Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]([OH:20])=O)[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:21][CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[CH2:29][CH2:30][CH3:31].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]([NH:21][CH2:22][C:23]3[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=3[CH2:29][CH2:30][CH3:31])=[O:20])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:15])([CH3:17])[CH3:16])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1nn(C(C)(C)C)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-cyclopropyl-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (53 mg, 0.194 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (71.3 mg, 0.242 mmol), 1-hydroxy-7-azabenzotriazole (52.8 mg, 0.388 mmol), EDC (74.3 mg, 0.388 mmol) and N-methylmorpholine (0.085 mL, 0.776 mmol) were suspended in Dimethyl Sulfoxide (DMSO) (10 mL) and stirred at room temperature for 16 hours. Added 25 mL of water and stirred for 10 minutes. The contents were filtered and dried, and collected as 70 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3 H), 0.96-1.09 (m, 4 H), 1.54 (m, J=7.52, 7.52, 7.52, 7.52, 7.33 Hz, 2 H), 1.68 (s, 9 H), 2.12 (s, 2 H), 2.17-2.27 (m, 1 H), 2.33 (s, 3 H), 2.5(2 H), 4.34 (d, J=5.05 Hz, 2 H), 5.89 (s, 1H), 7.01 (s, 1 H), 8.54 (t, J=4.80 Hz, 1 H), 11.50 (s, 1 H). LCMS(ES) [M+H]+ 436.1.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)=[CH:20][CH:21]=2)=[CH:26][CH:27]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A mixture of N-phenylnaphthalen-1-amine (4.41 g, 20 mmol), 4,4′-dibromo-1,1′-biphenyl (15 g, 48 mmol), sodium tert-butoxide (NaOBut) (4.8 g, 50 mmol) and Pd(dppf)Cl2 (0.44 g, 0.6 mmol) in anhydrous toluene (100 mL) was degassed and heated at 80° C. for about 10 hours. After cooling to RT, the mixture was poured into dichloromethane (400 mL) and stirred for about 30 min., then washed with brine (100 mL). The organic solution was collected and dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes to hexanes/ethyl acetate 90:1) to give a solid which was washed with methanol and dried under air to give a white solid Compound 4 (5.58 g, in 62% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[CH2:10]1.[OH:20][C:21]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:22]=1>>[C:21]([O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH2:10][C:11]2=[O:19])(=[O:20])[CH3:22]
Reactant: O=C1CC(c2ccc(F)cc2F)c2ccc(O)cc21
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccc(F)cc1F
Yield: 90 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(2,4-difluorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one to obtain the title compound (90%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:34])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[O:26][C:25]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=O)=[CH:24][CH:23]=2)=[CH:4][C:3]=1[Cl:35].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1C=CC=CC=1.CCOCC>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[O:26][C:25]([CH2:27][N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[CH:24][CH:23]=2)[OH:34])=[CH:4][C:3]=1[Cl:35]
Reactant: CCN(CC)C(=O)c1ccc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCN(CC)Cc1ccc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)o1
Yield: 73 %

Procedure:
A solution of 5-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]-N,N-diethyl-2-furancarboxamide (0.83 g) in benzene (6 ml) was added dropwise over 10 min to a stirred suspension of lithium aluminium hydride (175 mg) in dry ether (15 ml) under nitrogen. The mixture was stirred under nitrogen at 22° for 24h, then quenched sequentially with water (1 ml), 2N sodium hydroxide solution (1 ml) and water (2 ml). The mixture was filtered through hyflo and the solids washed with toluene-ether (1:1, 10 ml). The combined filtrate and washings were dried and evaporated in vacuo to an oil. Purification by FCC eluting with System C (93:5:2) afforded the title compound as a pale yellow oil (0.59 g), t.l.c. (System A 39:10:1) Rf 0.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[Br-].[CH2:13]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:14][CH3:15].C([Li])CCC.CCCCCC>>[CH2:7]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=1)[CH:13]=[CH:14][CH3:15]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC=CCc1cccc([N+](=O)[O-])c1
Yield: 96.7 %

