Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]CCN[C:5]1[CH:10]=[C:9]([CH3:11])N=[C:7]([CH3:12])[C:6]=1[N+]([O-])=O.C(N1CCNCC1)=O.C(N(CC)CC)C.[CH3:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[C:36]([NH:41][CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:35]=[C:34]([CH3:50])[N:33]=1.C([Cl:58])C1C=CC=CC=1>C(O)(C)C>[ClH:1].[ClH:58].[ClH:1].[CH2:12]([N:47]1[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][NH:41][C:36]2[CH:35]=[C:34]([CH3:50])[N:33]=[C:32]([CH3:31])[C:37]=2[N+:38]([O-:40])=[O:39])[CH2:49][CH2:48]1)[C:7]1[CH:6]=[CH:5][CH:10]=[CH:9][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(NCCN2CCNCC2)c([N+](=O)[O-])c(C)n1
Reactant: Cc1cc(NCCCl)c([N+](=O)[O-])c(C)n1
Agent: O=CN1CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cc(NCCN2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c(C)n1
Product: Cl
Reaction time: 2 h

Procedure:
13.3 g (0.05 mol) of 4-(2-chloroethylamino)-2,6-dimethyl-3-nitropyridine, 8.56 g (0.075 mole) of 1-formylpiperazine and 10 g (0.1 mol) of triethylamine were heated to boiling in 300 ml of isopropanol for 10 hours. The liquids were removed by distillation in vacuo, and the remaining solid residue was partitioned between dichloromethane an water by shaking. The dichloromethane phase was evaporated, and the residue was recrystallized once from isopropanol and heated to boiling in 6N hydrochloric acid for 2 hours. The solution was then adjusted to pH 7 with 10% strength sodium hydroxide solution, and the water was removed by distillation. The solid residue was purified on silica gel using dichloromethane/methanol (8:2; vol). 4.5 g (0.016 mol) [31.8% of theory] of 2,6-dimethyl-3-nitro-4-[(2-(1-piperazinyl)ethyl)amino]pyridine (melting point of the trihydrochloride 128°-129° C.) were obtained and were heated to reflux with 2.15 g (0.017 mol) of benzyl chloride and 2 g (0.02 mol) of triethylamine in 100 ml of isopropanol for 6 hours in accordance with process variant (b). The solvents were removed by distillation, and the oily residue was extracted by stirring with ethyl acetate, and the mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in ethanol, ethanolic HCl was added, nd the mixture was evaporated to dryness. The residue from evaporation was recrystallized from isopropanol/diisopropyl ether (4:1; vol.).
Reaction SMILES: [Cl:1][C:2]([F:4])=[CH2:3].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>ClCCl>[Cl:1][C:2]1([F:4])[CH2:3][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=C(F)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a suspension of tetrakis(triphenylacetate)dirhodium (3.66 g) and powdered molecule sieves (45 g) in dichloromethane (2.0 L) was added 1-chloro-1-fluoroethene (82 g, 1.02 mol) at −60° C. The reaction mixture was warmed to −35˜−40° C., ethyl 2-diazoacetate (90 g, 790 mmol) in DCM (200 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and evaporated in vacuo to yield 100 g Ethyl 2-chloro-2-fluorocyclopropanecarboxylate as yellow oil which was used directly in the next step without purification.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O>O1CCOCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][C:19]=3[C:10]=2[CH:9]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid (3.5 mL) was added to a solution of 4-chlorophenylhydrazine hydrochloride (2.0 g, 11.2 mmol) in dioxane (50 mL), and stirred for 5 min. at RT. N-methyl piperidone (0.76-1.4 equiv.) was added and the mixture was heated at 80° C. for 2 h. After reaction completion as determined by thin layer chromatography (TLC), the reaction mixture was concentrated to approximately 20 mL under reduced pressure and basified to pH 10 using a 10% aqueous KOH solution. The reaction product was extracted with EtOAc (3×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using a rotary evaporator to obtain the product (1.3 g) as a brown solid. 1H NMR (CDCl3, freebase) δ (ppm): 7.40 (s, 1H), 7.20-7.10 (d, 1H), 7.10-7.00 (d, 1H), 3.60 (s, 2H), 2.90 (s, 4H), 2.60 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[OH-].[Na+].I[CH2:18][CH:19]([OH:22])[CH2:20][OH:21].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: OCC(O)CI
Reactant: C=CCNc1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: C=CCNc1ccc(CC(=O)OCC(O)CO)cc1

Procedure:
A solution of 7.34 g. of 4-(allylamino)phenylacetic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(allylamino)phenylacetate.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C([Al](CC)CC)C.[C:20]([C:22]1[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=1)#[N:21]>ClC(Cl)C>[CH3:28][C:23]1[C:22]([C:20](=[NH:21])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1ncccc1C#N
