Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=1.Cl[CH2:20][CH2:21][CH2:22][CH:23]([O:29]C(=O)C)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[OH:29][CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21][CH2:20][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C:3]([OH:2])=[O:18])[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: COC(=O)COc1cccc(CNS(C)(=O)=O)c1
Reactant: CCCCCC(CCCCl)OC(C)=O
Product: CCCCCC(O)CCCN(Cc1cccc(OCC(=O)O)c1)S(C)(=O)=O

Procedure:
The title compound was prepared from [3-(methanesulfonylamino-methyl)phenoxy]-acetic acid methyl ester (Preparation 10) and acetic acid 1-(3-chloropropyl)-hexyl ester using the alkylation procedure described in U.S. Pat. No. 4,033,996. 1H NMR (CDCl3) δ 7.31-7.26 (m, 1 H), 7.02-6.84 (m, 3H), 4.68 (s, 2H), 4.35 (s, 2H), 3.91-3.89 (m, 1 H), 3.20-3.12 (m, 2H), 2.83 (s, 3H), 1.94-1.92 (m, 1H), 1.79-1.24 (m, 12H), 0.87 (t, 3H); MS 400 (M+ -1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH:13]1([C:16]#[CH:17])[CH2:15][CH2:14]1.CN(C=O)C>C1(C)C=CC=CC=1.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:4]1[CH:3]=[C:2]([C:17]#[C:16][CH:13]2[CH2:15][CH2:14]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CC1CC1
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#CC2CC2)cc1Cl
Yield: 75.8 %

Procedure:
A mixture of methyl 4-bromo-2-chlorobenzoate (450 mg, 0.0018 mol), copper(I) iodide (34 mg, 0.00018 mol), 70% solution of cyclopropylacetylene (0.26 g, 0.0027 mol) in toluene and bis(triphenylphosphine)palladium(II) chloride (130 mg, 0.00018 mol) in Et3N (5 mL) and DMF (3 mL) was heated at 100° C. in a 50 mL sealed reaction vessel for 36 hours. After cooling, the mixture was filtered through Celite® and the filter cake was washed repeatedly with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (320 mg, 76%) as a brown oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1.O>O1CCOCC1>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[N:10]=[CH:11][N:12]=[C:13]([NH:26][C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:30]=[CH:31][CH:32]=2)[C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])c1
Temperature: 70 °C
Yield: 88.7 %

