Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Fc1ccc(I)c(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccc(F)cc3Cl)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2-chloro-4-fluoro-1-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 504.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.C(OCC)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Yield: 75.1 %

Procedure:
To a solution of 22.6 g of 2,4-dichloro-3-nitroquinoline and 13.0 ml of triethylamine in 60 ml of N,N-dimethylformamide, a solution of 23.0 g of 4-(2-aminoethyl)-N-triphenylmethylpiperidine in 40 ml of N,N-dimethylformamide was added dropwise with stirring under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was added with ethyl acetate and water. The precipitated crystals were collected by filtration, and washed successively with ethyl acetate and diethyl ether to give 26.9 g of yellow crystals. Recrystallization from a mixture of N,N-dimethylformamide and ethyl acetate gave yellow crystals having the melting point of from 223.5 to 231° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:4][N:3]=1.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:36][C:28]1[CH:29]=[C:30]([N:4]2[C:5]3[C:10](=[C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[N:3]2)[CH:31]=[CH:32][C:27]=1[O:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1n[nH]c2cccc(OCc3ccccc3)c12
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nn(-c2ccc(OCc3ccccc3)c(F)c2)c2cccc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.7 %

Procedure:
A mixture of 3-methyl-4-[(phenylmethyl)oxy]-1H-indazole (D30) (0.952 g, 4 mmol), 4-benzyloxy-3-fluorobenzeneboronic acid (1.97 g, 8.0 mmol), copper (II) acetate (1.09 g, 6.0 mmol), pyridine (0.647 mL, 8.0 mmol) and powdered 4A molecular sieves (4 g) in dichloromethane (25 mL) was stirred in an air atmosphere at room temperature. After 48 hrs, the mixture was filtered through Celite, concentrated, redissolved in ethyl acetate, refiltered and concentrated and then chromatographed (0-50% ethyl acetate in hexane and 0-40% diethyl ether in hexane). A white solid crystallised out from some fractions and this was collected by filtration to give the title compound (D31) (0.45 g).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1>C(Cl)(Cl)Cl>[Cl:1][S:2]([C:14]1[CH:13]=[CH:12][C:11]2[O:6][CH2:7][CH2:8][O:9][C:10]=2[CH:15]=1)(=[O:5])=[O:3]
Reactant: c1ccc2c(c1)OCCO2
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Temperature: 20 °C

Procedure:
Chlorosulfonic acid (6 mL, 90 mmol) was added dropwise to an ice cooled solution of 1,4-benzodioxane (12 gm, 88 mmol) in chloroform (40 mL). After allowing the reaction mixture to warm to 20° C. (about 15 min.), this solution was poured on to ice (400 gm) and the product extracted into chloroform. This extract was dried (MgSO4) and the solvent evaporated to give the 6-chlorosulfonyl-1,4-benzodioxane as a white crystalline solid. This sulfonyl chloride was dissolved in methylene chloride (100 mL) and added to an ice cooled solution of 4-amino-1-butanol (10 gm, 112 mmol) and excess triethylamine (25 mL) in methylene chloride (250 mL). After stirring for 24 hours and gradually warming to ambient temp., the reaction mixture was washed with 6N HCl (100 mL), dried (MgSO4) and filtered. To this resulting solution was added 3,4-dihydro-2H-pyran (20 mL, 219 mmol) and p-toluenesulfonic acid (100 mg) and additional methylene chloride to bring the volume to 300 mL. After stirring at ambient temp. for 15-20 hours, the solution was washed with saturated aq. Na2CO3 (100 mL), dried (MgSO4) and the solvent evaporated. The oily residue was chromatographed on a column of silica gel and eluted with 30% ethyl acetate/hexane to give the purified product as a colorless oil.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.CN(C)C=O.[NH2:16][CH:17]([CH2:30][O:31][CH3:32])[CH2:18][O:19][C:20]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[O:22][N:21]=1>C(OCC)(=O)C.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]2[O:22][N:21]=[C:20]([O:19][CH2:18][CH:17]([NH:16][CH:1]=[O:3])[CH2:30][O:31][CH3:32])[C:24]=2[CH:25]=1
Reactant: O=CO
Reactant: COCC(N)COc1noc2ccc(Cl)cc12
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COCC(COc1noc2ccc(Cl)cc12)NC=O

