Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][S:10][C:9](=O)[CH:8]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>O1CCOCC1.C(#N)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][S:10][C:9](=[S:14])[CH:8]=1
Reactant: O=c1cc(-c2cnccn2)ss1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CC#N
Solvent: C1COCCO1
Product: S=c1cc(-c2cnccn2)ss1
Temperature: 100 °C
Yield: 170.2 %

Procedure:
A mixture of 5-(pyrazin-2-yl)-1,2-dithiole-3-one (2 g.) and phosphorus pentasulphide (2.3 g.) in dioxan (35 cc.) is heated for 15 minutes at 100° C., whilst stirring. The red suspension obtained is diluted whilst hot with acetonitrile (35 cc.). The solution is decanted and the precipitate obtained is taken up with a hot mixture (2 × 50 cc.) of dioxan and acetonitrile (50:50 by volume). The combined organic phases are filtered hot, diluted with distilled water (250 cc.), and the requisite amount of a 4N aqueous ammonia solution to adjust the pH to 7. The brown precipitate formed is filtered off, washed with distilled water (2 × 25 cc.) and then with diethyl ether (2 × 10 cc.) and dried. 5-(Pyrazin-2-yl)-1,2-dithiole-3-thione (1.87 g.) melting at 200°-201° C. is thus obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8].C(=O)([O-])[O-].[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O.O1CCOCC1>[CH2:21]([O:20][C:18]([NH:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(Cc1cccs1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a mixture of 3.0 g (16.9 mmol) of β-thienyl-D,L-alanine in 75 mL of water and 60 mL of dioxane, was added 5.6 g (40.6 mmol) of anhydrous potassium carbonate, followed by 2.85 mL (20 mmol) of carbobenzyloxychloride. The resulting mixture was stirred rapidly for approximately one hour. When the reaction was substantially complete, as indicated by thin layer chromatography (21/7/7/9, EtOAc/AcOH/CH3 CN/H2O), the reaction mixture was concentrated. The resultant layers were separated and the aqueous layer was washed with 75 mL of diethyl ether and then layered with 150 mL of methylene chloride. The resultant mixture was acidified with rapid stirring to pH=2.0 using 5N hydrochloric acid. The layers were then separated, and the organic layer was dried with sodium sulfate (Na2SO4), filtered and concentrated to provide 5.05 g of desired compound (98%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: Cc1ccc2ccccc2c1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccccc2c1Br
Temperature: 25 °C
Yield: 42.7 %

Procedure:
1-Bromo-2-methyl naphthalene (25 g), N-bromosuccinimide (24.2 g), carbon tetrachloride (250 mL) and a catalytic amount of azo(bis)isobutylnitrile were refluxed 40 hours under a nitrogen atmosphere. The reaction was cooled to room temperature and volatile materials were removed in vacuo on a rotary evaporator. the residue was treated with hot hexane (steam bath, about 2×250 mL). The hexane solution was decanted and cooled in ice. The product was collected on a Buchner funnel and air dried to give 14.5 g of 1-bromo-2-bromomethylnaphthalene as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCCCN
Solvent: CCO
Product: CCCCNc1cc(Cl)nc(N)n1
Reaction time: 1 h
Yield: 71.5 %

