Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:16][CH2:15]2)[C:7]1=[O:17])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C.O>[N+:18]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7](=[O:17])[C:8]12[CH2:16][CH2:15]1)([O-:20])=[O:19]
Reactant: CCCCCN1C(=O)C2(CC2)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCCCCN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Reaction time: 3 h

Procedure:
1′-Pentyl-spiro[cyclopropane-1,3′-indoline]-2′-one (24.8 g) is suspended in acetic acid (250 ml) and nitric acid (fuming, 11.9 ml) is added over a period of 15 min at 15° C. The mixture is stirred for 3 h, diluted with water and extracted with Et2O (3×300 ml). The combined organic layer is washed with water, saturated K2CO3 solution and brine, dried over MgSO4 and evaporated to give the compound (29.3 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:9][CH:8]=1)[CH3:2].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:22])(=[O:23])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCOCCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 44.3 %

Procedure:
To methyl 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.28 g) dissolved methanol (5 ml) and THF (10 ml) was added a 1 N aqueous solution of sodium hydroxide (0.6 ml), and the resulting mixture was stirred at 70° C. for 5 hours. The reaction mixture was concentrated, was then neutralized with 1 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.12 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([S:12][C:13]3[NH:14][C:15]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([S:12]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[O:32])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2nc(SC3CCCc4cc(C)cnc43)[nH]c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2nc(S(=O)C3CCCc4cc(C)cnc43)[nH]c2c1
Reaction time: 0.25 h

Procedure:
4.00 Grams of 3-methyl-8-(5-methoxy-2-benzimidazolyl)thio-5,6,7,8-tetrahydroquinoline was dissolved in 80 ml of dichloromethane, to this solution was added dropwise slowly at -10° C. a solution which was prepared by dissolving 2.37 g of meta-chloroperbenzoic acid (85%) in 30 ml of dichloromethane. After the dropwise solution was finished, the reaction mixture was stirred at -10° C. to -4° C. for 15 minutes. Water was added to the reaction mixture, then was made alkaline by adding sodium carbonate, then extracted with diethyl ether. The diethyl ether layer was washed with an aqueous solution saturated with sodium chloride, then was dried with anhydrous magnesium sulfate. The solvent was removed from the extract by evaporation, and was recrystallized from dichloromethane-diethyl ether to obtain 2.30 g of 3-methyl-8-(5-methoxy-2-benzimidazolyl)sulfinyl-5,6,7,8-tetrahydroquinoline in the form of white powdery crystals. Melting point: 114°-114.5° C. (decomposed).
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:9][C:8]2=[O:25])=[CH:4][CH:3]=1.[OH-].[K+].O.Cl>C(O)C>[CH3:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:9][C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1cc(=O)n(Cc2ccc(C)cc2)c2ccc(C)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Cn2c(=O)cc(C(C)C(=O)O)c3cc(C)ccc32)cc1

Procedure:
A solution of ethyl α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionate (0.1 g.) in ethanol (2.0 ml.), containing potassium hydroxide (0.07 g.) and water (0.2 ml.), was heated under reflux for 2 hours. The ethanol was then removed in vacuo and the residue was dissolved in water (10 ml.). The solution obtained was acidified, by addition of 5N-hydrochloric acid, to give a creamy solid, which was separated by filtration, washed with water and air dried to give α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionic acid, 0.08 g., m.p. 188°-190° C., (m.p. 193°-194° C., after recrystallisation from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>N1CCCCC1.O.[Cu]I.C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:10][CH:9]=1
Reactant: Nc1ccccc1-c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc(-c2ccccc2N)cc1
Temperature: 60 °C
Reaction time: 26 h