Agent: CC[Al](CC)CC
Agent: Cl
Solvent: CC(Cl)Cl
Product: Cc1ncccc1C(=N)Nc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6.85 g, 0.040 mol) in dichloroethane (400 mL) was added triethylaluminum (1.9M solution in toluene, 32.0 mL, 60 mmol) over 15 minutes at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 3-cyano-2-methylpyridine, from step 2, in 70 mL of dichloroethane was added over 10 minutes and the mixture was stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and treated with 50 g of silica gel. The mixture was stirred for 30 minutes and filtered. The filtrate and washings were concentrated under reduced pressure and the residue was washed with ether to give 7.3 g of crude 2-methyl-N-[4-(methylsulfonyl)phenyl]-3-pyridinecarboximidamide (60%). To a mixture of the above crude amidine (7.0 g, 0.024 mol) and sodium bicarbonate (4.0 g, 0.048 mol) in isopropanol (350 mL) was added 3-bromo-1,1,1-trifluoroacetone (6.9 g, 0.036 mol) rapidly at room temperature. After heating the reaction mixture at 75–80° C. for 16 hours, the solvent was removed and the residue was partitioned between water and methylene chloride. The organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (ethyl acetate/acetone, 98:2) to give 4.02 g of pure 2-methyl-3-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine as a yellow solid (25%): mp (DSC) 237–239° C. Anal. Calc'd. for C17H16F3N3O3S: C, 51.12, H, 4.04, N, 10.52, S, 8.03. Found: C, 50.92, H, 4.12, N, 10.04, S, 7.83.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[C:12]([N+:21]([O-])=O)[CH:11]=1.O1CCCC1>O.C(O)C>[NH2:21][C:12]1[CH:11]=[C:10]([Cl:9])[CH:15]=[CH:14][C:13]=1[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20]1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-n1cccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)ccc1-n1cccc1

Procedure:
10 g of sodium hydrosulfite are added portionwise to a stirred solution of 10.0 g (0.045 mole) of 1-(4-chloro-2-nitrophenyl)pyrrole, 200 ml. of tetrahydrofuran and 100 ml. of water, and the solution is heated on a steam bath for 5 minutes. An additional 10 g of sodium hydrosulfite are added and the solution is again heated on a steam bath for 5 minutes. Then 23 g more of sodium hydrosulfite and a solution of 200 ml. of ethanol in 250 ml. of water are added and heated for 5 minutes on a steam bath. The organic solvents are distilled, leaving a suspension of a tan solid. The solid is filtered, washed with water, dried, and recrystallized from hexane to give yellow needles, m.p. 89°-90°C. of 1-(2-amino-4-chlorophenyl)pyrrole.
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[N:5]=[C:4]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1>C1COCC1>[CH:34]1([S:37]([N:12]2[C:4]3=[N:5][C:6]4[C:7](=[N:8][O:9][C:10]=4[CH3:11])[C:2]([F:1])=[C:3]3[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:13]2=[O:23])(=[O:39])=[O:38])[CH2:36][CH2:35]1
Reactant: Cc1onc2c(F)c3c(nc12)[nH]c(=O)n3-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1onc2c(F)c3c(nc12)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-fluoro-7-(2-fluoro-4-iodophenyl)-3-methyl-5H-imidazo[4,5-b]isoxazolo[3,4-e]pyridin-6(7H)-one (143 mg, 0.33 mmol) in THF (10 ml) at −78° C. is added LiHMDS (0.38 ml, 1 M in THF, 0.38 mmol). The reaction mixture is stirred at −78° C. for 10 min and cyclopropylsulfonyl chloride (69 mg, 0.50 mmol) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction is quenched with saturated aqueous NH4Cl solution (20 ml) and extracted with EtOAc (2×20 ml). The combined organic solution is washed with brine (20 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)[CH3:29]>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][C@@H:28]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH3:29])=[O:13])=[CH:7][C:6]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)c(F)c1)c1ccc(NS(C)(=O)=O)cc1
Yield: 37.1 %

Procedure:
(4-tert-Butyl-3-fluorophenoxy)acetic acid (135 mg, 0.60 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (102 mg, 0.63 mmol), triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]phenyl}methanesulfonamide hydrochloride (150 mg, 0.60 mmol) were mixed in the same procedure described in Example 2(b) to furnish 94 mg (37% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:9][CH:10]=[CH:11][CH:12]=1.CI>C1COCC1>[CH2:6]([C:7]1[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:1]
Reactant: [Li]CCCC
