bromoacetate (125 g, 0.81 mol), K2CO3 (112 g, 0.81 mol) and acetone (2.0 L) was refluxed for 18 h. The mixture was cooled to room temperature and filtered, and the solvents were evaporated in vacuo. To the remaining oil (270 g) methanol (1.5 L) and 3N aqueous KOH (0.6 L) was added. After reflux for 1 h, the solution was cooled to room temperature and acidified by concentrated hydrochloric acid. The product thus precipitated was filtered off and dissolved in ethyl acetate and dried (Na2SO4). Evaporation of the solvents afforded 2-[2-carboxy-5-chloro-1-(4-fluorophenyl)-3-1H-indolyloxy]acetic acid (240 g) as an oil which was decarboxylated without further purification. A mixture of the crude dicarboxylic acid, copper (15 g) and N-methyl-2-pyrrolidone was refluxed for 1.5 h. The mixture was cooled to room temperature and water (2.0 L) was added. The product thus precipitated was filtered off and dissolved in ethyl acetate (1.5 L). The solution was washed with brine (3×1 L) and dried (Na2 SO4). Evaporation of the solvents afforded the crude 2-[5-chloro-1-(4-fluorophenyl)-3-1H-indolyloxy]acetic acid (223 g) which was dissolved in dry diethyl ether (1.5 L). The thus formed solution was added to a suspension of lithium aluminum hydride (70 g, 1.9 mol) in dry diethyl ether (1.0 L) over 45 min. After reflux for additional 0.5 h, the reaction mixture was cooled to 0° C. and carefully treated with water (70 ml), 4N aqueous NaOH and then water (300 mL). The reaction mixture was filtered and dried (Na2SO4). Evaporation of the solvents afforded crystalline title compound (110 g, 55%). An analytical sample was recrystallized from diethyl ether: mp 118°-120° C.; 1H NMR (CDCl3) δ 2.35 (broad s, 1 H),4.0 (t, 2 H), 4.15 (t, 2 H), 6.85 (s, 1 H), 7.10 (broad d, 1 H), 7.15 (t, 2 H), 7.40 (dd, 2 H), 7.65 (broad s, 1 H). Anal. (C16H13ClF--NO2) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[NH2:30][CH2:31][CH2:32][C@H:33]1[O:38][B:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]1.C(O)(=O)C(C)(C)C>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]([CH2:31][CH2:32][C@H:33]3[O:38][B:37]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OB(c2ccccc2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Temperature: 22.5 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
To a nitrogen-filled flask, 126 g of 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione, 2.5 L of toluene, 41 ml of triethylamine, 160 g of t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-phenyl-1,3,2-dioxaborinan-4-yl)acetate and 33 ml of pivalic acid were added. The mixture was heated to reflux with stirring for 14 hours while removing water with a Dean-Stark trap. The reaction mixture was cooled slowly to 20-25° C. and washed with purified water, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, thus obtaining 194 g of the title compound as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].[CH:34]1([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[CH2:38][CH2:37][CH2:36][CH2:35]1.[I-].[Na+].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:42][C@H:41]([C:40]([O:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)=[O:47])[CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(OCCCCCCl)cc1F
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC1CCCC1
Temperature: 90 °C
Yield: 52 %

Procedure:
From Intermediate 4G. To a solution of 6-Amino-1-{4-[(5-chloropentyl)oxy]-2,6-difluorophenyl}-5-(2,4-difluorobenzoyl)pyridin-2(1H)-one (138 mg, 0.29 mmol) in anhydrous DMF (3 ml) under an atmosphere of nitrogen was added cyclopentyl L-leucinate (Intermediate 8) (284 mg, 1.43 mmol, 5 eq), sodium iodide (86 mg, 0.57 mmol, 2 eq) and N,N-diisopropylethylamine (0.052 ml, 0.29 mmol, 1 eq). The mixture was heated at 90° C. for 16 hours, before being allowed to cool to room temperature and diluted with EtOAc (25 ml). The solution was washed with water (2×25 ml) and brine (25 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (3-4% MeOH in DCM) followed by preparative HPLC afforded the title compound as a cream coloured solid (96 mg, 52% yield).
Reaction SMILES: Br[C:2]1[C:3]([Cl:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1[Cl:8].[OH-:14].[Na+].[CH3:16][O-].[Na+]>CO>[Cl:13][C:3]1[C:2]([O:14][CH3:16])=[C:7]([Cl:8])[C:6]([F:9])=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)c(Br)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COc1c(Cl)c(F)cc([N+](=O)[O-])c1Cl
Yield: 728.6 %