Procedure:
To a solution of N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (7.0 g, 19.7 mmol) and TEA (5.5 mL, 40 mmol) in dioxane (100 mL) was added tert-butyl 3-aminophenylcarbamate (4.2 g, 20.0 mmol). The reaction mixture was heated to 70° C. for 6 hrs under N2. After the reaction was cooled down to room temperature, water (150 mL) was introduced. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layer was washed with water (150 mL×2) and brine (100 mL×1), dried over Na2SO4 and concentrated to dryness. tert-Butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenylcarbamate (2) (9.2 g, 88%) was obtained as a brown solid. LC-MS (ESI): m/z (M+1) 527.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]([NH:12][CH2:13][C:14]1([C:17]([O:19]CC)=O)[CH2:16][CH2:15]1)=[O:11])[CH3:6]>C1(C)C=CC=CC=1.O>[O:11]=[C:10]1[CH:9]([C:8]([O:7][CH2:5][CH3:6])=[O:22])[C:17](=[O:19])[C:14]2([CH2:15][CH2:16]2)[CH2:13][NH:12]1
Reactant: CCOC(=O)CC(=O)NCC1(C(=O)OCC)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1C(=O)NCC2(CC2)C1=O
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To a freshly prepared solution of sodium ethoxide [made from sodium (21 mg, 0.9338 mmol) and EtOH (0.5 mL)] was added a solution of ethyl 1-((3-ethoxy-3-oxopropanamido)methyl)cyclopropanecarboxylate (200 mg, 0.7782 mmol) in toluene (2 mL), and the resulting mixture was heated at reflux for 4 h. The mixture was cooled to RT, diluted with water (5 mL), and extracted with EtOAc (2×5 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to provide ethyl 6,8-dioxo-5-azaspiro[2.5]octane-7-carboxylate (150 mg, 0.710 mmol, 91% yield): m/z (ESI, +ve) 212.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:14](OCC1C=CC=CC=1)=[O:15])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2]>CCCCCC.CCOC(C)=O>[CH:14]([CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])=[O:15]
Reactant: CCC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(C=O)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from ethylmalonic acid, dibenzyl ester (from Step A) using a procedure analogous to that described for Aldehyde 3, Step B. RF: 0.35 (9:1 v/v hexane/EtOAc); 1H-NMR (500 MHz: Equilibrium mixture of aldehyde and enol) δ 0.92–1.00 (m), 1.04–1.08 (m), 1.93–2.01 (m), 2.14–2.18 (m), 5.17, 5.23, 5.26 (3s), 7.05 (d, J=12.6), 7.30–7.41 (m), 9.74 (d, J=2.3), 11.33 (d, J=12.6).
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(OCC)C>C(O)(=O)C>[C:1]1([CH2:7][C@H:8]([O:12][C:18](=[O:20])[CH3:19])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)O[C@@H](Cc1ccccc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
Combine (S)-3-phenyllactic acid (11.17 g, 67.2 mmol) and sulfuric acid (0.3 mL of a 10% solution in acetic acid). Add acetic anhydride (6.34 mL, 67.2 mmol) over 10 minutes. Warm to 90° C. with stirring for 45 minutes. Allow to cool, pour into diethyl ether and extract with water three times. Separate the organic layer, dry (MgSO4) and concentrate in vacuo to yield (S)-3-phenyl-2-acetyloxypropionic acid as a white oil.
Reaction SMILES: C[Mg]I.[Mg].CI.BrC1C=CC([CH:14]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=2)C2C=CC=CC=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17]C=2)=CC=1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CCOCC.O>[CH2:40]([O:39][C:37]([C:19]1[CH:20]=[CH:15][C:14]([O:21][CH2:22][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:17][CH:18]=1)=[O:38])[CH3:41]
Reactant: Brc1ccc(C(OC(c2ccccc2)c2ccc(Br)cc2)c2ccccc2)cc1
Reactant: CCOC(=O)Cl
Agent: C[Mg]I
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: CI
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a solution of methyl magnesium iodide prepared from magnesium (0.72g.; 0.03 mole) and methyl iodide (1.42g.; 0.01 mole) in ether (20ml) using standard methods, 4-bromo-phenylbenzyl ether in ether (20ml) was added dropwise with stirring then stirred until reaction was complete (1hr.). Ethyl chloroformate (3.24g.; 0.03 mole) in dry ether (20ml) was then added to the reaction mixture which was then boiled under reflux for 2 hrs. After cooling the reaction mixture was allowed to stand at room temperature for two days then worked up by the addition of water (40ml) and dilute hydrochloric acid (20ml). Separation of the ether layer followed by drying (anhyd. MgSO4), yielded 4-ethoxycarbonylphenoxy phenyl methane, m.p. 45° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([I:22])[CH:24]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1cccc(I)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide was prepared according to method C with triethylamine (2.23 mL; 15.90 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.5 g; 6.36 mmol) and 3-iodobenzoyl chloride (1.82 g; 6.68 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to provide 2.56 g (95%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[CH:14]=[CH:15][C:16]([OH:18])=O)(=[O:10])[CH3:9].CCN=C=NCCCN(C)C.Cl.Cl.[NH2:36][C@H:37]([C:48]([O:50][CH3:51])=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1>C(Cl)Cl>[C:8]([O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[CH:14]=[CH:15][C:16]([NH:36][C@H:37]([C:48]([O:50][CH3:51])=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)=[O:18])(=[O:10])[CH3:9]
Reactant: CC(=O)Oc1ccccc1C=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.4 %

