Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.Br[CH2:22][CH:23]1[CH2:25][CH2:24]1.[O:26]=[C:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>C1COCC1>[CH:25]1([CH2:24][C:27]2([OH:26])[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:31][CH2:32]2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrCC1CC1
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2)CC1
Temperature: -78 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a suspension of 4,4′-di-tert-butylbiphenyl (DTBB, 30.33 mg, 0.114 mmol) and Li (56.7 mg, 8.09 mmol) in 50 mL of anhydrous THF was added dropwise a solution of (bromomethyl)cyclopropane (307.9 mg, 2.28 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.5 mmol) in anhydrous THF (5 mL) at −78° C. under N2. The resulting mixture was stirred at −78° C. under N2 for 8 h. The reaction mixture was quenched by satd. NH4Cl solution at −78° C. The resulting mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 262.5 mg of title compound as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 3.90-3.78 (m, 2H), 3.25-3.12 (m, 2H), 1.60 (dd, J=9.4, 4.3 Hz, 4H), 1.48 (s, 9H), 1.42 (d, J=6.9 Hz, 2H), 0.82-0.70 (m, 1H), 0.57-0.47 (m, 2H), 0.16-0.06 (m, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[N:12][CH:13]=1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[N:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NCC#Cc1ccc(C#CCNC(C)=O)nc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCCc1ccc(CCCNC(C)=O)nc1
Yield: 98.1 %

Procedure:
A mixture of N-(3-{5-[3-(acetamido)prop-1-ynyl]pyridin-2-yl}prop-2-ynyl)acetamide (2-1) (10 g), 10% Pd/C (1.5 g) in methanol (200 mL) was hydrogenated under 20 psi hydrogen at room temperature for 16 hours. The catalyst was removed by filtration using Solka-floc and washed with methanol. The filtrate and washings were combined and concentrated under reduced pressure to provide 10-1 as a crystalline compound (10.1 g); m.p. 95.2-97.8° C.
Reaction SMILES: C1(N[C@H](C(O)=O)CC(C)C)C2C(=CC=CC=2)C=CC=1.[CH3:20][C:21]1[CH:22]=[C:23]2[C:32](=[CH:33][C:34]=1[CH3:35])[CH:31]=[CH:30][C:29]1[CH2:28][CH2:27][C@@H:26]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46])[C@@H:25]([NH:47][C:48](=[O:61])[C:49]3[CH:54]=[C:53]([N+:55]([O-:57])=[O:56])[CH:52]=[C:51]([N+:58]([O-:60])=[O:59])[CH:50]=3)[C:24]2=1.[K+].[Br-]>C(Cl)Cl>[CH3:20][C:21]1[CH:22]=[C:23]2[C:32](=[CH:33][C:34]=1[CH3:35])[CH:31]=[CH:30][C:29]1[CH2:28][CH2:27][CH:26]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46])[CH:25]([NH:47][C:48](=[O:61])[C:49]3[CH:50]=[C:51]([N+:58]([O-:60])=[O:59])[CH:52]=[C:53]([N+:55]([O-:57])=[O:56])[CH:54]=3)[C:24]2=1
Reactant: C=CCCCCCCCCC[C@@H]1CCc2ccc3cc(C)c(C)cc3c2[C@@H]1NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CC(C)C[C@H](Nc1cccc2ccccc12)C(=O)O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCCCCCCCCCC1CCc2ccc3cc(C)c(C)cc3c2C1NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
By chromatographing the mixture of cis and trans isomers of CS-8 on a (S)-N-(1-naphthyl)leucine chiral stationary phase packed into a MPLC column, which chiral stationary phase is described by Pirkle, Deming and Burke in Chirality, 3:183-187 (1991) the contents of which are incorporated herein by reference, 2.68 g of enantiomerically pure cis CS-8, i.e., (cis)-6,7-Dimethyl-4-[N-(3,5-dinitrobenzoyl)]amino-3-(10-undecenyl)-1,2,3,4-tetrahydrophenanthrene, (last elUted enantiomer) was obtained, as were samples of the trans form of CS-8 (the first eluted enantiomer). Physical data for cis CS-8, obtained as a yellowish solid, were as follows: mp 181°-182° C., 1H NMR (CDCl3) δ 1.19-1.39 (m,14H), 1.42-1.77 (m,3H), 1.96-2.07 (m,4H), 2.36 (s,3H), 2.40 (s,3H), 3.03-3.10 (m,2H), 4.89-5.03 (m,2H), 5.74-5.88 (m,1H), 6.08 (dd, J=9.2 Hz, J= 2.8 Hz,1H), 6.20 (d, J=9.2 Hz,1H), 7.16 (d, J=8.2 Hz,1H), 7.52 (s,1H), 7.61 (d, J=8.2 Hz,1H), 7.85 (s,1H), 8.84 (d, J=1.7 Hz,2H), 9.08 (t, J=1.7 Hz,IH), IR (KBr) CM-1 3440, 2920, 2850, 1680, 1650, 1540, 1500, exact (EI) mass. calcd. for C34H41N3O5: 571.3046, Found: 571.3046, [α]D20 -126.2 (c 091, CH2Cl2).