Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[CH3:38][O:39][C:40]([CH:42]1[CH2:46][CH2:45][NH:44][CH2:43]1)=[O:41].C(N(C(C)C)C(C)C)C>CN(C=O)C>[NH2:8][C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([N:44]2[CH2:45][CH2:46][CH:42]([C:40]([O:39][CH3:38])=[O:41])[CH2:43]2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: COC(=O)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)C1
Temperature: 180 °C

Procedure:
A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-pyrazolo-[1,5-a]pyrimidin-7-amine (55 mg, 0.10 mmoL), methylpyrrolidine-3-carboxylate (52 mg, 0.30 mmoL) and EtN(iPr)2 (86 uL, 0.50 mmoL) in DMF (1.0 mL) was heated at 180° C. under microwave condition for 45 min. The mixture was purified by prep-LC to afford the title compound. LC/MS RT=3.30 min. Mass calculated for, M+H 389.17, observed 389.17.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH:4]([C:12](Cl)=[O:13])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC.C(Cl)Cl>[N+:1](=[CH:3][C:12]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13])=[N-:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: [N-]=[N+]=CC(=O)C=Cc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of diazomethane (9.66 g, 0.23 mole) in dry ether (1250 ml.) maintained at 0° to -5°, was added a suspension of the styrene-carbonyl chloride polymer (10.0 g) from Example 7(c) in methylene chloride (50 ml.) over 15 minutes. Stirring was maintained for 5 hours at 0° to -5° and then for 16 hours at room temperature. The reaction mixture was filtered and the polymer washed with ether (2 × 100 ml.) and chloroform (2 × 100 ml.) and dried in vacuo at room temperature to constant weight. The title polymer (10.76 g) was deep yellow in colour and the IR spectrum exhibited absorptions at 2100 (diazo) and 1610 (carbonyl) cm-1. The composition of the polymer was confirmed by microanalysis.
Reaction SMILES: [CH:1]1([Si:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17].[O-]CC.[Na+].C[Si](C)(C)Cl>>[C:16]([O:20][Si:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCO[Si](OCC)(OCC)C1CCCC1
Reactant: CC(C)(C)O
Agent: CC[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCO[Si](OCC)(OC(C)(C)C)C1CCCC1
Yield: 64.2 %

Procedure:
In a 500 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 29.3 g (0.129 mole) of cyclopentyl triethoxysilane, 165.9 g (2.24 mole) of tert-butyl alcohol and 2.06 g (30.3 m mole) of sodium ethoxide, which were then reacted with each other in an oil bath of 85° C. for 24 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 21.6 g (0.0828 mole) of tert-butoxy cyclopentyl diethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 64%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:14]>C(O)C.[Pt]=O>[ClH:14].[ClH:14].[N:1]1([CH2:7][CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cc(CN2CCCCC2)ccn1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: C1CCN(CC2CCNCC2)CC1
Reaction time: 15 h

Procedure:
A solution of 4-(piperidin-1-ylmethyl)pyridine (10.0 g, 0.056 mol; prepared using a similar procedure to that described in US430491) and platinum oxide (1.5 g) in 55 mL of ethanol and 18 mL of 12 N HCl was placed under an atmosphere of hydrogen (4.1 bar, 60 psig). After 15 h, the mixture was filtered, concentrated, and residue triturated with methanol affording 9.0 g of the title compound as a bis hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:30][CH:31]1[CH2:36][NH:35][CH2:34][CH:33]([CH3:37])[NH:32]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:35]4[CH2:34][C@@H:33]([CH3:37])[NH:32][C@@H:31]([CH3:30])[CH2:36]4)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CC1CNCC(C)N1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Product: C[C@@H]1CN(C(=O)c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(Cl)cc4Cl)cc2CCO3)C[C@H](C)N1