Procedure:
Triethylamine (4.8 mL), 2-acetoxycinnamic acid (7.1 g) and WSC.HCl (6.6 g) were added to a methylene chloride (180 mL) suspension of methyl L-tryptophanate hydrochloride (7.3 g) at 0° C. The mixture was stirred for 20 hours at room temperature. The reaction mixture was washed with water, and thereafter the organic layer was dried over anhydrous sodium sulfate. The residual oily product obtained by distilling off the solvent under a reduced pressure was purified by silica gel column chromatography (BW-127ZH, chloroform:methanol=100:1), to give the captioned compound (8.9 g, 76%) as crystals.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH3:2]
Reactant: NS(N)(=O)=O
Reactant: CCOCCN
Solvent: C1CCOC1
Product: CCOCCNS(N)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
According to Reference Example 9-26, tetrahydrofuran (3 mL) and 2-ethoxyethylamine (0.37 mL, 4.2 mmol) were added to sulfamide (400 mg, 4.2 mmol) and the mixture was stirred by use of a microwave chemical reactor at 300 W at 100° C. for 10 minutes. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/3) was performed to give N-(2-ethoxyethyl)sulfuric diamide (Compound GH) (296 mg, yield: 42%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[C:13](I)[C:12]([NH2:16])=[C:11]([Cl:17])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.O>[NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[C:13]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:12]([NH2:16])=[C:11]([Cl:17])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under protective argon gas a mixture of 235 mg (0.64 mmol) ethyl (R)-2-amino-3-(4-amino-3-chloro-5-iodo-phenyl)-propionate, 45.9 mg (0.064 mmol) bis-(triphenylphosphine)-palladium(II)-dichloride, 6.0 mg (0.032 mmol) copper(I)- iodide and 15 ml triethylamine was combined with 0.19 ml (1.32 mmol) trimethylsilylacetylene and stirred for 3 hours at ambient temperature. The reaction mixture was combined with 30 ml of water and extracted with 40 ml of ethyl acetate. The organic phase was dried over sodium sulphate, evaporated down under reduced pressure and the residue was purified by column chromatography through silica gel.
Reaction SMILES: [NH2:1][OH:2].N#[N+:4][O-:5].N#N.[S:8](=[O:12])(=[O:11])([OH:10])[OH:9]>>[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[OH:5][NH3+:4].[OH:2][NH3+:1]
Reactant: O=S(=O)(O)O
Reactant: NO
Reactant: N#[N+][O-]
Agent: N#N
Product: O=S(=O)([O-])[O-]
Product: [NH3+]O

Procedure:
In a 50 m3 stirred tank, 32 m3/h of a suspension of 30 g/l of catalyst (0.5% Pt on graphite) in sulfuric acid (16.6% by weight) were pumped continuously. The liquid level in the stirred tank was approximately 75%. Into the liquid in the stirred tank were introduced at 39.2° C., 1100 Nm3/h of exhaust gas from a hydroxylamine plant comprising 73.9% by volume H2, 18.0% by volume NO, 3.8% by volume N2O and 4.3% by volume N2. In this case the NO was virtually completely reacted to form hydroxylammonium sulfate. 450 Nm3/h of exhaust gas comprising 84.4% by volume H2, 0.1% by volume NO, 6.8% by volume N2O and 8.7% by volume N2 left the stirred tank. The conversion rate based on NO was 99.8%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42]C3[C:36](=[CH:37]C(CBr)=CC=3)[CH:35]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][CH2:53][CH2:54][OH:55].C(OCCCOC1C=CC(C2CCN(C(OC(C)(C)C)=O)CC2OCC2C=CC3C(=CC(CN(C)C)=CC=3)C=2)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:51]([CH:50]=[CH:49][C:48]([CH2:47][O:52][CH2:53][CH2:54][OH:55])=[CH:37]3)=[CH:42][CH:43]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccc(CBr)cc3c2)C1
Agent: CN(C)Cc1ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4)cc3)cc2c1
Product: OCCOCc1ccc2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4)cc3)cc2c1

