Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:42]([CH:39]2[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]2)=[O:43])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (74) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (30%→50% ethyl acetate in hexanes) affording the desired product (75) as a solid. ESMS: MH+ 590.6
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[I-].[K+].Cl[CH2:14][CH:15]([OH:17])[CH3:16]>O1CCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH:15]([OH:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(O)CCl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(O)COc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3.87 g of p-chlorophenol in 30 ml of tetrahydrofuran is added 1.2 g of sodium hydride (60% dispersion in oil). After one hour, 4.98 g of potassium iodide and 2.54 ml of 1-chloro-2-propanol in 10 ml of tetrahydrofuran is added. The mixture is heated at 80° C. for 18 hours. The mixture is chilled, poured into 300 ml of ice-water containing 3 ml of acetic acid. The mixture is extracted with dichloromethane and the extract washed with saturated sodium bicarbonate and sodium chloride solution. Drying (MgSO4) and removal of the solvent under reduced pressure gives 5.1 g of product as an oil.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]=1.Cl[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26].O>CN(C)C=O>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:13][CH:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4](=[O:3])[N:5]2[C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ncccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ncccc3n2)CC1
Temperature: 13 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A suspension of sodium hydride (50% dispersion in mineral oil) (1.46 g.) in anhydrous dimethylformamide (80 cc.) is added to a suspension of 3-hydroxy-2-(1,5-naphthyridin-2-yl)isoindolin-1-one (7 g.) in anhydrous dimethylformamide (410 cc.). When the evolution of gas has ceased, a solution of 1-chlorocarbonyl-4-methyl-piperazine (4.6 g.) in anhydrous dimethylformamide (25 cc.) is added dropwise. After stirring for 4 hours, the reaction mixture is poured into water (3,000 cc.) cooled to 13° C. The precipitate is filtered off, washed with water (75 cc.) and then dried to yield 3-(4-methylpiperazin-1-yl)carbonyloxy-2-(1,5-naphthyridin-2-yl) isoindolin-1-one (5.7 g.) melting at 170°-171° C. After recrystallisation from acetonitrile (50 cc.), the products melts at 173° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[C:29]1([C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[ClH:74]>CN(C=O)C.C(O)C.CC(O)C.O>[ClH:74].[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:36](=[O:37])[C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([CH3:40])[CH3:39])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCc3cccnc3)ccc21
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)C(C)(C)c3ccccc3)ccc21
Temperature: 40 °C
Reaction time: 10 h

Procedure:
To a solution of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.5 g), 2-Phenylisobutyric acid (0.24 g), and diisopropylethylamine (0.23 ml) in DMF (10 ml), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.50 g) was added and stirred at 40° C. for 10 hours. Water was added to the reaction mixture, and stirred for 1 hour, and, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.35 g) as a white amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14]([CH3:16])=O)[C:12]=2[OH:13])=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH:18]=1>CS(C)=O>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:14]([C:11]3[C:12]([OH:13])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)[S:9][CH:10]=3)[CH3:16])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH:18]=1
Reactant: CC(=O)c1csc(-c2ccc(Br)cc2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCc2cccnc2)s1
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2cccnc2)s1)c1csc(-c2ccc(Br)cc2)c1O
Temperature: 110 °C
Yield: 81 %

Procedure:
2-(4-Bromophenyl)-3-hydroxy-4-methylcarbonylthiophene (50.5 mg, 0.17 mmol) (synthesized in accordance with WO2004/108683) and 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-picolylamide prepared in Reference Synthetic Example 11 were dissolved in dimethylsulfoxide (4.0 mL) and heated at 110° C. for 24 hours. The solvent was evaporated, and the residue was washed with methanol and water to give the desired product (yield 81%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[CH2:19][CH2:18][C@H:17]3[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][C@@H:16]23)[CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([N:15]2[CH2:19][CH2:18][C@H:17]3[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][C@@H:16]23)[CH:12]=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCN(c3cncc(OCc4ccccc4)c3)[C@@H]2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCN(c3cncc(O)c3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The product of Example 82A (1.27 g, 3.21 mmol) in methanol (25 mL) was treated with ammonium formate (2.00 g, 30.2 mmol) and 10% Pd/C (0.27 g, wet). The mixture was warmed to reflux and allowed to stir for 20 hours. The reaction mixture was then allowed to cool to ambient temperature, filtered through Celite and the filtrate was concentrated under reduced pressure to provide the crude title compound which was taken on directly to the next step without further purification. MS (DCI/NH3) m/z 306 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COCC(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COCC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (34.2 mg, 0.059 mmol) and triethylamine (0.025 mL, 0.178 mmol) in DCM (0.5 mL) was added methoxyacetyl chloride (10.8 μL, 0.119 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (19.0 mg, 54.4%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.18 (d, J=6.6 Hz, 6H), 1.83-1.93 (m, 2H), 2.03-2.11 (m, 2H), 2.63 (t, J=5.8 Hz, 0.9H), 2.72 (t, J=5.3 Hz, 1.1H), 2.84-2.93 (m, 2H), 3.22-3.36 (m, 5H), 3.66 (t, J=5.8 Hz, 1.1H), 3.74 (t, J=6.1 Hz, 0.9H), 4.10-4.16 (m, 1H), 4.17 (br s, 0.9H), 4.19 (s, 1.1H), 4.49-4.56 (m, 1H), 5.65-5.72 (m, 1H), 6.99-7.05 (m, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]+ 476.5.
Reaction SMILES: [OH:1][CH:2]1[CH2:12][N:11]2[CH:4]([CH2:5][CH:6]3[CH:10]2[CH2:9][N:8](C(OCC)=O)[CH2:7]3)[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Ba+2]>O>[OH:1][CH:2]1[CH2:12][N:11]2[CH:4]([CH2:5][CH:6]3[CH:10]2[CH2:9][NH:8][CH2:7]3)[CH2:3]1
Reactant: CCOC(=O)N1CC2CC3CC(O)CN3C2C1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Agent: [K+]
Solvent: O
Product: OC1CC2CC3CNCC3N2C1

