Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)=O.[NH2:5][C:6]1[CH:10]=[C:9]([Cl:11])[S:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=S)(=[O:14])=[O:13].C(N(CC)CC)C>O1CCCC1>[Cl:11][C:9]1[S:8][C:7]2[S:12](=[O:14])(=[O:13])[N:15]=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[NH:5][C:6]=2[CH:10]=1
Reactant: CC(C)NC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
Phosgene (1.14 ml, 20% in toluene) was added dropwise to a solution of N-(3-amino-5-chloro-2-thienylsulfonyl)-N'-isopropylthiourea (0.63 g, 2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry tetrahydrofuran (10 ml) with stirring at 0° C. The mixture was stirred for 1 h at 0° C., and evaporated to dryness. The residue was triturated with water, and the precipitate was isolated by filtration, washed with water and dried affording 0.52 g (93%) of the title compound.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[OH:10][C:9]1[N:11]=[CH:12][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: NC(=O)NNc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: Oc1ncn(-c2ccccc2)n1

Procedure:
One hundred g of 1-phenylsemicarbazide was added to 500 ml of trimethyl orthoformate, and about 400 mg of p-toluenesulfonic acid was added to the mixture. It was heated on a steam bath with strong agitation for 2 hours, and was then transferred to a large flask, cooled and evaporated under vacuum. The residue was recrystallized from about 1600 ml of acetic acid to obtain 97 g of the desired intermediate, m.p. 277°-280°.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]([CH2:18][CH2:19][C:20]([O:22]C)=O)[C:10]([CH2:12][C:13]([O:15][CH2:16]C)=[O:14])=[O:11])[CH:3]=1>CO.C1C=CC=CC=1>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:18][CH2:19][C:20](=[O:22])[CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:10]2=[O:11])[CH:3]=1
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1cccnc1
Agent: [Na]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C1C(=O)CCN(Cc2cccnc2)C1=O
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Sodium (0.77 g) is dissolved in methanol (30 ml), and thereto is added dropwise a solution of ethyl [N-(3-pyridylmethyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (10.0 g) in benzene (170 ml) at 3°-8° C. The mixture is stirred at the same meperature for 2 hours. The mixture is distilled to remove the solvent, and the residue is dissolved in water. The aqueous solution is extracted with benzene, and the aqueous layer is neutralized with 10% HCl, and extracted with chloroform. The extract is dried and distilled to remove the solvent to give methyl 1-(3-pyridylmethyl)-2,4-dioxopiperidine-3-carboxylate (8.50 g, quantitative) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](OC)=[O:25])=[CH:15][C:13]=2[N:14]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N+:30]=1[O-:39].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][N+:30]=3[O-:39])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(C(F)(F)F)c[n+]3[O-])c3c(c2[nH]1)CC(C)(C)O3
Yield: 27.2 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.100 g, 0.207 mmol) and 2-amino-5-trifluoromethylpyridine-N-oxide (Intermediate-41, 0.053 g, 0.301 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.030 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.25 (s, 3H), 3.13 (s, 2H), 7.26-7.33 (m, 2H), 7.43 (d, J=6.9 Hz, 1H), 7.53 (s, 1H), 7.79 (d, J=6.9 Hz, 1H), 8.68 (d, J=9.3 Hz, 1H), 8.94 (s, 1H), 9.20 (s, 1H), 11.02 (s, 1H), 12.26 (s, 1H); MS [M+H]+: 532.11.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C>ClCCCl>[CH2:33]([N:16]([CH3:15])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:31][CH:32]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CNCCc1ccc(Oc2ccc(O)cc2)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(CCc1ccc(Oc2ccc(O)cc2)cc1)Cc1ccccc1
Yield: 58 %

Procedure:
Sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added to a solution of 4-[4-(2-Methylamino-ethyl)-phenoxy]-phenol (75 mg, 0.31 mmol), benzaldehyde (34 mg, 0.32 mmol), acetic acid (19 mg, 0.32 mmol), and 1,2-dichloroethane (5 mL). Stirred the reaction at room temperature overnight, quenched with a pH=10 buffer, then extracted with dichloromethane (3×25 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (100 mg). The crude product is purified by flash column chromatography on silica gel eluting with ethanol in dichloromethane to yield 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol, (60 mg): m/z=334.01 (M+1); HPLC=97% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. 1H NMR (CDCl3, 300.00 MHz): 7.42-7.28 (m, 7H), 7.11-7.05 (m, 2H), 6.97-6.79 (m, 4H), 3.63 (s, 2H), 2.86-2.78 (m, 2H), 2.71-2.63 (m, 2H), 2.33 (s, 3H),