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C:36]1[CH:37]=[C:38]([C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[CH:48][N:47]=[C:46]3[NH2:53])[CH:39]=[C:40]([F:42])[CH:41]=1>C(Cl)Cl>[NH2:53][C:46]1[C:45]2[C:50](=[CH:51][CH:52]=[C:43]([C:38]3[CH:37]=[C:36]([NH:35][C:8](=[O:10])[CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:41]=[C:40]([F:42])[CH:39]=3)[CH:44]=2)[N:49]=[CH:48][N:47]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: Nc1cc(F)cc(-c2ccc3ncnc(N)c3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2ccc(-c3cc(F)cc(NC(=O)CN4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-morpholinoacetic acid (0.175 mmol, 25 mg) in a 4 mL vial was added HATU (0.175 mmol, 69 mg), 6-(3-amino-5-fluoro-phenyl)quinazolin-4-amine, 0.15 mmol, 38 mg), and TEA (0.30 mmol, 0.042 mL). The vial was capped and shaken overnight at room temperature. The reaction was then diluted with 3 mL DCM, then washed with 2 mL water. Organic phase was concentrated, and then purified by reverse phase HPLC yielding 20 mg of desired product. 1H NMR (400 MHz, DMSO) δ 10.07-9.93 (s, 1H), 8.60-8.52 (d, J=1.8 Hz, 1H), 8.42-8.39 (s, 1H), 8.08-8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.93-7.66 (m, 4H), 7.44-7.35 (d, J=10.0 Hz, 1H), 3.71-3.63 (m, 4H), 3.20-3.17 (s, 2H), 2.56-2.51 (m, 4H). LCMS M/Z (M+H) 382.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=1)[CH2:18]Cl)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C=O)C>[CH2:5]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:8][CH2:9][CH3:10])[CH:22]=1)[CH2:18][N:1]=[N+:2]=[N-:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:5][CH2:6][CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCCC)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
Sodium azide (3.25 g, 50.0 mmol) and DMF (25 mL) were introduced into a 1 L RBF containing 3,5-dinonoxybenzylchloride (10.0 g, 25.0 mmol) and a stir bar. The reaction mixture was then capped with a septum and an out-vent needle. The mixture was heated until warm to the touch, allowed too cool to room temperature, then heated again, (repeated 4 times). The mixture was then washed in a separatory funnel with 500 mL distilled water and ether (4 times with 100 mL). The combined ether layers were washed with ammonium chloride (2 times with 50 mL), and then the ether layer was dried with magnesium sulfate and gravity filtered into a 1 L RBF. Thin layer chromatography (10% dichlormethane/hexanes) analysis revealed that there was still a starting material in the product so the product was purified by silica gel flash chromatography (2 L 5% dichloromethane and hexanes, 2 L 7% dichloromethane and hexanes). The solvent was removed under reduced pressure and the trace solvent was removed with high vacuum. There was a 5.3 g yield or a 80% yield. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.87 (t, J=6.6, 6H, CH2CH3), 1.15-1.6 (m, 36H, CH2(CH2)9), 1.76 (p, J=8.0, 4H, OCH2CH2), 3.93 (t, J=6.3, 4H, OCH2CH2), 4.24 (s, 2H, ArCH2), 6.41 (d, J=2.2, 3H, ArH).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][N+:12]=1[O-:20]>O>[N+:17]([C:15]1[CH:14]=[CH:13][N+:12]([O-:20])=[C:11]([O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=1)([O-:19])=[O:18]
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])c(Oc2cccnc2)c1
Yield: 83 %

Procedure:
Sodium hydride (0.27 g of an 80% dispersion in oil, 9 mmol) was added to a solution of 3-hydroxypyridine (0.854 g, 9 mmol) in ThF (3 ml) at 0° C. The mixture was then stirred for 1 h at room temperature before 2-chloro-4-nitropyridine-N-oxide* (2 g, 9 mmol) was added. The resulting solution was heated at reflux for 16 h, cooled, poured into water (100 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using ethyl acetate as eluant to afford the title compound (1.74 g, 83%) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:38])(=[N:27][C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[O:26])=[CH:21][CH:20]=1>>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:24][CH:23]=2)([CH3:38])=[O:26])=[O:37])=[CH:35][CH:34]=1
