Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:10]([CH3:16])=[C:11]([C:13](Cl)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:10]([CH3:16])=[C:11]([C:13]([NH:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)nc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1Cl
Reactant: NN1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
Part C: 2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carbonyl chloride (1.5 gram, 3.75 mmol), 1-aminopiperidine (0.725 gram, 7.25 mmol) and triethylamine (0.549 gram, 5.44 mmol) are dissolved in dichloromethane and stirred for one hour at room temperature. The mixture is washed with a saturated aqueous NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo and further purified by column chromatography (heptane/ethyl acetate=1/1 (v/v), silicagel) to give 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (0.220 gram, 13% yield) as a white foam. MS: 463.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:22]2[N:21]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH:29]4[CH2:33][C:32](=[O:34])[N:31]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=5)[CH2:30]4)[CH:27]=3)[NH:19][C:18]=2[C:17](=[O:45])[N:16]([CH2:46][CH2:47][CH3:48])[C:15]1=[O:49]>CCO>[NH2:3][CH2:12][CH2:13][N:14]1[C:22]2[N:21]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH:29]4[CH2:33][C:32](=[O:34])[N:31]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=5)[CH2:30]4)[CH:27]=3)[NH:19][C:18]=2[C:17](=[O:45])[N:16]([CH2:46][CH2:47][CH3:48])[C:15]1=[O:49]
Reactant: CCCn1c(=O)c2[nH]c(-c3cnn(CC4CC(=O)N(c5cccc(C(F)(F)F)c5)C4)c3)nc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC4CC(=O)N(c5cccc(C(F)(F)F)c5)C4)c3)nc2n(CCN)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-8-{1-[5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1-propyl-3,7-dihydro-purine-2,6-dione (56 mg, 0.083 mmol) was taken in EtOH (10 ml) to this monohydrated N2H4 (8.3 mg, 0.16 mmol) was added and stirred the reaction mixture for 1 h at room temperature. After completion of the reaction, solvent was evaporated under vacuum, solid was filtered, washed with DCM and the fitrate was concentrated to give the pure product (20 mg, 44%) as white solid.
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19]Br)=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-:26])(=[O:25])[CH3:24].[K+].CN(C)C=O.[I-].[K+]>CCOCC>[C:1]([C:9]1[C:18]([CH2:19][O:26][C:23](=[O:25])[CH3:24])=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=C(c1ccccc1)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a solution of 3.0 g. (8.4 mmol.) of 2-benzoyl-3-bromomethylquinoxaline 1,4-dioxide and 0.90 g. (9.2 mmol.) of potassium acetate in 40 ml. of N,N-dimethylformamide, was added 0.22 g. (1.3 mmol.) of finely ground potassium iodide. The reaction mixture was stirred for 1.5 hours at ambient temperature, and then it was poured into 1,000 ml. of ether. The solid which precipitated was removed by filtration and discarded. Evaporation of the filtrate in vacuo left a yellow solid which was washed with methanol and dried, to give 2.7 g. (94% yield) of 2-benzoyl-3-acetoxymethylquinoxaline 1,4-dioxide, m.p. 164°-167° C.
Reaction SMILES: Br[C:2]1[C:3]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:15])=[N:12][O:13][CH:14]=1)=[O:8].[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:5]2[CH:4]=[C:3]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[C:11]([CH3:15])=[N:12][O:13][CH:14]=2)=[O:8])=[CH:20][CH:21]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nocc1NC(=O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
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: [Na+]
Solvent: COCCOC
Product: Cc1nocc1NC(=O)c1cc(-c2cnn(C)c2)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-(3-methyl-4-isoxazolyl)-4-(4-morpholinylmethyl)benzamide (may be prepared as described in Example 16; 89 mg, 0.18 mmol) in 1,2-dimethoxyethane (3 ml) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.4 mg, 0.19 mmol), sodium carbonate (0.35 ml, 0.35 mmol) and Pd(Ph3P)4 (12.23 mg, 10.59 μmol). The mixture was heated at 120° C. in a microwave for 35 minutes, the solvent removed in vacuo and the residue purified by MDAP to yield the title compound as a white solid. 12 mg.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@H]([C@@H](C(O)=O)O)O)O)O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)O
Product: O=C[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)C(=O)O