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[Si:27]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(C=O)c1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (9.0 g, 39.8 mmol) and imidazole (2.98 g, 43.8 mmol) in N,N-dimethylformamide (100 mL) was added tert-butyldimethylchlorosilane (6.6 g, 43.8 mmol) under stirring at room temperature and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (10.5 g, yield 77%) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl-].[CH:15](=[N+:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:23][N:22]([CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][C:11](=[O:13])[CH3:12])[NH:1][CH:2]=1)[CH3:24]
Reactant: C[N+](C)=Cc1ccccc1
Reactant: CC(=O)Oc1cccc2[nH]ccc12
Agent: [Cl-]
Product: CC(=O)Oc1cccc2[nH]cc(C(c3ccccc3)N(C)C)c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from acetic acid 1H-indol-4-yl ester and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: C[O:2][C:3](=[O:14])[C@@:4]([CH3:13])([CH2:7][O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH2:6].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:13][C@:4]([CH2:7][O:8][C:9]([F:10])([F:12])[F:11])([CH:5]=[CH2:6])[C:3]([OH:14])=[O:2]
Reactant: C=C[C@](C)(COC(F)(F)F)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@](C)(COC(F)(F)F)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 103.8 %

Procedure:
A solution of crude (R)-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid methyl ester (98 mg) in tetrahydrofuran (4 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (63 mg, 1.5 mmol) in water (1 mL) was added and the reaction mixture was stirred at 5° C. for 1 h and then at room temperature for 3 days. Water was added and the mixture was acidified to pH 2 with hydrochloric acid (2 M) and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the crude title compound (95 mg) as a clear oil which was used in the next step. LCMS (m/z) 197.1 [M−H], Tr=2.16 min.
Reaction SMILES: [CH2:1]([S:8]([C:11]1[N:16]=[C:15]2[NH:17][C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Cl)[CH:35]=1>CN(C)C=O>[CH2:1]([S:8]([C:11]1[N:16]=[C:15]2[N:17]([CH2:40][C:36]3[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=3)[C:33]([O:32][CH3:31])=[O:42])[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CCl)c1
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(S(=O)(=O)Cc4ccccc4)nc32)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
A solution of 1 g (2.2 mmol) of 7-benzylsulfonyl-3-(2-bromophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 20 ml of dimethylformamide was cooled to 0° C. under a nitrogen atmosphere, treated with 112 mg (4.2 mmol) of 60% sodium hydride in mineral oil then stirred for 30 minutes. 440 mg (2.4 mmol) of methyl-3-(chloromethyl)benzoate was added, then the reaction was heated at 90° C. for 3 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (40 ml) and water (40 ml), the ethyl acetate layer was separated, washed with saturated aqueous sodium bicarbonate (40 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 750 mg (56%) of methyl 3-[[7-benzylsulfonyl 3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimid-1-yl]methyl]benzoate as a white solid. [Mass spectrum (ESI) MH+ =607].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: OC1CCNCC1
Solvent: O
Solvent: CCCCO
Product: OC1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of 4,6-dichloro-2-phenyl pyrimidine (1 g. 4.42 mmol) and triethyl mol amine (1.78 g, 17.6 mmol) in n-butanol (10 mL) was added 4-hydroxy piperidine (0.44 g, 4.4 mmol) to temperature in the range of 20-40° C. with stirring. The mixture was then stirred under reflux for 16 hours under nitrogen. The mixture was cooled to room temperature, poured into water (25 mL) and extracted with EtOAc (2×15 mL). Organic layers were collected, combined dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography using EtOAc-pet ether to give the desired compound (1.15 g, 91% yield).