Reactant: CS(=O)(=NC(=O)Nc1ccc(Cl)cc1)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)Nc3ccc(Cl)cc3)cc2)ncc1-c1cccs1
Yield: 35 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (164 mg, 0.61 mmol) with (RS)—S-(4-aminophenyl)-N-(4-chloro-phenylcarbamoyl)-S-methylsulphoximide (179 mg, 0.55 mmol) according to procedure 5c, the desired product is obtained in 35% yield (109 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:32][CH2:31][CH2:29][OH:30])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:26])[F:27])[CH:3]=1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 11.70 (1H, br), 10.33 (1H, m), 8.49 (1H, s), 7.70 (1H, d, J=9 Hz), 7.56 (2H, m), 7.32 (1H, s), 4.91 (1H, br t), 4.32 (2H, s), 3.56 (2H, m), 3.45 (2H, m); ES− MS: 424 (M−1, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([CH2:9][C:10]#[N:11])=[O:8])([O-:3])=[O:2].[C:15]1([N:21](C2C=CC=CC=2)[CH:22]=N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([C:9](=[CH:22][NH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]#[N:11])=[O:8])([O-:3])=[O:2]
Reactant: N=CN(c1ccccc1)c1ccccc1
Reactant: N#CCC(=O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1C
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 2-(3-nitrobenzoyl)acetonitrile (13.75 g, 72.3 mmol) and N,N-diphenylformamidine (14.2 g, 72.3 mmol) in xylene (200 ml) was heated at reflux under nitrogen atmosphere. After 3 h, the reaction mixture was cooled to room temperature and diluted with xylenes to give 2-(3-nitrobenzoyl)-3-phenylaminoacrylonitrile (15.7 g) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([F:27])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:12]1[C:13]2[C:9](=[CH:8][C:7]([F:27])=[CH:6][C:5]=2[O:4][CH2:3][CH2:2][Cl:1])[C:10]([S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[N:11]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cc(F)cc12
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A mixture of 7-(2-chloro-ethoxy)-5-fluoro-3-(naphthalene-1-sulfonyl)-1H-indazole (0.9 g, 2.2 mmoles), 3-chlorobenzyl bromide (0.35 mL, 2.7 mmoles), and cesium carbonate (0.87 g, 2.7 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.85 g, 2 mmoles).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:4]([CH3:5])[O:3]1.CCOCC.[Mg+2].[Br-].[Br-].[C:14]1([C@@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[C:14]1([CH:20]([NH:22][CH:4]([CH3:5])[CH:2]([OH:3])[CH3:1])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: C[C@@H]1O[C@@H]1C
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(NC(C)C(C)O)c1ccccc1
Temperature: 90 °C
Yield: 60 %

Procedure:
To a solution of 0.445 ml (5 mmol) cis-2,3-dimethyl-oxirane in 5 ml tetrahydrofuran was added at room temperature 0.26 g (1 mmol) magnesium bromide diethyl etherate. The mixture was treated under argon with stirring with 0.67 ml (5.5 mmol) (S)-(−)-1-phenyl-ethylamine. The yellow suspension was heated at 90° C. in a dosed container for 110 hours, whereby after 21 and 64 hours 0.25 ml and 0.122 ml respectively of cis-2,3-dimethyl-oxirane was added. The reaction mixture was cooled to room temperature and stirred vigorously with 5 ml of 5N aqueous ammonium chloride solution for 10 minutes. The organic phase was separated, dried over 2 g of sodium sulfate, filtered and evaporated in a rotary evaporator to obtain 0.58 g of 3-(1-phenyl-ethylamino)-butan-2-ol as a mixture of diastereoisomers as a brown oil. The oily residue was separated by chromatography on a silica gel column using ethyl acetate as the eluent to obtain the two diastereoisomers A and B as yellowish oils.