Procedure:
As the standards for PA hexuronic acids, use is made of those prepared by pyridyl-(2)-amination of glucuronic acid manufactured by Sigma Chemical Co., galacturonic acid manufactured by Wako Pure Chemical Industries, Ltd., iduronic acid obtained by hydrolyzing 4-methylumbelliferyl-α-L-iduronide manufactured by Sigma Chemical Co., and mannuronic acid and guluronic acid obtained by hydrolyzing alginic acid (mfd. by Wako Pure Chemical Industries, Ltd.) in accordance with the method described in Acta Chemica Scandinavicaj, 15, 1397-1398 (1961) followed by the separation with an anion exchange resin.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=[CH:10][C:9]=2[C:8]([CH3:20])=[CH:7]1.ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N+:11]([O-:26])=[CH:10][C:9]=2[C:8]([CH3:20])=[CH:7]1
Reactant: CCOC(=O)c1cc2c(cn1)c(C)cn2CCCOC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2c(c[n+]1[O-])c(C)cn2CCCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
To a solution of ethyl 1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (100 mg) in chloroform (2 mL) was added meta-chloroperoxybenzoic acid (250 mg) under ice-cooling, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and then the resulting residue was purified by NH-silica get column chromatography (eluent: ethyl acetate→ethyl acetate/methanol=10/1) to give ethyl 1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate 5-oxide [REx(105-5)] (40 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[N:16]=O)[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH2:1]([N:5]1[C:6]2[CH:15]=[CH:14][C:13]3[C:8]([C:7]=2[N:16]=[C:24]1[C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ccccc2c1N=O
Reactant: COc1ccc(C=O)cc1
Product: CCCCn1c(-c2ccc(OC)cc2)nc2c3ccccc3ccc21
Yield: 53 %

Procedure:
The compound of the title is prepared by following essentially the same procedure described in example 2 but starting from 2-butylamino-1-nitrosonaphthalene instead of 2-methylamino-1-nitrosonaphthalene and employing 4-methoxybenzaldehyde instead of 4-ethoxybenzaldehyde. Yield 53%. M.p. 99,5°-100,5° C.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[C:16]([OH:18])=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:35])[CH2:3][CH2:2]1.[CH:36]([N:39](C(C)C)[CH2:40]C)(C)C.[Cl-].ClC1N(C)CC[N+]=1C.CNC>CN(C)C=O.C1COCC1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:10][CH2:11][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[C:16]([N:39]([CH3:40])[CH3:36])=[O:18])[CH2:13][CH2:14]3)[O:7][CH2:6][C:5]2=[O:35])[CH2:2][CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: CN1CC[N+](C)=C1Cl
Agent: CNC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A solution of 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(4-(quinolin-7-yl)phenyl)acetic acid (0.191 mmol) in N,N-dimethylformamide (1 mL) was treated with diisopropylethylamine (0.573 mmol) and 2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium chloride (25% in dichloromethane, 0.108 mL) at room temperature. The reaction was stirred for 10 min at which point dimethylamine (2M in THF, 0.286 mmol) was added in one portion. The reaction was allowed to stir overnight, at which point additional dimethylamine (50 μL of a 2M solution in THF) and 2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium chloride (25% in dichloromethane, 0.030 mL) was added. The reaction mixture was stirred for an additional 30 minutes and then concentrated in vacuo. The crude material was purified by reverse phase HPLC (5-35% acetonitrile with 0.1% TFA/water with 0.1% TFA). The product fractions were combined, the pH was adjusted to ˜10 with 30% w/v ammonium hydroxide solution, and the mixture was extracted with dichloromethane three times. The combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white solid (26%). MS(ES)+ m/e 499.4 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC3)c2)cc1
Yield: 102.4 %

Procedure:
Azetidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (118.7 mg) was dissolved in tetrahydrofuran (6 ml), and 20% palladium hydroxide on carbon (26.6 mg) was added under a nitrogen atmosphere at room temperature while stirring, followed by stirring under a hydrogen atmosphere for 7 hr. The atmosphere in the reaction vessel was replaced with nitrogen, and the catalyst was removed by filtration and washed with tetrahydrofuran. The solvent was removed under reduced pressure to provide the titled compound as a pale yellow solid (110 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[N+:10]([O-])=O)[CH:3]=1.[Li+].[BH4-].C[Si](Cl)(C)C>C1COCC1>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:3]=1
Reactant: Cc1cccc(/C=C/[N+](=O)[O-])c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CCN)c1
Yield: 200.9 %