Reaction SMILES: Cl.C([O:5][C:6]1[C:7]([CH3:23])=[N:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([CH2:14]Cl)[C:11]=1[CH2:12]Cl)(=O)C.[CH3:24][NH2:25]>CS(C)=O>[CH3:24][N:25]1[CH2:12][C:11]2[C:6]([OH:5])=[C:7]([CH3:23])[N:8]=[C:9]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH2:14]1
Reactant: CN
Reactant: CC(=O)Oc1c(C)nc(Cc2ccccc2)c(CCl)c1CCl
Agent: Cl
Solvent: CS(C)=O
Product: Cc1nc(Cc2ccccc2)c2c(c1O)CN(C)C2
Temperature: 80 °C

Procedure:
A mixture of 37.5 g (100 millimoles) of 2-methyl-4,5-di-(chloromethyl)-6-benzyl-pyridin-3-yl acetate hydrochloride (Example 4), 50 ml of dry dimethylsulfoxide and 16 g (500 millimoles) of methylamine is heated for 5 hours at 80° C. in an autoclave. The solvent is stripped off in a high vacuum and the residue is partitioned between methylene chloride and water, taking care that the pH of the aqueous phase is 7.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])[N:5]=[C:4]([C:24]#[N:25])[N:3]=1.C([O-])([O-])=[O:27].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9]([F:16])=[CH:10][C:11]([F:15])=[CH:12][C:13]=2[F:14])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:20])([F:21])[F:22])[N:5]=[C:4]([C:24]([NH2:25])=[O:27])[N:3]=1
Reactant: C[C@H](Nc1nc(C#N)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Nc1nc(C(N)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
5.0 g of 4-chloro-6-((S)-2,2,2-trifluoro-1-methylethylamino)-5-(2,4,6-trifluorophenyl)-pyrimidine-2-carbonitrile (see WO 03/04993, pages 28 and 29) were initially charged in 5 ml of DMSO, 344 mg of K2CO3 were added and the mixture was cooled to 10° C. 1.4 ml of 30% strength H2O2 were then added. The mixture was stirred in an ice bath for 5 min and then at room temperature for another 30 min. The reaction mixture was introduced into 150 ml of water. During the addition, the amide precipitated out. The amide was filtered off, washed and dried under high vacuum. This gave 4.7 g of the beige title compound of m.p. 157-162° C.
Reaction SMILES: C(Br)C.[Mg].[C:5]1([C:11]#[CH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=[O:15].[Cl-].[NH4+]>CCOCC>[CH2:19]([O:18][C:13](=[O:17])[C:14]([OH:15])([CH3:16])[C:12]#[C:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:20]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)C(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)C#Cc1ccccc1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A Grignard reagent was prepared under dry nitrogen by the addition over a 1 hour period of a solution comprising 10.9 g (0.10 mole) of ethyl bromide in 15 ml of anhydrous ether to a magnetically stirred suspension of 2.4 g (0.10 g atom) of clean magnesium metal turnings in 70 ml of dry ether. Stirring at 25° C. was continued for an additional hour and then a solution of 10.2 g (0.10 mole) of phenyl acetylene in 15 ml of dry ether was added over 30 minutes. The stirred solution was then heated at reflux for one hour, during which time the acetylenic Grignard reagent separated into a two phase grey-black liquid. After cooling, the two phase liquid was transferred under dry nitrogen to a 200 ml addition funnel followed by flushing with two 15 ml portions of dry ether. The contents of the funnel were rendered homogeneous, by efficient overhead mechanical stirring, and this mixture was added over 35 minutes to a magnetically stirred solution of 11.6 g (0.10 mole) of ethyl pyruvate in 80 ml of dry ether cooled to -20° C. The mixture was stirred at -20° C. for 2 hours and allowed to warm to room temperature overnight. The resulting yellow-orange solution was cautiously treated with 75 ml of saturated ammonium chloride solution and after stirring for 5 minutes, the phases were separated. The aqueous phase was extraced with two 60 ml portions of ether and the combined organic phases were washed with three 75 ml portions of brine and dried over MgSO4. After filtration and concentration at the stripper, a residual reddish-orange oil (19.6 g) was fractionated through a 15 cm Vigreux column to afford, after a small forerun, a single volatile fraction, b.p. 96.0°-105.0° C./0.10 mm. Redistillation of this cut provided 8.9 g (41% yield) of ethyl-2-hydroxy-2-methyl-4-phenylbutynoate, as a colorless, viscous oil, b.p. 98.0°-101.0° C./0.05 mm.