Procedure:
Treatment of 3-nitrobenzaldehyde (8.2 g) with propyltriphenyl phosphonium bromide (25 g) and n-butyllithium in hexane (64.9 mmol), as described in Example 1a, gave 3-(2-butenyl)nitrobenzene (9.3 g), δ (360 MHz, CDCl3) 1.1 (3H, t, CH3), 2.4 (2H, m, CH2CH3). 5.8 (1H, m, =CH--CH2), 6.3 (1H, m, CH=CH2), 7.2 to 8.0 (4H, m, ArH). Treatment of the above 3-(2-butenyl)nitrobenzene (9.3 g) with hydrogen and palladium on carbon (10%, 0.93 g) as described in Example 1a, gave 3-butylaniline (7.0 g), δ (60 MHz, CDCl2) 0.9 (3H, t, CH3), 1.4 (4H, m, CH2CH2CH3), 2.5 (2H, t, ARCH2), 3.4 (2H, bs, NH2 ) and 6.2 to 7.0 (4H, m, ArH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]([O:14][CH2:15][CH3:16])=[S:13])[N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[O:20]>C(#N)C>[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]([O:14][CH2:15][CH3:16])=[S:13])[N:3]=1)=[O:32])(=[O:28])=[O:29])=[O:20]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CCOC(=S)SCc1cc(OC)nc(N)n1
Solvent: CC#N
Product: CCOC(=S)SCc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)n1

Procedure:
7.0 g of 2-amino-4-methoxy-6-ethoxythiocarbonylthiomethyl-pyrimidine and 6.5 g of 2-methoxycarbonylphenylsulfonylisocyanate are suspended in 20 ml of abs. acetonitrile, and the suspension is stirred at 20° to 26° C. for 2 hours. A clear solution is firstly formed during this time, and the final product subsequently crystallises out. To isolate the final product, the reaction mixture is cooled to 0° C. and then filtered. The yield is 9.0 g (67% of theory) of N-(2-methoxycarbonylphenyl-sulfonyl)-N'-(4-methoxy-6-ethoxythiocarbonylthiomethyl-pyrimidin-2-yl)-urea, m.p. 160°-162° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:43]>ClCCl.C(#N)C>[ClH:43].[ClH:43].[F:41][C:2]([F:1])([F:42])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COCCOc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: COCCOc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.20 g, 0.33 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5-6M in 2-propanol; 8.3 mL, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the solid obtained was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid formed was collected by vacuum filtration to give the title compound (0.17 g, 91%). LCMS APCI (+) m/z 487 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O.CCCCCC.C(O)(C)C>CC(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:21])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: CC(C)=O
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCCCCC
Product: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 10 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A stirred solution of (9RS,10RS)-2-chloro-9,10-dihydro-9,10-methanoanthracene-9-carboxaldehyde prepared as in Example 1i (290.5 g, 1.14 moles) dissolved in acetone (5.0 L) was cooled to 10° C. and treated with Jones Reagent (950 ml, ~ 1.19 moles) over a period of 1 h. The reaction mixture was stirred overnight at room temperature, then analyzed by TLC [silica gel/methylene chloride:hexane (1:1)]. Conversion of the aldehyde (Rf =0.50) to the desired carboxylic acid (Rf =0.0-0.15) was shown to be complete. Isopropanol (150 ml) was added, and the mixture stirred for another 3 h to quench any excess Jones Reagent. The acetone supernatant was decanted away from the green-black sludge that had formed, and the sludge was washed with acetone (2×1 L). The combined acetone solutions were concentrated on the rotary evaporator to a volume of 1.5 L, then poured into ice/water (6 L) with vigorous stirring. A yellow-white gum precipitated and gradually solidified with continued stirring. The solid was collected by filtration, pulverized to a fine off-white powder in a mortar & pestle, then rewashed with cold water (2×1 L). Vacuum drying afforded the title compound as an off-white powder (304.8 g, 98.7%), mp 175°-178° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[C:8]1([C:14]#[CH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1COCC1>[C:8]1([C:14]2[N:1]([CH2:4][CH2:5][CH2:6][OH:7])[N:2]=[N:3][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#Cc1ccccc1
Reactant: [N-]=[N+]=NCCCO
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OCCCn1nncc1-c1ccccc1
Yield: 82 %