Procedure:
(E)-1-Methyl-3-(2-nitrovinyl)benzene (9 g, 55.214 mmol) was reacted with LiBH4 (4.81 g, 2220.85 mmol), trimethylsilyl chloride (55.86 mL, 441.7 mmol) and dry THF (120 mL) to afford 15 g of the crude product.
Reaction SMILES: [CH:1]([CH:3]1[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4]1)=O.C(O)(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH3:31][C:27]1[N:26]=[C:25]([NH:24][CH2:1][CH:3]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:5]3([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:4]2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1C=O
Reactant: Cc1cccc(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cccc(NCC2CC3(CCCC3)CCN2C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
(±)tert-butyl 7-formyl-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 72, 2 g, 7.48 mmol) was dissolved in dichloroethane (25 ml), then acetic acid (5 eq) and 2-amino 6 picoline (810 mg, 7.48 mmol) were added. After 3 hours at room temperature NaBH(OAc)3 (2.53 g, 11.96 mmol) was added and the reaction was maintained under stirring at room temperature for 18 hours. The reaction was poured in aqueous NaHCO3 and extracted with ethylacetate. The organic layers were combined, dried (Na2SO4) and concentrated under vacuum; the crude was then purified by silica gel column chromatography (petroleum ether/ethyl acetate=9/1) to obtain 1.3 g of intermediate as colourless oil.
Reaction SMILES: [CH:1]([N:3]=[C:4]=[O:5])=[CH2:2].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)(=O)C>[CH:1]([NH:3][C:4](=[O:5])[O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:2]
Reactant: OC1CCCCC1
Reactant: C=CN=C=O
Solvent: CCOC(C)=O
Product: C=CNC(=O)OC1CCCCC1
Temperature: 40 °C

Procedure:
69 parts of vinyl isocyanate and 89.5 parts of ethyl acetate are introduced into a reaction vessel and heated to 40° C. A mixture of 110 parts of cyclohexanol and 89.5 parts of ethyl acetate (containing 0.02% of dibutyl-tin dilaurate as catalyst) is added in the course of 1 hour. The mixture is then allowed to react for 2 hours at 40° C. A pale yellow solution is obtained, from which the reaction product crystallizes out on cooling. Blocked isocyanate content: 11.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12](=[O:16])C(O)=O)([O-:3])=[O:2].[OH-:17].[Na+].OO.Cl>O>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][C:12]([OH:16])=[O:17])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: O=C(O)C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
The filtrate of Step A, above, is adjusted to pH 8-9 with 2 N sodium hydroxide and is heated at 35°-40° C. while adding a 3-6% aqueous hydrogen peroxide solution until samples no longer turn dark on treatment with 2 N sodium hydroxide. The tan precipitate is suspended in 1500 ml. of water, adjusted to pH 8-9 and similarly treated with aqueous hydrogen peroxide. The combined reaction mixtures are then acidified with concentrated hydrochloride acid to obtain a precipitate which are recovered by filtration, washed 3 times with water and dried in vacuo. The crude product (mp 145°-150° C.) is recrystallized from ether to obtain 4-chloro-2-nitro-phenylacetic acid, m.p. 156°-159° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:14]=[C:13]([C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:28])[CH:11]=2)[CH:6]=1.[H][H].COC(=O)CC1C=C(CC2C=CC(S(=O)(=O)NC)=CC=2)C2C(=CC=C(F)C=2)C=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]([OH:27])[C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:20][CH:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:28])[CH:11]=2)[CH:6]=1
Reactant: [H][H]
Reactant: CNS(=O)(=O)c1ccc(C(=O)c2cc(CC(=O)OC)cc3ccc(F)cc23)cc1
Agent: [Pd]
Agent: CNS(=O)(=O)c1ccc(Cc2cc(CC(=O)OC)cc3ccc(F)cc23)cc1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(C(O)c2cc(CC(=O)OC)cc3ccc(F)cc23)cc1