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and 2,6-dimethylpiperazine were reacted by General Procedure B to give 360. NMR: (CDCl3): 1.01-1.20 (6 H, br m, Me), 2.40-2.62 (2 H, br, m), 2.73 (2 H, s), 2.82-2.87 (1 H, br, m), 2.98-3.00 (2H, m), 3.29 (3 H, s, Me), 3.52-3.60 (1 H, br m), 4.18-4.21 (2 H, m), 4.45-4.55 (1 H, br, s, NH), 6.76 (1 H, s, Ar), 6.94 (1 H, d, J 8.3, Ar), 7.15 (1 H, dd, J 8.3 and 1.9, Ar), 7.23 (1 H, d, J 8.4, Ar), 7.28 (1 H, dd, J 8.5 and 2.2, Ar) and 7.44-7.48 (2 H, m, Ar). MS: (ESI+) MH+=544.11
Reaction SMILES: C(OC(=O)N(CCCC1C=CC=C(Br)N=1)CC=O)(C)(C)C.[C:22]([O:26][C:27](=[O:40])[CH2:28][C@H:29](N)[C:30]1[CH:31]=[N:32][CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=1)([CH3:25])([CH3:24])[CH3:23].C(O)(=O)C.CC([O-])=O.[Na+].[BH3-]C#N.[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>CC(O)C.C(OCC)(=O)C>[C:22]([O:26][C:27](=[O:40])[CH2:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOc1cncc([C@@H](N)CC(=O)OC(C)(C)C)c1
Agent: CC(=O)[O-]
Agent: CC(C)(C)OC(=O)N(CC=O)CCCc1cccc(Br)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1cncc(CCC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
A mixture of the crude aldehyde 20-8 (0.671 g,.1.88 mmol), amine 15-8 (0.651 g, 2.44 mmol), acetic acid (0.107 mL, 1.88 mmol), NaOAc (1.54 g, 18.8 mmol), and powdered molecular sieves (1.20 g) in 2-propanol (15 mL) was stirred for 20 minutes. The mixture was cooled to 0° C. and then NaBH3CN (0.354 g, 5.64 mmol) was added. After stirring 6 hours, the pH of the mixture was adjusted to ~2 with 1N HCl. The solution was stirred for an additional 10 minutes, ethyl acetate (20 mL) was added, and the pH was adjusted to ~11 with 10% potassium carbonate. The organics were extracted with ethyl acetate, dried over Na2SO4, and removed in vacuo. The residue was chromatographed (silica gel, [70:25:5 CHCl3 /EtOAc/MeOH]) to give 20-9 as a yellow oil in 95% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Br:12])=[CH:5][N:6]=[CH:7]2.[CH2:13]([CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:20](O)=[S:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[Br:12][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:20](=[S:21])[CH:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[N:6][CH:5]=1
Reactant: Nc1cccc2cncc(Br)c12
Reactant: CCCCCCCCC(CCCCCC)C(O)=S
Product: CCCCCCCCC(CCCCCC)C(=S)Nc1cccc2cncc(Br)c12

Procedure:
5-Amino-4-bromoisoquinoline (prepared according to the process described by Gordon et al., J. Het. Chem., 4, 410 (1967)) was coupled with 2-hexylthiodecanoic acid (prepared by the procedures described in Examples 1 and 3) using the procedure described in Example 25 to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.CCOC(C)=O>Cl.CCCCO>[CH:17]([NH:20][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1)([CH3:19])[CH3:18]
Reactant: CC(C)N
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2cc(NC(C)C)ncn2)cc1
Temperature: 120 °C
Yield: 73 %