Procedure:
3-Azidopropanol (101 mg, 1 mmol), phenylacetylene (113 mg, 1.1 mmol), Cp*RuCl(PPh3)2 (8 mg, 0.01 mmol, 1 mol %). Solvent: THF, 10 mL, 60° C., 2 hours. White microcrystalline product was obtained in 82% yield (167 mg). ESI-MS: m/z 204, [M+H].
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[S:17]([O:3][CH2:4][C@@H:5]([OH:6])[CH2:7][OH:8])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CO)cc1
Yield: 67.8 %

Procedure:
8.6 g of (R)-glycerol acetonide [bp.: 88°-106° C. (18 mmHg); specific rotation: [α]D25 -12.10° (c 5.64, methanol)] was dissolved in 70 ml of chloroform, and 10.0 g of triethylamine was added. With stirring and ice cooling, a solution of 13.8 g of tosyl chloride in 30 ml of chloroform was added dropwise, and the mixture was stirred overnight. The reaction mixture was washed with an aqueous solution of potassium hydrogen carbonate and water, and the solvent was evaporated. The residue (18.7 g) was dissolved in 75 ml of acetone, and 225 ml of 1N hydrochloric acid was added. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was concentrated and extracted with 450 ml of ethyl acetate. The extract was washed with water, and the solvent was evaporated. The residue was purified by silica gel column chromatography [solvent: chloroform-methanol (40:1)] to give 10.86 g (yield 67.8%) of (S)-3-tosyloxy-1,2-propanediol as colorless needles having a melting point of 57° to 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[Cl:13].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:18][C:19]1[C:20]([OH:34])=[C:21]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:22]=[CH:23][C:24]=1[OH:25].Cl>C(OCC)(=O)C.ClCCCl>[Cl:13][C:12]1[C:2]([Cl:1])=[CH:3][C:4]([C:9]([OH:8])=[O:10])=[C:5]([C:6]([C:23]2[CH:22]=[C:21]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:20]([OH:34])=[C:19]([Cl:18])[C:24]=2[OH:25])=[O:7])[CH:11]=1
Reactant: COC(=O)CCCCc1ccc(O)c(Cl)c1O
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)CCCCc1cc(C(=O)c2cc(Cl)c(Cl)cc2C(=O)O)c(O)c(Cl)c1O
Temperature: -20 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
In a 2 L 3-neck round-bottomed flask equipped with a stir and addition funnel was added 4,5-dichlorophthalic anhydride (7.13 g, 32.9 mmol) followed by dry 1,2-dichloroethane (120 ml). After stirring for 30 minutes AlCl3 (11.4 g, 85.54 mmol) was added and the mixture was stirred for another 30 minutes. To this mixture was added via the addition funnel a solution of 5b (8.5 g, 32.9 mmol) with stirring. The solution in the flask became slightly warm and turned dark. Hydrogen chloride gas evolved for about 10 to 20 minutes. Stirring was continued overnight (15-18 hours) at room temperature. During this time, a tarry precipitate formed. To this mixture was added ice (160 g) and concentrated HCl (80 ml) followed by ethyl acetate (900 ml). The content of the flask was stirred until all the solids have completely dissolved. The mixture was transferred to a 2-liter separatory funnel. The organic layer was washed with about 300 ml of 1 N HCl, 2×200 ml of saturated NaCl and dried over sodium sulfate. The solution was filtered and evaporated to a solid, which was then triturated in 200 ml of dichloromethane for 30 minutes, and then cooled to −20° C. for at about 2 h. The crystalline precipitate was filtered off and washed with 2:1 hexanes/dichloromethane, followed by 4:1 hexanes/dichloromethane, and dried to afford 10.8 g (69%) of the desired benzophenone 14b. 1H NMR (DMSO-d6) δ: 12.44 (s, 1H), 10.3 (br s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 6.88 (s, 1H), 3.55 (s, 3H), 2.44 (t, J=6.8 Hz, 2H), 2.25 (t, J=6.9 Hz, 2H), 1.40 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](N)[CH:10](C)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[CH3:17].Cl>[Pd].O>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:9][N:8]([CH2:16][CH3:17])[CH2:1][CH3:2])[CH2:10][C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1C(=O)N(Cc2ccccc2)CC1N
Reactant: CC=O
Agent: [Pd]
Agent: Cl
Solvent: O
Product: CCN(CC)CC1CC(=O)N(Cc2ccccc2)C1