Reaction SMILES: [SH-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17](=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Cl)[O-].N1CCOCC1.[ClH:33]>>[Cl:33][N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Cl:10])[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [O-][N+](=Nc1ccccc1Cl)c1ccccc1Cl
Reactant: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [SH-]
Solvent: C1COCCN1
Product: Clc1ccccc1N(Cl)Nc1ccccc1
Temperature: 75 °C
Yield: 79 %

Procedure:
84 Parts of an aqueous solution of technical sodium hydrosulfide, free from sodium thiosulphate, were added to a mixture comprising 53.4 parts of 2,2'-dichloroazoxybenzene in 140 parts of morpholine at 60° C - 65° C within 90 minutes. Subsequently, the reaction temperature was raised to 75° C and maintained at that temperature for 2 1/2 hours. Next the temperature was further raised to 90° C and maintained at that temperature for 1 hour. The pH of the reaction mixture varied between 9.5 to 10. After this period the absence of the starting material was confirmed. Then the reaction mixture was cooled to 20° C and neutralized cautiously with 400 parts of hydrochloric acid of 15 percent strength at a temperature below 20° C. Then the reaction mixture was cooled to 0° C to 5° C, and the resulting precipiatate filtered off and washed with water until free of chloride. After drying below 70° C, 40.1 parts of 2,2'-dichlorohydrazobenzene of a melting point of 85° C to 87° C were obtained, this representing a yield of 79 percent of the theory.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:27]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][CH2:23]CO)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C(P(CCCCCCCC)CCCCCCCC)CCCCCCC.[C:62]([Br:66])(Br)(Br)Br.O>C(OCC)C>[Br:66][CH2:62][CH2:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:31]=2)=[CH:17][C:16]=1[C:7]1[CH:8]=[CH:9][C:10]([N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCO)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(CCCBr)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
6.4 g of ethyl 3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate obtained in Example 32c (13 mmol) are dissolved in 128 mL of diethyl ether. The dissolution is performed under cold conditions (0° C.), and 11.4 mL of trioctylphosphine are then added (26 mmol) followed by addition of a solution of 8.5 g of carbon tetrabromide (26 mmol) dissolved in 10 volumes of Et2O added dropwise. The reaction medium is stirred at 0° C. for 30 minutes and then for 1 hour 30 minutes at room temperature. The reaction is stopped by adding 100 mL of water and then extracted with 100 mL of ethyl acetate. The organic phases are washed with 400 mL of water and then dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: 9/1 heptane/ethyl acetate). 6 g of ethyl 4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=83%) in the form of a thick brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[C:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.[N+:16]([CH3:19])([O-:18])=[O:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:19][N+:16]([O-:18])=[O:17])[CH2:6][CH2:7][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:13][CH2:14]1
Reactant: COC(=O)C=C1CCC2(CC1)OCCO2
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC1(C[N+](=O)[O-])CCC2(CC1)OCCO2
Yield: 75.4 %

Procedure:
A solution of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.50 g, 25.9 mmol) in 14 mL of dry THF was treated by nitromethane (2.10 mL, 38.9 mmol) followed by a 1M solution of tetrabutylammonium fluoride in THF (26.5 mL, 26.5 mmol). The resulting mixture was stirred at reflux for 20 h under nitrogen. After cooling, the mixture was diluted with water and extracted with three portions of ether. The etheral portions were combined, washed with a 10% aqueous solution of potassium hydrogensulfate, dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (8-Nitromethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid methyl ester (5.34 g, 75%) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(Cl)(=O)=O.[H-].[Na+].O[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1>O1CCCC1.CN(C)C=O.C(OCC)C.O.C(N(CC)CC)C>[CH:1]1([CH2:6][O:7][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCC1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(OCC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyclopentane methanol (4.05 ml, Ald) in anhydrous tetrahydrofuran (abbreviated as “THF” hereinafter, 40 ml) was added with triethylamine (6.49 ml, WAKO), added dropwise with methanesulfonyl chloride (3.48 ml, WAKO) under ice cooling, and stirred for 30 minutes. The reaction mixture was added with water (50 ml), and extracted with diethyl ether (80 ml×2). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. A solution obtained beforehand by adding 60% sodium hydride (1.15 g, KANTO) to a solution of Intermediate 1 (4.50 g) in N,N-dimethylformamide (abbreviated as “DMF” hereinafter, 35 ml) under ice cooling and stirring the solution for 15 minutes was added with a solution of the aforementioned residue in DMF (10 ml) under ice cooling. The reaction mixture was stirred for 15 minutes, then warmed to room temperature, stirred for 45 minutes, and further stirred at 60° C. for 15 hours. The reaction mixture was added with water (100 ml) and diethyl ether (200 ml) for extraction. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:isopropyl ether=9:1) to obtain the title compound (Intermediate 2, 5.58 g).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:34]=[CH:35][CH:36]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1cccc(OCCCCBr)c1
Agent: Cl
Product: COc1cccc(OCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3-methoxyphenoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(4-(3-methoxyphenoxy)butyl)-piperidin-4-yl)methyl)benzamide.