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[CH:12]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])([CH3:14])[CH3:13].C(N(CC)CC)C>>[CH:12]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][S:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)(=[O:10])=[O:2])([CH3:14])[CH3:13]
Reactant: CC(C)NCCCN
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: CCN(CC)CC
Product: CC(C)NCCCNS(=O)(=O)c1ccc(N)cc1

Procedure:
Sulphanilyl fluoride (6.5 g, 37.1 mmol), N-isopropyl-1,3-propanediamine (5.71 ml, 40.8 mmol) and triethylamine (5.69 ml, 40.8 mmol) in N-butanol (15 ml) was heated at reflux for 10 hours. The mixture was allowed to cool, silica was added and the volatiles were evaporated. The residue was purified by chromatography eluting with DCM/methanolic ammonia (100:0) increasing in polarity to (90:10) to give the title compound as a clear oil which crystallized on standing (8.81 g, 88%). NMR: 0.89 (d, 6H), 1.43 (m, 2H), 2.41 (t, 2H), 2.58 (m, 1H), 2.68 (t, 2H), 3.16 (s, 2H), 5.85 (s, 2H), 6.58 (d, 2H), 7.38 (d, 2H); m/z: 272.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N+:26]([C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][C:33](=[O:42])[N:34]2[CH2:39][CH:40]=O)([O-:28])=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:40][CH2:39][N:34]4[C:35]5[C:30](=[C:29]([N+:26]([O-:28])=[O:27])[CH:38]=[CH:37][CH:36]=5)[CH:31]=[CH:32][C:33]4=[O:42])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2c([N+](=O)[O-])cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c([N+](=O)[O-])cccc32)CC1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To 1 mL of a chloroform solution containing 0.20 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.14 g of (5-nitro-2-oxoquinolin-1(2H)-yl)acetaldehyde, 10 μL of acetic acid and 0.18 g of sodium triacetoxyborohydride were added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography[Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-nitro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: [C:1]([N:5]1[CH2:37][CH2:36][C:35](C)(C)[CH2:34][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@H:21]5[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:40])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:48])C(=O)C1.O>CN(C=O)C>[C:1]([N:5]1[CH2:37][CH2:36][CH2:35][CH2:34][C:8]2[C:9]([Br:48])=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@H:21]5[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:40])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c-2cc2c1C(=O)N(C(C)(C)C)CCC(C)(C)C2
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O
Reaction time: 1 h
Yield: 104.1 %

Procedure:
A solution of 0.95 g of 21d in 10 ml of DMF was treated with 0.32 g of NBS. The reaction was stirred for 1 hr and then poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated and the product filtered through silica gel (using a gradient of heptane-ethylacetate as eluent), to provide 1.08 gr of 21e; LC-MS-ESI: [M+1] 603.13, 605.13. NMR (CDCl3) δ 8.57 and 6.70 (2×s, 2, Ar—H), 5.51 (d, 1, CHO), 4.20 (m, 2, CHO and ethyl ester), 1.25 (t, 3, ethyl ester), 4.32+3.80 (2×m, 2, CH2), 3.78 (3, 3, OCH3), 3.75 (and 3.50 (2×m, 2, CH2), 2.95 and 3.05 (2×m, 2, CH2), 2.65 and 2.70 (2×m, 2, CH2) 1.65-2.0 (bm, 4, 2×CH2) 1.62 and 1.64 (2×s, 6, dimethylketal) 1.57 (s, 9, tertC4H9)
Reaction SMILES: [C:1]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:50])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:49])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:48])[CH2:36][CH2:37][CH2:38][N:39](C(OC(C)(C)C)=O)[CH3:40])=[CH:31][CH:30]=2)[CH3:27])[CH3:19])[CH2:12][CH2:11]1.[ClH:57].O1CCOCC1.CO>O1CCOCC1>[ClH:57].[ClH:57].[ClH:57].[C:1]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:50])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:49])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:48])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40])=[CH:31][CH:30]=2)[CH2:12][CH2:11]1
Reactant: CN(CCCCCC(=O)N(C)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)Cc1ccc(C(=O)CCCN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNCCCC(=O)c1ccc(CN(C)CCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
The compound (460 mg, 0.598 mmol) obtained in Example 78b was dissolved in 1,4-dioxane (6 mL), a 4 N hydrochloric acid-dioxane solution (1.49 mL, 5.98 mmol) and methanol (1 mL) were added under ice cooling, and the mixture was stirred at room temperature for 5.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to give crude 1-(2-{methyl[6-(methyl{-4-[4-(methylamino)butanoyl]benzyl}amino)hexanoyl]amino}ethyl)piperidin-4-yl biphenyl-2-ylcarbamate trihydrochloride. The resulting crude product was used to give the title compound (101 mg; yield, 26%) as a white solid according to the method described in Example 11e.