Procedure:
A mixture of 11.5 g (0.056 mol) of (-)-1-benzyl-4-amino-methyl-pyrrolidin-2-one, 130 ml of water, 13 g of acetaldehyde, 5.8 ml of concentrated hydrochloric acid and 6.5 g of 20% palladium-on-charcoal was hydrogenated for 51/4 hours at 5 bar and at 25° C. The reaction mixture was filtered, the filtrate was evaporated, the residue was taken up in 30 ml of water, and the solution was extracted with methylene chloride. The aqueous hydrochloric acid solution was made alkaline and then extracted with methylene chloride. By distillation of the combined extracts in a bulbed tube, 11.2 g (76.4% of theory) of the title compound were obtained, αD =-9.4 (c =1.0; :ethanol).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([C@H:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[O:32][CH2:33][CH2:34][NH:35][C:36](=[O:39])[O:37][CH3:38])[CH2:26]2)=[O:24])[CH2:9][N:10](C)[C:11](OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:7][C@H:8]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([C@H:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[O:32][CH2:33][CH2:34][NH:35][C:36](=[O:39])[O:37][CH3:38])[CH2:26]2)=[O:24])[CH2:9][NH:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)NCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2ccccc2)C1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A 100 mL flask was charged with methyl 2-((R)—((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(benzyloxycarbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)(phenyl)methoxy)ethylcarbamate (230 mg, 0.35 mmol) and Pd(OH)2 (45 mg) dissolved in MeOH (35 mL) under H2 and stirred for 1 hr. After completion of the reaction, the mixture was filtered. The solution was evaporated to give the crude product (120 mg), which was purified by preparative HPLC to obtain the target molecule (50.2 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].C(N(CC)CC)C.[CH3:36][O:37][CH2:38][CH2:39]Br>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][N:22]([CH2:39][CH2:38][O:37][CH3:36])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:25][CH:26]=1
Reactant: O=C(Nc1ccc2cccc(N3CCNCC3)c2c1)c1ccc(Cl)cc1
Reactant: COCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCN1CCN(c2cccc3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1