Procedure:
100 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 44 mg of isopropylamine and 95 mg of DIPEA were dissolved in 1 mL of n-BuOH in a screw cap vial and the vial obtained was heated to 120° C. for 1 hour. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated off and the evaporation residue obtained was subjected to flash column chromatography (PE:EtOAc 1:1). N4-Isopropyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine was obtained in the form of a colorless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH2:33][CH3:34])[C:10]([NH:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[N:20]([CH3:29])[C:19]=3[CH:30]=[O:31])[N:15]([CH3:32])[CH2:14]1)=[O:11])[CH3:8].Cl.C(O)(=O)C(C(C(O)=O)O)O.N>C(OCC)(=O)C.O1CCCC1>[CH2:33]([N:9]([CH2:7][CH3:8])[C:10]([NH:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[N:20]([CH3:29])[C:19]=3[CH2:30][OH:31])[N:15]([CH3:32])[CH2:14]1)=[O:11])[CH3:34]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(c(C=O)n4C)C[C@H]2N(C)C1
Agent: Cl
Agent: N
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(c(CO)n4C)C[C@H]2N(C)C1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
Under argon, 320 mg (8 mmol) of lithium aluminum hydride is suspended in 20 ml of absolute, freshly distilled tetrahydrofuran. At room temperature, a solution of 1.53 g (4 mmol) of 1,1-diethyl-3(1,6-dimethyl-2-formyl-8α-ergolinyl)urea in 40 ml of freshly distilled, absolute tetrahydrofuran is added dropwise. Subsequently the mixture is stirred for 1 1/4 hours at room temperature. The batch is then cooled in an ice bath and combined with 20 ml of 1N hydrochloric acid. To this is added 20 ml of 2N tartaric acid and the batch is layered over with ethyl acetate. For neutralizing, 80 ml of 2N ammonia solution is added dropwise. The ethyl acetate phase is separated and the aqueous phase additionally extracted with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate. The concentrated crude product is chromatographed under pressure on silica gel with methylene chloride/methanol 95:5. The crude product (1.0 g) is crystallized from ethyl acetate, thus obtaining 0.72 g of 1,1-diethyl-3-(1,6-dimethyl-2-hydroxymethyl-8α-ergolinyl)urea (47% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:35])=[C:5]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[C:6]=1[C:7]([NH:9][C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[N:21][NH:22][N:23]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+:37]>CCO>[CH3:1][C:2]1[S:3][C:4]([CH3:35])=[C:5]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)[C:6]=1[C:7]([NH:9][C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[N:21][N-:22][N:23]=3)=[CH:15][CH:14]=2)[CH2:11][CH2:12]1)=[O:8].[Na+:37]
Reactant: Cc1sc(C)c(C(=O)NC2(c3ccc(-c4nn[nH]n4)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(C)c(C(=O)NC2(c3ccc(-c4nn[n-]n4)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
A suspension of 2,5-dimethyl-N-{1-[4-(2H-tetrazol-5-yl)phenyl]cyclopropyl}-4-[4-(trifluoromethyl)benzyl]thiophene-3-carboxamide from Example 14, Step 3 (150 mg, 0.301 mmol) in EtOH (3 mL), was treated with NaOH (1.0N in water, 301 μL, 0.301 mmol). The solution then obtained was concentrated to dryness. Water (20 mL) was added to the residue. The turbid solution was frozen in a bath of dry ice and acetone and lyophilized to afford the desired product as an off-white fluffy solid. MS (−APCI): m/z 496 (M−23)−.
Reaction SMILES: [C:1]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C:9]3=[C:10]1[C:5](=[CH:6][CH:7]=[CH:8]3)[CH:4]=[CH:3][CH:2]=2.P([O-])([O-])([O-])=O.[OH:21][NH3+:22].O[NH3+].O[NH3+]>O>[OH:21][N:22]=[C:14]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[CH:3][CH:2]=1)[OH:15]
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: [NH3+]O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: O=C(O)c1cccc2cccc(C(O)=NO)c12

Procedure:
1.98 g (10.0 mmol) of 1,8-naphthalenedicarboxylic anhydride and 0.985 g (5.00 mmol) of hydroxylammonium phosphate were reacted with 2 ml of water analogously to Example 7 for 6 hours at a bath temperature of 130° C. Following cooling, the pale brown reaction mixture was digested with water, and the solid was filtered off with suction and dried. The yield was 1.89 g (89%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:27])[N:6]([CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[CH:7]2[CH3:13])#[N:2].O1CCOCC1.[ClH:34]>>[ClH:34].[F:12][C:10]1[CH:11]=[C:3]([C:1]#[N:2])[C:4]2[C:5](=[O:27])[N:6]([CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:7]([CH3:13])[C:8]=2[CH:9]=1
Reactant: CC1c2cc(F)cc(C#N)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1c2cc(F)cc(C#N)c2C(=O)N1C1CCNCC1
Yield: 95 %

Procedure:
A solution of tert-butyl 4-(4-cyano-6-fluoro-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-1-carboxylate (2.7 g, 7.5 mmol) in 4M hydrochloric acid in dioxane (18 mL, 75 mmol) was stirred at 50° C. for 2 hours until HPLC analysis revealed the disappearance of the starting material. The solvent was removed under reduce pressure and the product was dissolved in diethyl ether and decanted to obtain the title compound (2.09 g, 95%) as its corresponding hydrochloride.
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[C:15]([N+:31]([O-])=O)=[CH:14][N:13]=2)=[C:7]([O:34][CH3:35])[CH:6]=1)([CH3:4])=[O:3]>C(O)C.[Pd]>[CH3:4][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH:28]([CH3:29])[CH3:30])(=[O:27])=[O:26])[C:15]([NH2:31])=[CH:14][N:13]=2)=[C:7]([O:34][CH3:35])[CH:6]=1)([CH3:1])=[O:3]
Reactant: COc1cc(P(C)(C)=O)ccc1Nc1ncc([N+](=O)[O-])c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(P(C)(C)=O)ccc1Nc1ncc(N)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-nitro-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine (461 mg, 0.89 mmol) in Ethanol was added 184 mg of 10% Pd on carbon. The reaction mixture was stirred at room temperature overnight and filtered through celite. The filtrate was concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel chromatography with 10% Methanol in DCM to yield N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4,5-triamine as a solid. MS ES+: m/z=490.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[C:12]=2[O:15][CH3:16])[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:7][C:8]2[C:13](=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[C:9]=2[O:21][CH3:22])[CH2:14]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCCCC1(C(=O)OCC)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCC(=O)O)(C(=O)O)C2
Yield: 50.2 %