Procedure:
A solution of [6-fluoro-4-(4-methylsulfamoyl-benzoyl)-naphthalen-2-yl]-acetic acid methyl ester (prepared in an analogous manner to example 2-1) in methanol (20 mL) was hydrogenated using a H-cube hydrogenation reactor with a flow rate of 1 mL/min and a 10% palladium on carbon catalyst cartridge at 30° C. under 10 bar hydrogen pressure. The reaction gave a mixture of alcohol {6-fluoro-4-[hydroxy-(4-methylsulfamoyl-phenyl)-methyl]-naphthalen-2-yl}-acetic acid methyl ester and the corresponding fully hydrogenated product [6-fluoro-4-(4-methylsulfamoyl-benzyl)-naphthalen-2-yl]acetic acid methyl ester. Reverse-phase preparative HPLC (using a Waters® Delta-Prep™ 3000 with a Varian Pursuit® C-18 column [10 μm, 20×150 mm]) was used to separate these products, giving {6-fluoro-4-[hydroxy-(4-methylsulfamoyl-phenyl)-methyl]-naphthalen-2-yl}-acetic acid methyl ester (4.0 mg) as 3.0 mg of a white solid. MS cald. for C21H20FNO5S [(M−H)−] 417, obsd. 416.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH:22]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][CH:25]([F:28])[CH2:26][NH2:27].[BH3-]C#N.[Na+].O>C(O)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][NH:27][CH2:26][CH:25]([F:28])[F:24])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C=O
Reactant: NCC(F)F
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CNCC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
89.2 A mixture of 200 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 90 mg 2,2-difluorethyl amine (solution in 1 ml THF) and 0.33 ml tetraisopropyl orthotitanate was stirred at r.t. for 1 h 30. The mixture was diluted with 1.5 ml ethanol and 35 mg NaBH3CN was added. Stirring at r.t. was continued for 18 h. Then, 0.5 ml H2O was added and stirring was continued for 30 min. The mixture was concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 3:7) to give 105 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-[(2,2-difluoro-ethylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as white amorphous solid. MS 424.0 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[Cl:32])=[CH:9][C:8]=1[CH3:33])[CH3:2].C(OC(=O)CO[C:41]1[C:50]2CCCCC=2C(SC2C=CC(CO)=CC=2Cl)=C[CH:42]=1)C>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[C:8]2[CH2:33][CH2:50][CH2:41][CH2:42][C:9]=2[C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[Cl:32])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)cc1C
Reactant: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2Cl)c2c1CCCC2
Product: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 10.6, using compound 23.1 as the starting material. 1H NMR (400 MHz) (CDCl3) δ 7.54 (2H, d, J=8.7 Hz); 7.42 (1H, d, J=1.7 Hz); 7.37 (1H, d, J=8.5 Hz); 7.06 (1H, dd, J=1.8, 8.2 Hz); 6.99 (2H, d, J=8.7 Hz); 6.59 (1H, d, J=8.5 Hz); 6.52 (1H, d, J=8.2 Hz); 4.99 (2H, s); 4.68 (2H, s); 4.29 (2H, q, J=7.1 Hz); 2.80-2.73 (4H, m); 1.76-1.70 (4H, m); 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:27][C:28]#[N:29]>O.CN(C)C=O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:27][C:28]#[N:29])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: N#CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
A mixture of 3.1 g of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, 4.9 g of potassium carbonate and 30 ml of dimethylformamide was stirred at ambient temperature for 5 min. Potassium iodide (0.24 g) was added, followed by 0.76 ml of chloroacetonitrile. The mixture was stirred and heated under nitrogen at 80°-85° for 2 hrs and then poured into 300 ml of water. The solid was collected and dried (vacuum oven). Recrystallization from ethanol-water yielded 2.0 g (64%) of product. An analytical sample was obtained by combining the 2.0 g sample with 0.8 g of another sample and recrystallizing from ethanol-water to give 2.2 g of product, mp, 126°-128°.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:12]=[C:11]([OH:24])[C:10]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:4][CH2:5][CH2:6][O:24][C:11]1[C:10]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[C:9]([NH2:8])[N:13]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: Cc1ccc(-c2c(O)nn(CCO[Si](C)(C)C(C)(C)C)c2N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(CCO[Si](C)(C)C(C)(C)C)c(N)c1-c1ccc(C)cc1
Reaction time: 8 h
Yield: 46.8 %

Procedure:
2-Bromoethyl acetate (0.29 g) was added dropwise over 1 minute to a stirred suspension of 5-amino-1-{2-[(tert-butyl)dimethylsilyl]oxyethyl}-4-(4-methylphenyl)-1-H-pyrazol-3-ol (0.60 g) (Preparation 31) and caesium carbonate (1.69 g) in anhydrous dimethylformamide (10 ml), under a nitrogen atmosphere, at room temperature. The resulting mixture was stirred overnight. The reaction was quenched by adding 1.0M citric acid (40 ml) and the resulting aqueous mixture was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water (40 ml), brine (40 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography using a Biotage Flash™ 40 column at 10 psi, with a step gradient of ethyl acetate/hexane (1:3 to 1:2) to give the title compound as a yellow oil (0.35 g).