Procedure:
To 0.29 ml of formic acid is added 0.74 ml of acetic anhydride, and they are subjected to reaction at 40° C. for one hour. To the reaction mixture are added 5 ml of N,N-dimethylformamide and 1.00 g of 3-(2-amino-3-methoxypropoxy)-5-chloro-1,2-benzoisoxazole, and they are subjected to reaction at the same temperature for one hour. To the reaction mixture are added water and ethyl acetate, and after shaking, the organic layer is separated. Water is added again to the separated organic layer and the pH is adjusted to 8 with an aqueous sodium hydroxide solution, after which the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. Upon recrystallization from a mixed solvent of diisopropyl ether and ethyl acetate, there is obtained 0.50 g of colorless, crystalline 5-chloro-3-(2-formylamino-3-methoxypropoxy)-1,2-benzoisoxazole having a melting point of 90°-92° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.IC>C1COCC1>[CH3:22][O:21][C:19]([C:16]1([CH3:1])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)=[O:20]
Reactant: COC(=O)C1CCOCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCOCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (10.2 ml, 72.8 mmol) in THF (400 ml) at −78° C., n-BuLi (25.2 ml, 1.6 M in heptane) is added. The reaction is removed from the bath and stirred for 10 min. It is then cooled to −78° C. again and methyl tetrahydro-2H-pyran-4-carboxylate (6.48 ml, 48.6 mmol) is added. After 30 min, iodomethane (6.07 ml, 97 mmol) is added and the reaction allowed to reach rt. The reaction is then quenched with 1 N HCl (200 mL) and extracted with EtOAc. The organic layer is dried and evaporated to give 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester. MS (ESI) m/z 159.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:8]([OH:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.B1(/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:14][C:8]1[C:9]([CH3:12])([CH3:13])[C:10]2[C:5]([C:6](=[O:26])[C:7]=1[C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])=[CH:4][CH:3]=[C:2](/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:11]=2
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(Br)ccc2C1=O
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(/C=C/c3ccccc3)ccc2C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Tert-butyl 2-(7-bromo-2-hydroxy-1,1-dimethyl-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (360 mg, 848 μmol, Example 53A-E) was dissolved in 1,4-dioxane (8485 μL) and then beta-styrylboronic acid pinacol ester (293 mg, 1273 mmol), potassium carbonate (2 M in water, 2121 μL, 4242 μmol) and tetrakis(triphenylphosphine)palladium (98.0 mg, 84.8 μmol) were added. The reaction was stirred at 80° C. for 4 hours. The reaction mixture was diluted with 100 mL of EtOAc, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated to give crude product. The title compound was obtained by flash chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)(O)[O-].[Na+].CI>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:23])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-nitrophenyl)propanoic acid (45.0 g, 145 mmol) was dissolved in DMF (425 mL) and treated with sodium bicarbonate (24.4 g, 290 mmol) followed by methyl iodide (36.1 mL, 580 mmol). The solution stirred at rt for 16 h. The solution was diluted with ethyl acetate (500 mL), washed with water (500 mL), saturated aqueous sodium bicarbonate solution (300 mL), aqueous hydrochloric acid solution (1.0 N, 500 mL), and the organic phase dried over sodium sulfate. The solvent was removed in vacuo to afford product as a slightly yellow solid (46.2 g, 98%). 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 4.45–4.41 (m, 1H), 3.71 (s, 3H), 3.30–3.26 (m, 1H), 3.05–2.99 (m, 1H), 1.36 (s, 9H); LCMS found for C15H20N2O6Na (M+Na)+: m/z=347.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.[I-].[CH3:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:14])=[CH:4][CH:3]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the aldehyde from Example 28C [(1S,2S)-2-(4-bromophenyl)cyclopropanecarbaldehyde] and methyltriphenylphosphonium iodide [CAS 2065-66-9] in anhydrous dichloromethane was stirred at 0° C. under N2. Potassium t-butoxide was added to this chilled mixture. The ice bath was removed and the mixture was stirred at room temperature for one hour. The mixture was quenched with saturated aqueous NH4Cl. The mixture was extracted with dichloromethane and the combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel with hexanes to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([OH:12])(=O)[C:8]([CH3:10])=[CH2:9].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClCCl>[CH3:1][C:2]1[S:3][C:4]2[C:7](=[O:12])[CH:8]([CH3:10])[CH2:9][C:5]=2[CH:6]=1
Reactant: Cc1cccs1
Reactant: C=C(C)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(s1)C(=O)C(C)C2
Reaction time: 0.08 h
Yield: 22.7 %