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cccnc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Normal-butyllithium (2.69 M, 157.1 mL) was dropwise added to a solution of tert-butyl 3-methylpyridin-2-ylcarbamate (40.0 g) in THF (550 mL) at an internal temperature of −40 to −20° C., followed by stirring at 0° C. for 1 hr. Subsequently, a solution of methyl iodide (28.6 g) in THF (50 mL) was dropwise added to the reaction solution at an internal temperature of −70 to −60° C., followed by stirring at −78° C. for 30 min. The reaction solution was poured into ice water, followed by extraction with ethyl acetate twice. The organic layers were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled away. Hexane (300 mL) was added to the resulting residue, and the precipitate was collected by filtration and dried under reduced pressure to obtain compound (40a) (32.4 g, 76%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C(=O)([O-])[O-].[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1.O>CN(C=O)C>[N:19]1([C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:3]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)nc(-n2cnc3ccccc32)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
The obtained 2,4-dichloro-6-morpholino-1,3,5-triazine (6.0 g, 25mmol) dissolved in DMF (100 ml) was cooled to −5° C., added with anhydrous pottasium carbonate (5 g, 36 mmol) and benzimidazole (3.0 g, 35 mmol), stirred for 30 minutes and further stirred at room temperature for 15 hours. The reaction mixture was added with water (500 ml). The precipitated crystals were collected by filtration, washed with trace amount of acetone and dried to obtain 5.2 g (yield: 64%) of 2-(benzimidazol-1-yl)-4-chloro-6-morpholino-1,3,5-triazine with melting point of 201° C.-203° C. as colorless crystals.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27]>C1COCC1>[C:11]1([C:8]2[O:7][C:6]([C:4]([C:22]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=3)=[O:5])=[CH:10][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)o1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccc(-c3ccccc3)o2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of 38d (0.231 g, 1 mmol.) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 4.0 mL, 2 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with water, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1d as white crystals (35.5%). 1H NMR (CDCl3) δ 7.85-7.82 (m, 1H), 7.48-7.36 (m, 4H), 7.35 (s, 2H), 7.25 (d, 1H, J=4.0 Hz), 6.86 (d, 1H, J=4.2 Hz), 3.96 (s, 3H), 3.95 (s; 6H); MS (ESI) m/z 339.1 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([P:20](=[O:31])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([P:20](=[O:31])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (1.75 mL) in CH2Cl2 (60 mL) cooled at −78° C. was added DMSO (2.8 mL) dropwise. The mixture was stirred for 10 min at −78° C. and a solution of di(tert-butyl) hydroxy(4-methylphenyl)methylphosphonate (3.14 g in 20 mL of CH2Cl2 was introduced dropwise. After stirring for 30 min at −78° C., 14 mL of Et3N was added. The resulting mixture was stirred for 30 min at −78° C. and 45 min at room temperature, and then quenched with 200 mL of 50% saturated aqueous NaCl solution. The mixture was extracted with 2×200 mL of 1:1 hexane/EtOAc and the extract was dried over MgSO4 and concentrated to give 3 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH:4]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH2:5][CH2:6]S([O-])(=O)=O.C(OCC)(=O)C.O.CC#[N:27]>[C-]#N.C([N+](CC)(CC)CC)C>[CH3:1][O:2][CH:3]([O:16][CH3:17])[CH:4]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH2:5][C:6]#[N:27]
Reactant: COC(OC)C(CCS(=O)(=O)[O-])C(OC)OC
Reactant: CC#N
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(OC)C(CC#N)C(OC)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tetraethylammonium cyanide (142.3 g, 910.8 mmol) was added portionwise over 10 minutes to a solution of [2-(dimethoxymethyl)-3,3-dimethoxypropyl]methanesulfonate (124 g, 455.4 mmol) in MeCN (1.24 L). The reaction mixture was stirred at room temperature for 72 h, then portioned between ethyl acetate (1.24 L) and water (1.24 L). The layers were separated and the organic layer was isolated, washed with brine. The organics were dried over MgSO4, filtered and evaporated to give 3-(dimethoxymethyl)-4,4-dimethoxybutanenitrile 11 as a dark brown oil (86.1 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]#[N:18])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]([NH:20][NH2:21])=[NH:18])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)sc1C(=O)NCc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=N)NN)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A mixture of N-benzyl-5-cyano-3-methylthiophene-2-carboxamide (0.80 g, 3.12 mmol) and hydrazine monohydrate (8.00 mL, 164.9 mmol) in ethanol was stirred at reflux for 18 h. The reaction mixture was allowed to cool to ambient temperature, and concentrated in vacuo. The residue was triturated with ethyl acetate to afford N-benzyl-5-(hydrazinyl(imino)methyl)-3-methylthiophene-2-carboxamide as a light yellow solid (0.65 g, 72%): MS (ES+) m/z 289.