Procedure:
8 g (33.3 mmol) of ethyl 10-hydroxy-1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate together with 21 g of Ba(OH)2 X 8H20 are refluxed overnight in 150 ml of water. The mixture is saturated with potassium carbonate, barium carbonate is filtered off with suction, and the mixture is extracted ten times using 100 ml portions of chloroform. The extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccccc1[N+](=O)[O-]
Product: O=C(O)Cc1ccccc1Nc1ccccc1[N+](=O)[O-]

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-nitroaniline to yield 2-[(2-nitrophenyl)amino]phenylacetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:14][CH2:15][CH:16]2[O:20][CH2:19][CH2:18][O:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:24]([O:23][C:21]([C:11]1([CH2:14][CH2:15][CH:16]2[O:17][CH2:18][CH2:19][O:20]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C1(CCC2OCCO2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(CCC2OCCO2)CCNCC1

Procedure:
To a solution of 4-ethoxycarbonyl-4-[2-(1,3-dioxolan-2-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester (450 mg) in chloroform (2 ml) was added trifluoroacetic acid (2 ml), and the mixture was stirred for several minutes. After completion of the reaction, the solvent was evaporated and to the obtained residue was added aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 4-[2-(1,3-dioxolan-2-yl)ethyl]piperidine-4-carboxylic acid ethyl ester. Then, in the same manner as in Example 10, Step 1, the title compound (460 mg) was obtained from sodium hydrogencarbonate (127 mg) and benzyloxycarbonyl chloride (0.22 ml).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([C:11]([CH3:13])=O)=[CH2:10]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[OH:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[CH:10][CH:9]=[C:11]2[CH3:13]
Reactant: C=CC(C)=O
Reactant: Nc1ccc(O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2ccc(O)cc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a stirred solution of 4-hydroxyaniline (1 g. 9.1 mmol.) in acetic acid (10 ml), activated silferc (1.46 g. ferric chloride 9.1 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.70 g, 10.1 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.24 g. 9.1 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 65%.
Reaction SMILES: [Br-].[CH3:2][CH:3]([CH2:24][CH3:25])[CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=O>O1CCCC1>[CH3:2][CH:3]([CH2:24][CH3:25])[CH:4]=[CH:26][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)CCCCCCCCCCCCCCC=O
Reactant: CCC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(C)C=CCCCCCCCCCCCCCCC(=O)OC
Reaction time: 0.5 h
Yield: 53 %

Procedure:
13 gm of 2-methylbutyltriphenylphosphonium bromide was pulverized and dispersed into 130 ml of anhydrous tetrahydrofuran. To this was added 23.7 ml of 1.5M butyl lithium-hexane solution under a nitrogen atmosphere and the mixture was stirred for 30 minutes. To the solution was slowly added 8.4 gm of methyl 15-formylpentadecanoate which had been dissolved in 130 ml of anhydrous tetrahydrofuran in advance. After stirring for 3 hours, the solvent was evaporated. The crude crystals thus obtained were purified by flash column chromatography (chloroform:hexane=1:1) to obtain 5.3 gm of methyl 18-methyl-16-eicosenoate (yield: 51%). The product was submitted to the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[C:39]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[C:39]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OCc2ccccc2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(OC)cc3)c2OCc2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.4 %

Procedure:
p-Methoxyaniline (0.035 g, 0.28 mmol), triethylamine (0.029 g, 0.28 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.048 g, 0.28 mmol) were added to a methylene chloride solution (5 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.060 g, 0.14 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.038 g, 0.072 mmol, 51%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH2:24])[CH2:17][CH2:16][CH2:15][C:14]2=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH:24][C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:9])[CH2:17][CH2:16][CH2:15][C:14]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Cn1cncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cncc1C(=O)NC1CCCc2c1[nH]c1ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.3 %