Procedure:
120 g of 3-bromo-2,4-dichloro-5-fluoronitrobenzene (0.415 mol), 1.66 g of NaOH (0.042 mol) and 26.9 g of sodium methoxide (0.498 mol) in 500 ml of methanol were stirred at 60° C. for 4 hours. The reactant was extracted with ethyl ether, washed successively with water, dilute hydrochloric acid solution, and water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from ethanol to give 73.5 g of 2,4-dichloro-5-fluoro-3-methoxynitrobenzene (0.306 mol) in 73.8% yield.
Reaction SMILES: [CH2:1]1COCC1.[C:6]1([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].CI>O>[CH3:1][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c(-c2ccccc2)cc2ccccc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
A solution of dry THF containing 2-phenylindole (1 mmole) was added NaH (1.1 mmole) and MeI (1.2 mmole, dropwise), and the reaction mixture was stirred at 65° C. for 3 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ether. The extracts was dried (MgSO4) and evaporated under reduced pressure to give yellow-orange solid. Further purification by column chromatography on silica gel with hexane as an eluent gave a pale yellow solid of 1-methyl-2-phenylindole (79% yield). The solid product (0.7 mmole) was dissolved in DMF (10 ml), a mixture of POCl3(0.09 mmole) and DMF (0.09 mmole) was added dropwise. After stirring at 75° C. for 1 h, the reaction mixture was added into saturate NaHCO3solution. The precipitated solid was collected by filtration and washed with ethanol to give a pale gray solid of 1-methyl-2-phenylindole-3-carboxaldehyde (85% yield). A dry DMF solution of the aldehyde (2 mmole) was added o-aminothiophenol (2.1 mmole) and Ac2O (0.5 ml) at room temperature. The mixture was stirred at 60° C. for 3 h. The reaction mixture was poured into stirred water and the precipitated solid was collected by filtration. The crude solid was washed with MeOH and recrystallized from benzene to afford compound 1-2 (38% yield). 1H-NMR (CDCl3, TMS) δ(ppm)=3.6 (s, 3H, —CH3), 7.3-7.8, 8.1, 8.9 (m, d, m, 13H, aromatic H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[H][H].C>C(O)(=O)C.[Pt]=O.C(OCC)(=O)C>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: O=C1CCCCC1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNc2ccccc2NC1=O
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of 50 g of (R)-(+)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine as described in WO98/25911 in 43.3 g of acetic acid were added 70.8 g of cyclohexanone and 1.5 g of platinum oxide. The resulting mixture was stirred at room temperature for 5 hours under pressure of 3 to 3.5 kg/cm2 in a hydrogen gas atmosphere. To the reaction mixture were added 200 ml of ethyl acetate and 5 g of active charcoal, followed by stirring for further 1 hour at room temperature. The reaction mixture was filtered. A 2N aqueous solution of sodium hydroxide was added dropwise to the filtrate to neutralize the same under stirring and then, it was separated into layers. The organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To the residue were added 200 ml of ethanol and 200 ml of water. The mixture was stirred at 50° C. for 1 hour and then for 2 hours under ice cooling. Crystals so precipitated were collected by filtration with suction, washed with a mixed solvent of ethanol and water (1:1) and then dried to obtain 59.3 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Mn]([O-])(=O)(=O)=[O:10].[K+].[OH2:15]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=[O:15])[N:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: Cc1cccc(Br)n1
Agent: [K+]
Product: O=C(O)c1cccc(Br)n1