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][N:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:37]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)[CH2:32][C:33]1[CH:34]=[N:35][N:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:37]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2cnn(-c3ccccc3)c2)cc1
Product: CC(C)c1ccc(N(Cc2cnn(-c3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 72.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.85 g) and (4-isopropylphenyl)[(1-phenylpyrazol-4-yl)methyl]amine (0.87 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.21 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([NH:27][CH3:28])=[CH:25][CH:24]=1>CN(C)C=O>[ClH:1].[F:22][C:23]1[CH:30]=[CH:29][C:26]([N:27]([C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH3:28])=[CH:25][CH:24]=1
Reactant: CNc1ccc(F)cc1
Reactant: Clc1nc(N2CCc3ccccc3C2)c2ccccc2n1
Solvent: CN(C)C=O
Product: CN(c1ccc(F)cc1)c1nc(N2CCc3ccccc3C2)c2ccccc2n1
Product: Cl
Yield: 78.3 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 2.2 g of the compound 7 mM prepared in Example 1 and 15 ml of dimethylformamide, 1.9 g of 4-fluoro-N-methylaniline(15 mM) was added, 2.45 g of the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]2.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].C(OC(=O)C)C>C1COCC1>[C:23]1([O:22][C:20](=[O:21])[NH:1][C:2]2[C:11]3[CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc2c1C[C@H](O)CC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1C[C@H](O)CC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Next, a solution of (R)-8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol -(36.2 g) and pyridine (18.8 ml) in THF (850 ml) cooled at 0° C. was added phenyl chloroformate (28.8 ml). The mixture was stirred for 3 hours at room temperature, and then poured into ethylacetate. The mixture was washed with aqueous NH4Cl then with water, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. To the obtained residue was added acetonitrile, and the precipitates were collected and washed with a mixture of acetonitrile and diisopropyl ether (2:3) to obtain {(R)-7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl}carbamic acid phenyl ester (33.0 g).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]=[C:5]3[CH2:11][C@H:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:13][C:3]=1[C:4]=23.[OH:21][C:22]1C=CC=C[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:35]N>C(#N)C.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C@H:12]1[CH2:11][C:5]2=[CH:6][NH:7][C:8]3=[CH:9][CH:10]=[C:2]([C:22]([NH:23][NH2:35])=[O:21])[C:3](=[C:4]23)[CH2:13]1)[CH2:16][CH3:17]
Reactant: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(I)c(c23)C1
Reactant: Oc1ccccn1
Reactant: NN
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(C(=O)NN)c(c23)C1
Reaction time: 15 h

Procedure:
To a solution of 5.0 g (13.1 mmol) of (4S)-6-iodo-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole in 250 ml of acetonitrile was added 3.5 g (37 mmol) of 2-hydroxypyridine, 16.9 g (122 mmol) of powdered potassium carbonate, and 0.30 g (0.26 mmol) of tetrakis(triphenylphosphine)palladium. The resultant mixture was heated at 65° C. under a carbon monoxide atmosphere for 14 hours. The cooled mixture was then treated with 2 ml of hydrazine hydrate and stirred for another 15 hours. After filtering, the mixture was concentrated in vacuo to provide a residue. This residue was taken up in methylene chloride and extracted with aqueous tartaric acid solution. The aqueous layer was basified with 1M sodium hydroxide solution and the product was extracted into methylene chloride. Evaporation of solvent in vacuo left an oily solid which, after thorough washing with a 1:2 mixture of toluene and hexane, afforded 0.60 g of (4R)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxylic hydrazide. m.p. 199°-201° C.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN.O>C(O)C>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCC(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCCC(c1ccccc1)c1ccccc1

Procedure:
Batch size: 18.5 g (45.0 mmol) 2-(8,8-diphenyl-octyl)-iso-indol-1,3-dione and 8.0 ml (160 mmol) hydrazine.hydrate in ethanol.