Procedure:
--by reaction of tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(7-bromomethyl-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with rac-2-[(tetrahydro-2H-pyran-2-yl)oxy]-1-ethanol, a mixture of (3RS,4RS)- and (3SR,4SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-{7-[2-[(RS)-tetrahydro-pyran-2-yloxy]-ethoxymethyl]-naphthalen-2-ylmethoxy}-piperidine-1-carboxylate [colourless oil, MS:740 (M+H)+ ] and tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(7-dimethylaminomethyl-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [byproduct, colourless oil, MS: 639 (M)+ ]. Simultaneous cleavage of the BOC and tetrahydropyranyl groups from the main product gave 2-(7-{(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxymethyl}-naphthalen-2-ylmethoxy)-ethanol as a colourless oil; MS: 556 (M+H)+. Cleavage of the BOC group from the byproduct gave (7-{(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxymethyl}-naphthalen-2-ylmethyl)-dimethyl-amine as a colourless oil; MS: 539 (M+H)+.
Reaction SMILES: C1(S([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=4)[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:31]([CH3:33])[CH3:32])[C:11]2=[O:34])(=O)=O)C=CC=CC=1.[Mg]>CO>[CH:31]([N:12]1[CH:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:14][NH:10][C:11]1=[O:34])([CH3:33])[CH3:32]
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Agent: [Mg]
Solvent: CO
Product: CC(C)N1C(=O)NCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Yield: 29.4 %

Procedure:
1-Benzenesulfonyl-3-isopropyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (example 12, step 2, 1.386 g) and magnesium (0.541 g) were suspended in methanol (30 mL). The mixture was heated to reflux for 4 h and subsequently filtered. The filtrate was concentrated and the product was purified by column chromatography (SiO2, cyclohexane/ethyl acetate 7:3=>0:1) to give 1-isopropyl-5-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (0.293 g) as a colorless solid. MS: 359.1 ([M+H]+)
Reaction SMILES: C(Cl)(Cl)=[O:2].[CH3:5][N:6]([C:8]([C:11]1[C:19]2[C:14](=CC=CC=2)[C:13]2([CH2:23][CH2:22][CH2:21][CH2:20]2)C=1)(O)C)C.[OH-].[K+].[CH:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[CH3:5][NH:6][CH2:8][CH:11]([C:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:14]=1)[OH:2]
Reactant: CN(C)C(C)(O)C1=CC2(CCCC2)c2ccccc21
Reactant: O=C(Cl)Cl
Reactant: c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNCC(O)C1=CC2(CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosgene (1 g) is added to dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (2.9 g) in benzene (25 ml). The mixture is stirred at room temperature for 30 minutes and then under reflux for 2 hours. Evaporation of the solvent under reduced pressure gives an oil which crystallizes. Recrystallization from diisopropyl ether gives a pure product, m.p. 75°-77° C. This compound, 5-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (2 g), is refluxed for 2 hours with a solution of potassium hydroxide (5 g) in ethanol (50 ml) and water (10 ml). Most of the solvent is evaporated under reduced pressure, water (25 ml) is added and the amine is extracted into chloroform. Drying and evaporation of the solvent gives the crystalline title compound, which after recrystallization from diisopropyl ether melts at 133°-134° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:22][CH:21]=4)=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][I:33]>CN(C=O)C>[I-:33].[CH3:32][N+:27]1([CH2:26][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:17]([C:13]3[CH2:12][CH2:11][C:10]4[C:15](=[CH:16][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:8][CH:9]=4)[CH:14]=3)=[O:18])=[CH:25][CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Nc1ccc(CN2CCCC2)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Reactant: CI
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccccc5)ccc4CC3)cc2)CCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In DMF (2 ml) was dissolved 7-phenyl-N-[4-(1-pyrrolidinylmethyl)phenyl]-3,4-dihydronaphthalene-2-carboxamide (70 mg), and to the mixture was added methyl iodide (32 μl). The mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give 1-methyl-1-[4-(7-phenyl-3,4-dihydronaphthalene-2-carboxamido)benzyl]pyrrolidinium iodide (Compound 11) (78 mg) as pale yellow crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:10][CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:10][CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(CCN2CCCN(Cc3ccc(S(C)(=O)=O)cc3)CC2)c2ccccc2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CN2CCCN(CCC(c3ccccc3)c3ccc(O)cc3)CC2)cc1
Reaction time: 3 h
Yield: 37.4 %