Procedure:
10 g of 2-amino-4,6-dichloropyrimidine are suspended in 100 ml of ethanol. 11.15 g of butylamine are added. The reaction mixture is refluxed for 2 hours and then evaporated to dryness. The residue is taken up in 100 ml of water. After 1 hour's stirring the precipitate is filtered off on sintered glass and is then recrystallized from 80 ml of 6/4 water/acetonitrile. 8.75 g of 2-amino-4-butylamino-6-chloropyrimidine are obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:24])[CH:11]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:30]([Si:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)Cl)([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH:10]([OH:24])[CH:11]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][O:15][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO)C(=O)c1cccnc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4.69 g (0.0133 mole) of 1-(t-butyldimethylsilyloxy)-3-nicotinoylhexan-2,6-diol, 2.18 g (0.032 mole) of imidazole in 12 ml of dimethylformamide is added at once 4.38 g (0.0159 mole) of t-butyldiphenylchlorosilane, the mixture is stirred at room temperature overnight, diluted with 30 ml of ethyl acetate and washed with water (2×10 ml) and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using ethyl acetate-methylene chloride (2:3) as eluent to give 1-(t-butyldimethylsilyloxy)-6-(t-butyldiphenylsilyloxy)-3-nicotinoylhexan-2-ol as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCSC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N1CCSC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
(2S, 4R)-4-Hydroxy-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.34 g, 0.0111 mol, Example 17A) was dissolved in DMSO and cooled to 0° C. To the cold solution, triethylamine (7.37 g, 0.0729 mol) and sulfur trioxide pyridine complex (8.44 g, 0.0530 mol) were added. The mixture was stirred at 0° C. for 2 hours, brought to room temperature and quenched with water. The mixture was extracted with ethyl acetate and washed with 1 M HCl (60 mL), saturated NaHCO3 (2×40 mL) and brine (1×30 mL). The organic layer was dried with Na2SO4, filtered, concentrated, and purified by column chromatography (ethyl acetate/hexane, 1/1) to give the titled compound 2.05 g. MS (ESI APCI) m/e 299 (M−H)+; 1H NMR (300 MHz, methanol-d4): δ ppm 5.07 (d, 1H), 4.80 (m, 1H), 4.57-4.68 (m, 2H), 4.45 (m, 1H), 3.85 (d, 2H), 3.78 (m, 2H), 3.17 (t, 1H), 3.05 (m, 2H), 2.44-2.49 (d, 1H), 1.47 (s, 9H).
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O-].[Na+].[CH2:15]([CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[CH3:16]>CO>[CH2:15]([C:17]1[C:18](=[O:19])[NH:10][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][C:23]=1[OH:24])[CH3:16]
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1c(O)nc(-c2ccccc2)[nH]c1=O
Yield: 50.9 %

Procedure:
A mixture of 45.19 g (0.29 mol) of benzamidine hydrochloride hydrate, 127.42 g (0.59 mol) of 25% sodium methoxide in methanol, 55 mL (0.29 mol) of diethyl ethylmalonate and 175 mL of methanol was heated at reflux for 25 h. The mixture was rotovapped to remove the bulk of the methanol. The residue was diluted with 300 mL of water and the pH was adjusted to 7 with concentrated hydrochloric acid. The solid precipitate was collected by filtration and dried under vacuum at 50° C. to afford 31.89 g (51%) of crude 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone as a pale yellow solid. 1H-NMR (d6 -DMSO)δ1.05(3H, t), 2.39(2H,q), 7.5(3H,m), 8.1(2H,m).
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:27]1([N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:40](=O)[O:41]C3C=CC=CC=3)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:2][S:3]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:9][CH2:10][N:11]([C:40]([NH:39][CH:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[O:41])[CH2:12][CH2:13]2)[CH2:7]1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: O=C(NC1CCN(c2ccccc2)CC1)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC2(CCN(C(=O)NC3CCN(c4ccccc4)CC3)CC2)c2ccccc21
Yield: 31.6 %

Procedure:
1-Methanesulfonyl-spiro[indoline-3,4′-piperidine] hydrochloride (37 mg) and triethylamine (170 μL) were added to a solution of phenyl N-(1-phenyl-4-piperidyl)carbamate (36 mg) in chloroform (3 mL), and the mixture was heated to reflux for 15 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from diethyl ether to give the title compound (18 mg) as a colorless crystal.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC1(C)[O:28][C:27](=O)[C:24]2([CH2:26][CH2:25]2)[C:23](=[O:30])[O:22]1>>[O:28]=[C:27]1[CH:24]([C:23]([OH:30])=[O:22])[CH2:25][CH2:26][N:15]1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]2[CH:16]=[CH:17][C:3]([C:2]([F:18])([F:19])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Product: O=C(O)C1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)C1=O

Procedure:
The title compound is prepared in analogy to Example 3c) from 4-(4-trifluoromethyl-benzyloxy)-phenylamine and 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione. Yield: 37% of a colorless solid. MS: m/e=380.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2[N+:32]([O-])=O)[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.O.[Fe]>[NH2:32][C:7]1[CH:8]=[C:9]([CH:22]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(C)C)c1cc(N)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 78.2 %