Procedure:
A mixture comprised of an ethanol (4 ml) solution of ethyl 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoate (200 mg, 0.416 mmols) and an aqueous sodium hydroxide solution (3 M, 0.553 ml, 1.66 mmols) was heated under reflux for 12 hours. The reaction mixture was concentrated in vacuo, which was made acidic with 1 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to ethyl acetate only) to obtain the entitled compound (88.6 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][NH:7][C:6]=2[CH:14]=1.[N:15]([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>Cl.O.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]([NH2:15])[C:6]=2[CH:14]=1
Reactant: O=N[O-]
Reactant: CN1CCNc2cc(F)ccc2CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2ccc(F)cc2N(N)CC1
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 9-Fluoro-4-methyl-1,2,3,4,5,6-hexahydro-benzo[e][1,4]diazocine (1.9 g, 0.0096 mole approximately) in hydrochloric acid (2 N, 100 mL) cooled to 0° C. was added sodium nitrite (2.5 g, 0.036 mole) in water (20 mL). The mixture was stirred for 1 hour and treated with sodium bicarbonate and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated sodium chloride (200 mL), dried and concentrated to a light brown oil. The oil was redissolved in THF (50 mL) and added to a suspension of lithium aluminum hydride (2.5 g, 0.063 mole) in THF (100 mL) and the mixture refluxed for 3 hours. The excess hydride was destroyed at 0° C. by the cautious addition of ethyl acetate. The mixture was washed with aqueous potassium sodium tartrate (10% v/w, 150 mL) and saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Evaporation in vacuo provided 1.9 g of the title compound as a light yellow oil. This oil was used for indole formation without further purification. MS (ES) m/z 210.1 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([NH:20][CH2:21][CH2:22][NH2:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][NH:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Product: COc1ccc([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)n1
Yield: 59 %

Procedure:
Starting from 2-chloro-6-methoxy-3-nitropyridine (5.0 g; commercial) and N-Boc-ethylenediamine (4.15 mL; commercial), and proceeding in analogy to Example 17, step 17.i, the title compound was obtained as a yellow solid (4.79 g; 59% yield).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[O:20]=[C:21]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:28][CH2:27]1)[CH2:22][C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[N:56]1([C:62]2[CH:67]=[CH:66][C:65]([NH2:68])=[CH:64][CH:63]=2)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>CN(C=O)C.O>[O:20]=[C:21]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:30][CH2:31]1)[CH2:22][C:23]([NH:68][C:65]1[CH:64]=[CH:63][C:62]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:67][CH:66]=1)=[O:25]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc(N2CCCCC2)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
HOBt (43 mg, 0.31 mmol) and DIEA (150 mg, 1.1 mmol) were added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (100 mg, 0.29 mmol) in DMF. The reaction mixture was cooled to 10° C. and EDCI.HCl (111 mg, 0.58 mmol) followed by 4-piperidin-1-yl-phenylamine (61.4 mg, 0.34 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 69 mg (47%) of. LCMS: 503.22 (M+1)+, 94.4%, 1H NMR: (CDCl3): δ 9.3 (d, 1H), 7.8 (d, 1H), 7.7 (m, 2H), 7.5 (m, 3H), 7.0 (d, 2H), 4.5 (s, 1H), 4.1-3.8 (m, 2H), 3.8-3.6 (m, 3H), 3.6-3.4 (m, 3H), 3.3-3.2 (m, 2H), 3.1 (t, 4H), 1.9-1.7 (m, 7H), 1.6 (q, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([CH2:19][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[C:11]([OH:13])=[O:12])[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(Cc1cccc(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
To a solution of 10.8 g of 60% sodium hydride in 400 mL of tetrahydrofuran was added 44.7 g of methyl 4-fluorophenylacetate dropwise. Then, 50 g of 3-fluorobenzyl bromide was added dropwise. The mixture was then heated to reflux for approximately 18 hours. After this time, the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ether and 5% aqueous sodium bicarbonate, and the ether extracts were dried over magnesium sulfate and concentrated to 77.57 g of a yellow oil. The crude product was combined with 275 mL of methanol, 20 mL of 50% aqueous NaOH and 50 mL of H2O and the mixture was refluxed for about 18 hours. The reaction was then cooled to room temperature, concentrated and partitioned between water and ether. The aqueous extracts were made acidic with concentrated HCl and extracted with ether. The ether extracts were dried over MgSO4, filtered, concentrated and the crude product was triturated with hexane to afford 43.62 g of a white solid; mp 92°-94° C.