Procedure:
To deionized water (75 mL) was added 2-bromo-6-methylpyridine (5.0 g) and potassium permanganate (4.74 g). After refluxing for 1 h another portion of potassium permanganate (4.74 g) in deionzied water (75 mL) was added. The mixture was heated at reflux for an additional 5 h and filtered through ceiite. The filtrate was acidified with 6 N hydrochloric acid and the product precipitated as a white solid. The solid was collected by suction filtration and the filtrate was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated to yield more title product (total 2.65 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCOCC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)CCO[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(CCO[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 1 h

Procedure:
The product of Example 457A (2.0 g, 9.88 mmol) in anhydrous THF (50ml) under at 0 C under nitrogen was reacted with phenylmagnesium bromide as a 3.0M solution in ether (5.0 ml, 15 mmol) dropwise via syringe then stirred for one hour. The reaction was quenched by the drop wise addition of a saturated solution of ammonium chloride and the reaction was partitioned with ether and water. The combined organics were dried over magnesium sulfate and concentrated in vacuo to give the desired compound as a clear oil (2.71 g, quantitative).
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:36]=[CH:35][C:16]([C:17]([N:19]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[S:26][CH:27]=[C:28](/[CH:30]=[CH:31]/[C:32](O)=[O:33])[N:29]=3)[CH2:20]2)=[O:18])=[CH:15][CH:14]=1.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][NH2:44].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[S:26][CH:27]=[C:28](/[CH:30]=[CH:31]/[C:32]([NH:44][O:43][CH:38]4[CH2:39][CH2:40][CH2:41][CH2:42][O:37]4)=[O:33])[N:29]=3)[CH2:20]2)=[O:18])=[CH:35][CH:36]=1
Reactant: O=C(O)/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
EDCI (0.30 g) was added to the solution of (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylic acid (0.6 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.22 g), and HOBT (0.26 g) in DMF (10 ml) under ice-cooling and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.66 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:18])[NH:4][C:3]1=[O:19]>CO.CC#N.C(NCC)C>[CH3:1][N:2]1[C@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:18])[NH:4][C:3]1=[O:19]
Reactant: CN1C(=O)NC(=O)C12Cc1ccc([N+](=O)[O-])cc1C2
Solvent: CO
Solvent: CC#N
Solvent: CCNCC
Product: CN1C(=O)NC(=O)[C@]12Cc1ccc([N+](=O)[O-])cc1C2

Procedure:
(±)-3-Methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (described in Intermediate 7) was dissolved in a mixture of MeOH, CH3CN and diethylamine and the enantiomers were resolved by HPLC, utilizing a Chiralpak AD column and eluting with CH3CN:MeOH—90:10. The first major peak to elute was (S)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione and the second major peak to elute was (R)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione, the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Br[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([NH:4][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)[N:7]=1)[CH:2]=[CH2:3]
Reactant: FC(F)(F)c1ccc(-c2cccc(Br)n2)cc1
Reactant: C=CCN
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: C=CCNc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of of allylamine (0.447 mL, 5.96 mmol) and 2-bromo-6-[4-(trifluoromethyl)phenyl]pyridine (0.1 g, 0.298 mmol) in ethanol (5 mL) were heated at 100° C. in a 25 mL pressure vessel. After heating overnight the reaction was cooled and copper sulfate was added and heating continued at 100° C. overnight. After this time the reaction was allowed to coole to room temperature and concentrated in vacuo. Purification by SPE (Silica, 10 g) eluting 3:1 cyclohexane:chloroform afforded the title compound as a dark yellow solid (0.062 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:24])[CH:19]=[C:20]([CH3:23])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[ClH:12].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[C:18]([CH3:24])[CH:19]=[C:20]([CH3:23])[CH:21]=3)[N:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Cc1cc(C)c2nccc(Cl)c2c1
Product: Cc1ccc2[nH]c(C)c(-c3ccnc4c(C)cc(C)cc34)c2c1
Product: Cl