Procedure:
5.0 mL solution in dichloromethane of 33 mg of 1-[3-(4-methoxyphenyl)3-phenyl propyl]-4-[4-(methylsulfonyl)benzyl]homopiperazine was cooled under nitrogen to −78° C. followed by adding 0.022 mL of boron tribromide. The mixture was gradually allowed to rise to room temperature, at which temperature the mixture was stirred for 3 hours, followed by adding 3 mL of an aqueous saturated sodium hydrogencarbonate solution and extracting with a 50 mL×2 of ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate/methanol 9:1) to obtain 12 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O>[N:14]1([CH2:20][CH2:21][NH:22][C:2]2[S:3][C:4]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(NCCN3CCOCC3)sc2c1
Temperature: 65 °C
Yield: 26.2 %

Procedure:
To a mixture of 2-chloro-6-nitrobenzothiazole (1.00 g, 4.66 mmol) in water (9.0 mL) was added 2-morpholin-4-yl-ethylamine (2.45 mL, 18.6 mmol). The dark reaction mixture was stirred under argon and refluxed for 4.5 hours at which time the reaction became red-brown in colour. The mixture was then cooled to 65° C. and stirred an additional 17.75 hours. The precipitate was then collected by suction filtration after cooling to room temperature giving a yellow solid (377 mg, 26%). 1H NMR (DMSO-d6) δ: 8.69 (d, 1H, J=2.1 Hz), 8.10 (dd, 1H, J=2.1, 8.9 Hz), 7.46 (d, 1H, J=8.9 Hz), 3.59 (m, 6H), 2.55 (t, 2H, J=6.2 Hz), 2.51 (m, 4H), 2.43 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1)CCC.BrC1C=CC=CC=1CC(OC)=S>>[S:22]1[CH:23]=[CH:24][C:20]([C:2]2[CH:3]=[C:4]([S:8][CH:9]([CH3:14])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[CH:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reactant: COC(=O)C(C)Sc1cccc(Br)c1
Agent: COC(=S)Cc1ccccc1Br
Product: CC(Sc1cccc(-c2ccsc2)c1)C(=O)O

Procedure:
The same procedure as in Reference Example 6 was carried out using methyl 2-(3-bromophenylthio)propionate and tributyl(3-thienyl)tin in place of the starting methyl 2-bromophenylthioacetate and tributylphenylthin to give 2-[3-(3-thienyl)phenylthio]propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCCNCCCc2cccc(Cl)c2)s1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(3-(3-(3-chloro-phenyl)-propylamino)-propyl)-thiophene-2-carboxylic acid methyl ester (from Preparation 8, 0.0855 g, 0.243 mmol), triethylamine (0.0541 g 0.534 mmol), and pyridine-3-sulfonyl chloride hydrochloride (from Preparation 2, 0.0572 g, 0.267 mmol) in 10 mL CH2Cl2 combined at 0° C. was stirred at room temperature overnight. The organic solution was washed with water, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step A as an oil. MS 494 (M+1).