Procedure:
Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (300 mg, 0.626 mmol) was taken in 30 ml of Toluene:Water (1:1) and to it added Fe powder (203 mg, 3.62 mmol), Ammonium formate (228 mg, 3.62 mmol). The reaction mixture was refluxed for 3 h and then filtered through celite. The toluene was distilled off under reduced pressure and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 220 mg of ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. 1H NMR (CDCl3): δ 7.40-7.20 (m, 5H), 6.90(s 1H), 4.50(bs,2H),4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d,2H),1.95-2.00(m,1H), 1.75-1.80 (m,1H), 1.45-1.50(m,1H), 1.20(t,3H), 1.00 (m,6H), 0.35-0.25 (m,5H). Mass: (450, M+1, 100%).
Reaction SMILES: [C:1]1(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[O:9])O1.[NH2:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1.CN(C1C=CN=CC=1)C>[O:19]=[C:13]1[CH:12]([N:11]2[C:3](=[O:9])[C:4]3=[CH:8][S:7][CH:6]=[C:5]3[C:1]2=[O:10])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C1OC(=O)c2cscc21
Reactant: NC1CCC(=O)NC1=O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cscc3C2=O)C(=O)N1
Yield: 79.5 %

Procedure:
1.54 g thieno(3,4-c)furan-1,3-dione was dissolved in 20 mL of anhydrous THF, and 12.8 g of 3-aminopiperidine-2,6-dione was added. The reaction mixture was allowed to react at room temperature for 4 h. Then, 2 g of CDI and a catalytic quantity of DMAP were added, and the reaction mixture was allowed to reflux for 6 h until a large amount of white solid precipitated. The solid was cooled and filtered to yield 2.1 g of the title product.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:15][O:13][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
Under ice cooling, 18.7 g of N-Boc-L-serine was dissolved in 200 ml of DMF and 13.25 g of solid K2CO3 was added and suspended for 15 minutes, and then 41.6 g (3.2 eq) of Mel was added, followed by stirring for 24 hours. After the reaction, the reaction solution was filtered through celite and concentrated. The residue was extracted by liquid separation using 400 ml of water and 150 ml×4 of ethyl acetate and dried over sodium sulfate. The ethyl acetate layer was concentrated and subjected to silica gel column chromatography to obtain 17.1 g (87.4%) of an N-Boc-L-serine methyl ester as a transparent oily product.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH:6]=[N:7]2.P(Cl)(Cl)([Cl:19])=O>[OH-].[NH4+]>[Cl:19][C:4]1[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=2[CH3:1])[N:7]=[CH:6][CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1N=CCC2=O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc([N+](=O)[O-])c(C)c2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flask is placed 5,8-dimethyl-6-nitro-4-quinolone (3.01 g, 13.8 mmol) with phosphorus oxychloride (41.3 g, 268 mmol). The mixture is refluxed under argon with stirring for 3 hours. After cooling to room temperature the mixture is poured on crushed ice, and concentrated ammonium hydroxide (100 mL) is added. Extraction with chloroform (2×200 mL), drying over potassium carbonate, filtration and solvent removal by rotary evaporation gives 4-chloro-5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH:7]=1.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[S:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)(=[O:35])=[O:34])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCCO3)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)OCCO3)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-(3-{[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12n, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.66 (m, 1H), 7.95 (d, 1H), 7.85 (m, 1H), 7.45 (m, 1H), 7.15-6.91 (m, 4H), 6.68-6.54 (m, 3H), 4.45 (s, 2H), 4.36 (s, 2H), 4.19 (s, 4H), 3.68 (s, 3H), 2.82 (t, 2H), 2.53 (t, 2H); MS 483 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2.C(OCC)(OCC)O[CH2:22][CH3:23].S(=O)(=O)(O)O>C(O)C.C(OCC)(=O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2
Reactant: O=C(O)c1ccc2c(c1)CCc1ccccc1C2=O
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)CCc1ccccc1C2=O
Yield: 93.9 %

Procedure:
[step 1] 5-Oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid (JP-B-2526005, 19.9 g, 79 mmol) and triethyl orthoformate (17.0 mL, 102 mmol) were dissolved in ethanol (130 mL), followed by adding concentrated sulfuric acid (1.68 mL, 32 mmol) and the mixture was stirred under reflux for 12 hr. The mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10) to give ethyl 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylate (20.8 g, 94%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O)=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:3][C:1]([C:5]1[CH:6]=[C:7]2[C:8]([N:9]=[C:18]3[C:17](=[C:15]2[OH:14])[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:11]=1)([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc2nc3c(c(O)c2c1)CCCC3
Temperature: 25 °C