Procedure:
To a solution of 1-methyl-1H-imidazole-5-carboxylic acid (45 mg, 0.36 mmol) in dichloromethane (3.6 mL) was added 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (95 mg, 0.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (83 mg, 0.43 mmol), and 1-hydroxybenzotriazole (54 mg, 0.40 mmol). After 5 minutes, triethylamine (100 μL, 0.72 mmol) was added and the reaction was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, washed with water, 1 N hydrochloric acid, 1 N sodium hydroxide, brine, dried with magnesium sulfate, filtered, and concentrated. The residue was purified by preparative chromatography (10-90% acetonitrile-water (0.1% trifluoroacetic acid)) and then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and dried with magnesium sulfate to give 43 mg (36% yield) of a white solid. 1H-NMR (CDCl3): δ 9.21 (s, 1H), 7.43 (m, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.20 (d, 1H), 7.07 (dd, 1H), 6.60 (d, 1H), 5.25 (m, 1H), 3.81 (s, 3H), 2.67 (m, 2H), 2.21 (m, 1H), 1.90 (m, 3H); MS m/z 327 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O-])=[O:22])[C:9]=2[S:24][CH3:25])=[CH:4][CH:3]=1.[Li+].[N:27]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:34][N:27]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])[C:9]=2[S:24][CH3:25])=[CH:4][CH:3]=1
Reactant: NN1CCCCCC1
Reactant: CSc1c(C(=O)[O-])nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1c(C(=O)NN2CCCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 52 %

Procedure:
Compound 3 was prepared analogously as described for compound 2 hereinabove from crude lithium 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate, azepan-1-ylamine, TBTU and Et3N in DMF in 52% yield.
Reaction SMILES: [OH:1][C@H:2]1[CH2:36][N:5]2[C:6](=[O:35])[C@@H:7]([NH:26][C:27]([C:29]3[CH:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH:15]3[CH2:20][C@@:16]3([C:21]([O:23]CC)=[O:22])[NH:17][C:18](=[O:19])[C@@H:4]2[CH2:3]1.[Li+].[OH-]>C1COCC1.CO.ClCCl>[OH:1][C@H:2]1[CH2:36][N:5]2[C:6](=[O:35])[C@@H:7]([NH:26][C:27]([C:29]3[CH:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH:15]3[CH2:20][C@@:16]3([C:21]([OH:23])=[O:22])[NH:17][C:18](=[O:19])[C@@H:4]2[CH2:3]1
Reactant: CCOC(=O)[C@@]12CC1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12CC1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: Cc1cc(C(=O)N[C@H]2CCCCC/C=C\C3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](O)CN3C2=O)no1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@H]2CCCCCC=CC3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](O)CN3C2=O)no1
Temperature: 10 °C
Reaction time: 22 h

Procedure:
To a solution of (2R,6S,14aR,16aS,Z)-ethyl 2-hydroxy-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate in THF (62.5 grams, 16% w/w, 10 g starting material) and methanol (33 mL) at 0° C. was added 10% aq. LiOH (14.3 g, 3 equiv) keeping the temperature below 10° C. The solution was stirred at 10° C. for 22 h, then diluted with dichloromethane (150 mL). The reaction mixture was extracted with 1N HCl (100 mL) followed by water (100 mL). The solvent was changed to acetonitrile by distillation. The final acetonitrile level was approximately 70 mL. The slurry in acetonitrile was heated to 50° C. for 4 h, then allowed to cool to ambient temperature for 12 h. The slurry was filtered and the cake was washed with acetonitrile (20 mL) then dried in a vacuum at 50° C. (8.5 g, 86% pure, 77% yield of the title compound).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][C:7]2=[O:17])([O-])=O>CO.[Ni].Cl>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][C:7]2=[O:17]
Reactant: O=C1CC2(CCCC2)c2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)CC21CCCC1
Yield: 93.4 %

Procedure:
A solution of 5'-nitro-spiro(cyclopentane-1,1'-indan)-3'-one (23.1 g; 0.1 mole) in methanol (250 ml) is hydrogenated in a shaking autoclave at about 4 atg with a Raney-nickel catalyst at 40°-60° C. The mixture is chilled, the catalyst filtered off and washed with methanol, after which the filtrate is evaporated to dryness. A light yellow powder is obtained (19.5 g; yield 97%). Said powder is dissolved in 2 N hydrochloric acid and extracted with ether, and then the aqueous phase is neutralized with 2 N sodium hydroxid solution. The precipitate is filtered off, washed with water and dried, and 18.8 g of a yellow-white crystal powder is obtained. A sample is recrystallized twice from benzene and then melts at 125° C.