Procedure:
A mixture of 150 g of 2-methylthiophene (1.5 mol) and 157.5 g of methacrylic acid (1.8 mol) was added within 30 minutes at about 80° C. to 1500 ml of Eaton's reagent, and the temperature was between 78° C. and 83° C. On completion of addition, the reaction mixture was stirred for a further 5 minutes and then gradually poured into a vigorously stirred mixture of 3000 ml of water and 500 ml of dichloromethane. The organic phase was removed and dried over magnesium sulfate. The solvent was distilled off on a rotary evaporator and 263.5 g of crude product were obtained in a purity of 88.2% according to GC-MS analysis. A portion of the crude product (79 g) was distilled (92° C., 0.02 torr). 56.5 g (76%) of product were obtained as a mixture of two isomers in a ratio of approx. 9:1 (thiophen-6-one: thiophen-4-one).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.ClC1N=CC(CN2C(=O)C3=CC=CC=C3C2=O)=CC=1>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)nc1
Agent: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Product: NCc1ccc(Br)nc1

Procedure:
The reaction procedure of Reference Example 3 was repeated except that N-(6-bromo-3-pyridylmethyl)phthalimide was used in lieu of N-(6-chloro-3-pyridylmethyl)phthalimide, to give the title compound as pale yellow crystals.
Reaction SMILES: C1N=C[N:3]([C:6](N2C=NC=C2)=[S:7])C=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C([O-])(=O)C.[NH4+]>C(#N)C.CO>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[NH:13][C:6]([NH2:3])=[S:7]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2ccccc2n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC#N
Product: NC(=S)Nc1ccc2ccccc2n1
Reaction time: 1 h
Yield: 41 %

Procedure:
1.496 g (8.394 mmol) N,N′-thiocarbonyldiimidazole was dissolved in 30 mL acetonitrile, and 1.210 g (8.394 mmol) 2-amino-quinoline dissolved in 15 mL acetonitrile was added dropwise at room temperature. After 1 hr a precipitate deposited, and stirring was performed for an additional 12 hr. The solid was filtered off, and without further purification was reacted directly with 1.294 g (16.789 mmol) ammonium acetate in 50 mL methanol for 5 hr at 40° C. After mass spectrometric analysis the solvent was removed under vacuum, and the batch was dissolved in dichloromethane and shaken out with water (1×50 mL). The organic phase was dried over magnesium sulfate and filtered, and the solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel (column Ø=3 cm, h=15 cm), first with dichloromethane as eluent, then with methanol to increase the polarity, and finally with pure methanol. The clean fraction was purified and the solvent was removed under vacuum, resulting in a total of 0.70 g (3.445 mmol, 41%) N-quinolin-2-yl-thiourea.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].CO[CH2:19][Cl:20]>>[Cl:20][CH2:19][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:8]([CH:9]=[O:10])[C:7]=1[OH:12]
Reactant: COCCl
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: [Al+3]
Agent: [Cl-]
Product: O=Cc1cc([N+](=O)[O-])cc(CCl)c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Nitrosalicylaldehyde (2.42 g, 14.5 mmols) was suspended in 20 ml of chloromethyl methyl ether, and aluminum chloride (7.97 g, 60.0 mmols) was added while cooling in an ice bath. After stirring at room temperature for 10 minutes, the mixture was heated at 60° C. for one hour. Then, the reaction solution was poured into 100 ml of ice water while cooling in an ice bath and the resulting yellow precipitate was filtered. The resulting precipitate was recrystallized from 330 ml of hexane to give 3-chloromethyl-5-nitrosalicylaldehyde (2.49 g, 11.6 mmols) as a yellow needle-like crystal (yield 80%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[CH3:31][CH:32]([CH3:36])[C:33](O)=[O:34].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:31][CH:32]([CH3:36])[C:33]([O:30][C:27]1[CH:28]=[CH:29][C:24]([N:8]2[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:23]=[C:7]2[C:3]2[C:2]([NH2:1])=[N:6][O:5][N:4]=2)=[CH:25][CH:26]=1)=[O:34]
Reactant: CC(C)C(=O)O
Reactant: Nc1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccc(O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Oc1ccc(-n2c(-c3nonc3N)nc3cnc(Oc4cccc(N)c4)cc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.2 %