Procedure:
A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.15 g, 0.41 mmol, product of example 12), sodium iodide (0.064 g, 0.431 mmol), triethylamine (0.164 mL, 0.431 mmol) and 2-bromoethyl methyl ether (0.040 mL, 0.431 mmol) in acetonitrile (7 mL) was refluxed overnight. The reaction was cooled and concentrated at reduced pressure. The residue was taken up in methylene chloride and washed with 1N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×2.5 inches). Elution proceeded as follows: 50% ethyl acetate hexane (100 mL) and 75% ethyl acetate/hexane (100 mL), nil; 75% ethyl acetate/hexane (100 mL) and ethyl acetate (150 mL), 0.121 g (69%) of 7-(4-chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene as an oil. This oil was converted to the HCl salt from an ether solution. An amorphous white powder hydrochloride salt of the title compound was obtained. mp 134°-148° C. 1H NMR δ 8.54 (br s, 1 H), 8.05 (br s, 1 H), 7.84 (long range coupled t, J=9 Hz, 3 H), 7.66 (dd, J -2, 9 Hz, 1 H), 7.55-7.43 (m, 3 H), 7.36 (t, J=8 Hz, 1 H), 7.11 (dd, J=1, 7.5 Hz, 1 H), 3.57 (t, J=5.5 Hz, 2H), 3.38 (s, 3 H), 3.19 (br s, 4 H), 2.83 (br s, 4 H), 2.70 (t, J=5.5 Hz, 2 H). Analysis calculated for C24H26ClN3O2 ·2HCl·1.5H2O: C, 55.02; H, 5.96; N, 8.02. Found: C, 55.53; H, 6.31; N, 7.78.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[N:20]=[CH:21][NH:22][CH:23]=4)[C:11]3=[O:24])[CH2:9]2)=[CH:4][CH:3]=1.C[O:26][C:27](=[O:30])[CH2:28]Br.[OH-].[K+]>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[N:20]=[CH:21][N:22]([CH2:28][C:27]([OH:30])=[O:26])[CH:23]=4)[C:11]3=[O:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1N(c2c[nH]cn2)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(O)Cn1cnc(N2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.7 %

Procedure:
To a mixture of racemic (1S,2R) and (1S,2R)-2-(4-chlorophenyl)-1′-(1 H-imidazol-4-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (0.4 mmol, 134 mg), methyl-bromoacetate (61.2 mg, 0.4 mmol) and 5 mg of TEBA (0.008 mmol) in 2 mL of DCM was added 50% KOH (0.5 mL). The reaction mixture was stirred at room temperature for 14 hours. Then the mixture was concentrated under reduced pressure and acidified to pH˜4. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as a white powder (113 mg, 68%). LC/MS m/e calcd. for C21H16ClN3O3: 393, observed (M+H)+: 394.2 1H NMR (400 MHz, DMSO-d6) δppm 2.05-2.16 (m, 1 H) 2.39 (dd, J=7.96, 4.93 Hz, 1 H) 3.20 (t, J=8.72 Hz, 1 H) 4.97 (s, 2 H) 6.18 (d, J=7.07 Hz, 1 H) 6.79 (t, J=7.20 Hz, 1 H) 7.06-7.22 (m, 1 H) 7.38 (s, 4 H) 7.54 (d, J=1.01 Hz, 1 H) 7.69 (d, J=7.83 Hz, 1 H) 7.74 (d, J=1.26 Hz, 1 H). MS calcd. for C21H16ClN3O3 393, obsd. (ESI+) [(M+H)+] 394.3.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[NH2:28][C:29]1[CH:34]=[C:33]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]=1[OH:42].Cl>C(Cl)Cl.CN(C)C=O.O.CCOC(C)=O>[CH2:35]([C:33]1[CH:32]=[CH:31][C:30]([OH:42])=[C:29]([NH:28][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:2]=2[F:1])[CH:34]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Nc1cc(Cc2ccccc2)ccc1O
Reactant: O=Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(C(=O)Nc2cc(Cc3ccccc3)ccc2O)c(F)c1
Reaction time: 4 h

Procedure:
To a mixture of 2-fluoro-4-formylbenzoic acid (0.600 g, 3.57 mmol) in 15 mL DCM was added oxalyl dichloride (0.374 mL, 4.28 mmol) and N,N-dimethylformamide (0.00261 g, 0.0357 mmol) (a few drops). The mixture was allowed to stir for several h, treated with additional (COCl)2 (0.100 mL), stirred further for 1 h, concentrated in vacuo, and the semi-solid was suspended in 15 mL THF. N,N-diisopropylethylamine (0.808 mL, 4.64 mmol) was added followed by 2-amino-4-benzylphenol (0.711 g, 3.57 mmol). After 4 h, the reaction was treated with EtOAc, water, and 1N HCl. The organic layer was washed 1× brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by silica gel chromatography to give title compound as a solid. MS (ESI) m/z: Calculated: 349.1; Observed: 347.7 (M−−1).