Procedure:
A solution prepared from 25.0 g of 4-t-butylaniline-29.0 g of 2-ethoxycarbonylcyclohexanone, 100 ml of benzene and 0.20 g of p-toluenesulfonic acid was refluxed for 6 hours. At the end of this time no more water was collected from the reaction (Dean-Stark trap), so the benzene was evaporated and the residue was dissolved in 80 ml of diphenyl ether. This mixture was refluxed for 1 hour and then allowed to cool to room temperature overnight. The product which had precipitated from this solution was filtered off and washed well with diethyl ether to give 11.52 g of analytically pure product, m.p. 320°-322°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30].[O:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH:34]5[CH2:35][CH2:36][O:31][CH2:32][CH2:33]5)[CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30]
Reactant: O=C1CCOCC1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCNC1)C3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C2CCOCC2)C1)C3
Yield: 44.5 %

Procedure:
A mixture of Example 80 (150 mg; 0.35 mmol; 1 eq.), tetrahydropyran-4-one (52 mg; 0.52 mmol; 1.5 eq.) and sodium triacetoxyborohydride (74 mg; 0.35 mmol; 1 eq.) in DCE (4 mL) was stirred at 50° C. for 16 hours. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to EA/MeOH/TEA, 90/10/2) afforded the title compound (80 mg, 45%) as white foam. 1H NMR (DMSO-d6) δ 7.41-7.31 (m, 1H), 6.99 (dd, J=11.5, 2.2 Hz, 1H), 6.87 (td, J=8.4, 2.3 Hz, 1H), 5.03-4.94 (m, 1H), 4.85-4.77 (m, 2H), 4.75-4.44 (m, 2H), 3.74-3.59 (m, 2H), 3.22-3.06 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.79-2.64 (m, 3H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.35-2.15 (m, 2H), 2.14-2.00 (m, 1H), 1.82-1.68 (m, 1H), 1.63-1.50 (m, 2H), 1.31-1.03 (m, 2H). HPLC (max plot) 95.1%, Rt 2.83 min. UPLC/MS: (MS+) 514.5 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Rh]>[C:1]([O:5][C:6]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CC1CCCCC1)C(=O)O
Yield: 71.4 %

Procedure:
A solution of 4.8 g of t-butoxycarbonyl-N-methylphenylalanine in 150 ml of tetrahydrofuran was hydrogenated at 60° for about four days using 60 psi hydrogen gas and 5% rhodium on carbon. The mixture was filtered and the filtrate concentrated to give the title compound (3.5 g) as a colorless oil. The oil was used without further purification. Structure assignment was supported by the nmr spectrum (loss of aromatic protons and appearance of cyclohexyl protons) and by elemental analysis.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)#[N:2].[ClH:17].[CH2:18]([OH:20])[CH3:19]>ClCCl>[ClH:17].[CH2:18]([O:20][C:1](=[NH:2])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH3:19]
Reactant: CCO
Reactant: Cc1ccc(OCC#N)cc1NS(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)COc1ccc(C)c(NS(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
N-(5-Cyanomethoxy-2-methylphenyl)-methanesulfonamide (3.48 g) was dissolved in a mixture of 70 ml of dichloromethane and 3.5 ml of ethanol. The reaction mixture was cooled in an ice bath, saturated with hydrogen chloride gas (Matheson, Newark, Calif.), and slowly allowed to come to room temperature and kept there for 16 hours. The solvent was evaporated leaving 5.2 g of 2-(4-methyl-3-methanesulfonylaminophenoxy)-acetimidic acid ethyl ester hydrochloride. ##STR67##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:46]([C:49]1[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=1)([O-:48])=[O:47].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:53](=[O:54])[C:52]2[CH:51]=[CH:50][C:49]([N+:46]([O-:48])=[O:47])=[CH:57][CH:56]=2)[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)C2C1CCN2C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
To a solution of bicyclic alcohol 11 (4.0 g, 11.0 mmol) in benzene (55 mL) at ambient temperature was added Ph3P (5.8 mg, 22.1 mmol) and p-nitrobenzoic acid (3.7 g, 22.1 mmol). DIAD (4.6 mL, 22.1 mmol) was added dropwise via syringe over 1 h, keeping the temperature below 25° C. After 12 h, the reaction mixture was concentrated in vacuo and the residue was purified by flash silica gel chromatography (3:1 to 1:1 hexanes/EtOAc). The partially-purified product (42) was used without further purification. Mass spectrum, m/z [511.9] (M+H)+.