Procedure:
A solution of the product of Step 4 (80 mg, 0.20 mmol) and 2-methylpropanoic acid (18.4 mg, 0.21 mmol) in 2 ml DMF was treated with 1-hydroxybenzotriazole hydrate (HOBT)(29.7 mg, 0.22 mmol). The resulting mixture was stirred for 10 minutes at room temperature before being treated with triethylamine (22 mg, 0.22 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (42 mg, 0.22 mmol). The reaction was kept at room temperature overnight. Purification of the crude mixture by reverse phase (CH3CN 30%-80% in H2O with 0.1% TFA) afforded 20 mg (31%) oil as title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.89 (s, 1H), 7.68 (d, 2H, 8.8 Hz), 7.38 (d, 2H, 8.8 Hz), 7.32 (t, 1H, 8.0 Hz), 6.85 (d, 1H, 7.6 Hz), 6.79-6.91 (m, 3H), 5.5-6.8 (M, 6H), 2.88 (m, 1H), 1.28 (d, 6H, 6.8 Hz). MS (ES+) m/e 372.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][C@@H:5]([OH:18])[CH2:4]1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([S:8]([N:7]2[CH2:6][C@@H:5]([O:18][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH2:4][C@@H:3]2[CH2:2][O:1][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H](O)C[C@@H]2CO)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To an ice-cold solution of 5-hydroxymethyl-1-(toluene-4-sulfonyl)-pyrrolidin-3-ol (4) (0.45 g, 1.66 mmol) in pyridine (3 mL) is added 4-toluylsulfonyl chloride (1.11 g, 5.81 mmol) in one portion. The temperature rises to 50° C., then the reaction mixture is cooled to 10° C., kept at that temperature for an additional 2 h and then left at room temperature overnight. The mixture is poured into 2N HCl (13 mL). On cooling the compound precipitates out and separated by filtration, washed with cold water (2×5 mL), and dried under reduced pressure to give compound (5) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.C(Cl)(=O)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.C1COCC1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[C:3]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1CCc1ccccc1

Procedure:
The title compound was prepared as described in General Method 5 using 3.0 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one, 3.2 mmol of hydrocinnamoyl chloride, 3.2 mmol of triethylamine, and 30 mL of THF, followed by 30 mL of toluene and catalytic DMAP. Chromatography of the residue afforded 1.5 mmol of the intermediate 3-acyl compound. Reduction of this acyl derivative was accomplished with 3 mmol of sodium cyanoborohydride. The product was triturated from ether:hexane (1:5) to give the title compound (m.p. 68°-70° C.). 1H NMR (DMSO-d6) δ2.20 (m, 2H), 2.35 (m, 2H), 2.42-2.59 (m, 4H plus DMSO), 3.06 (q, 2H), 7.00 (dd, 2H), 7.07-7.43 (m, 13H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([S:6](Cl)(=[O:8])=[O:7])=[CH:2]1.[NH3:10]>>[O:1]1[CH:5]=[CH:4][C:3]([S:6]([NH2:10])(=[O:8])=[O:7])=[CH:2]1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccoc1
Product: NS(=O)(=O)c1ccoc1

Procedure:
3-Furylsulfonyl chloride was treated with ammonia according to the procedure described in Example 46, step 1, to produce the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C:42]([O:44]CC3C=CC=CC=3)=[O:43])=[O:36])[N:30]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C:42]([OH:44])=[O:43])=[O:36])[N:30]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 3.9 g 4-[(S)-2-({5-[2-((S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-tert-butoxycarbonyl-butyryl]-piperazine-1-carboxylic acid butyl ester in 80 ml ethyl acetate were added under argon 2 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 24 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 2.6 g.