Procedure:
The sub-title compound was prepared by the method of Example 15 step a) using 2,5-dimethylindole and 4-chloro-6,8-dimethylquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:10][C:11](=[O:12])[CH:13]=[CH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH3:5])[CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C=O)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C=CC(=O)C=Cc2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
3-Methylbenzaldehyde (1ab, 3.00 ml, 25.4 mmol) and acetone (19, 0.94 ml, 12.7 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.50 g, 37.5 mmol) and water (20 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 2.39 g (72%) of a yellow solid: mp 68-72° C. [expected mp 68-72° C.]; 1H NMR: δ 2.38 (s, 6H), 7.06 (d, 2H, J=15.9 Hz), 7.26 (m, 4H), 7.40 (m, 4H), 7.70 (d, 2H, J=15.9 Hz); 13C NMR: δ 21.3, 125.1, 125.4, 128.6, 128.8, 131.1, 134.6, 138.4, 143.1, 188.6.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[C:13]=2[O:20][CH3:21])[N:4]=1)[CH3:2].CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:25][CH3:24])[C:13]=2[O:20][CH3:21])[N:4]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCc1ccc(C#N)c(Oc2cccc(C=O)c2OC)n1
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(C#N)c(Oc2cccc(CNC)c2OC)n1
Yield: 62.7 %

Procedure:
6-Ethyl-2-(3-formyl-2-methoxy-phenoxy)-nicotinonitrile (0.28 g, 1.0 mmol), methylamine (33% in ethanol, 0.8 mL, 6.4 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (60 mL) for 16 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 6-ethyl-2-(2-methoxy-3-methylaminomethyl-phenoxy)-nicotinonitrile difumarate (166 mg, 32%) as a beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[C:5]([CH3:18])[CH:4]=1)#[N:2].[CH3:19][N:20]([CH3:35])[CH2:21][CH2:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][C:25]=1[O:33][CH3:34].C(C1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1C)(=O)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:30]3[C:31]4[C:27](=[CH:26][C:25]([O:33][CH3:34])=[C:24]([O:23][CH2:22][CH2:21][N:20]([CH3:19])[CH3:35])[CH:32]=4)[CH:28]=[CH:29]3)=[O:17])=[CH:13][CH:14]=2)=[C:5]([CH3:18])[CH:4]=1)#[N:2]
Reactant: COc1cc2cc[nH]c2cc1OCCN(C)C
Reactant: Cc1cc(C#N)ccc1-c1ccc(C(=O)O)cc1
Agent: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1C
Product: COc1cc2ccn(C(=O)c3ccc(-c4ccc(C#N)cc4C)cc3)c2cc1OCCN(C)C

Procedure:
The title compound was prepared from 4'-cyano-2'-methylbiphenyl-4-carboxylic acid (D15) and 6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (D13) using a similar procedure to Example 4 as a white solid mp 140°-142° C. (42%).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:35]>CN(C)C=O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:35])[CH:14]=[C:13]3[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
A solution of methyl 4-[5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]-3-methoxybenzoate (C) (1.52 g) in N,N-dimethylformamide (5 ml) was added to a slurry of sodium hydride (0.088 g) in N,N-dimethylformamide (3 ml) at 0° C. The mixture was stirred under a nitrogen atmosphere for 20 minutes at 0° C. and for 15 minutes at 25°0 C. The reaction was cooled to 0° C., treated with a cold solution of iodomethane (0.57 g) in N,N-dimethylformamide (2 ml), and then allowed to warm to 25°. The mixture was recooled to 0°, quenched with saturated aqueous ammonium chloride, and evaporated. The residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The amber residue was purified by flash chromatography on silica gel (500 ml), eluting with 1:9 v/v ethyl acetate:chloroform, to yield the title compound (0.86 g, 55%) as a white foam; partial NMR (80 MHz, CDCl 3): 3.4(dd, 2H, CH2N), 3.73(s, 3H, NCH3), 3.89(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.12(s, 2H, ArCH2), 6.11(t, 1H, NH), 6.8(s, 1H, H2 -indole), 8.00(br s, 1H, H4 -indole).