Procedure:
To 2.5 g 2-amino-4′-bromo-biphenyl (WO0264562) in piperidine (25 ml) under nitrogen were added in sequence CuI (0.1 g), bis(triphenylphosphino)palladium dichloride (0.35 g) and trimethylsilylacetylene (2.8 ml). The mixture was stirred for 22 hours at room temperature and for a further 26 hours at 60° C. After cooling the reaction mixture was diluted with water and extracted with ethylacetate. Then the organic phase was washed with water and dried over sodium sulfate. After evaporation of the solvents in vacuum the mixture was chromatographed on silica gel (hexane:ethylacetate 9:1) to yield 2- amino-4′-(trimethylsilyl)ethinyl-biphenyl (2 g) (Compound No.12.02).
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: CS(=O)(=O)NCCN
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Product: CS(=O)(=O)NCCNc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and N-[2-aminoethyl]-methanesulfonamide,
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[O:11][N:10]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1.O1CCCC1.[C:24](=[O:26])=[O:25]>CCCCCC>[NH2:6][C:7]1[O:11][N:10]=[C:9]([CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:24]([OH:26])=[O:25])[N:8]=1
Reactant: O=C=O
Reactant: Nc1nc(Cc2ccccc2)no1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1nc(C(C(=O)O)c2ccccc2)no1
Reaction time: 2 h

Procedure:
260 g. (0.507 mole + 20%) of a 15% solution of butyl lithium in n-hexane is cooled to -60° under nitrogen. At this temperature a solution of 27.6 g. of 5-amino-3-(phenylmethyl)-1,2,4-oxadiazole in 300 ml. of absolute tetrahydrofuran is added dropwise with stirring over a period of about 21/2 hours. The reaction mixture is stirred for an additional 30 minutes. Then over a period of 2 hours a proportionate stream of carbon dioxide is passed through the mixture. The cold bath is removed and the reaction mixture is permitted to come to room temperature. This mixture is concentrated in a rotary evaporator, the residue is treated with water and adjusted to pH 8. The aqueous solution is extracted with ether and the aqueous phase is acidified with 2N hydrochloric acid. The precipitate is filtered under suction and reprecipitated twice by dissolving in dilute sodium hydroxide solution and acidifying with dilute hydrochloric acid. 7.4 g. of 5-amino-α-phenyl-1,2,4-oxadiazole-3-acetic acid are obtained, m.p. 163°-164° (dec.).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[N:22]([NH2:23])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:33][CH2:34][C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:11][CH2:12][C:13]1[N:22]([NH:23][C:35](=[O:36])[CH2:34][Cl:33])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCl)NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of 2-carbobenzoxyaminomethyl-3-amino-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (18.84 g) in dimethylformamide (100 ml), chloroacetyl chloride (8.48 g) is added, and the resultant mixture is stirred at room temperature for 1 hour and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The ethyl acetate layer is evaporated under reduced pressure to remove the solvent, and the residue is washed with ether to give 2-carbobenzoxyaminomethyl-3-(2-chloroacetamido)-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (18.9 g). This product is recrystallized from ethyl acetate to give crystals melting at 130° to 134° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[S:8][CH2:9][C:10]([OH:12])=O.[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:24][N:23]([C:10](=[O:12])[CH2:9][S:8][C:3]2[N:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CSc1ncccn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CSc1ncccn1
Yield: 33.5 %

Procedure:
Proceeding as in Example 1, but substituting 2-(pyrimidin-2-ylthio)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 94, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(pyrimidin-2-ylthio)acetyl)pyrrolidine-2-carboxamide (10.9 mg, 33.5%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.92 (s, 1H), 8.59 (d, 2H), 7.53 (m, 2H), 7.27 (m, 2H), 7.23-7.15 (m, 8H), 6.93 (m, 2H), 4.47 (m, 1H), 4.09 (m, 2H), 3.78 (m, 1H), 3.39 (m, 1H), 2.68 (m, 3H), 1.93 (m, 2H). MS (EI) for C30H27FN4O3S. found 543.6 (MH+).
Reaction SMILES: [CH2:1]1[C@@H:5]2[C@@H:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[C@@H:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@H:6]1[C@H:5]2[CH2:1][C@H:2]([CH:3]=[CH:4]2)[C@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: O=C1OC(=O)[C@H]2[C@@H]1[C@@H]1C=C[C@H]2C1
Reactant: CO
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1[C@H](C(=O)O)[C@H]2C=C[C@@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
This compound was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-exo-2,3-dicarboxylic anhydride (5 g, 30.45 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (150 mL). The mixture was stirred for 10 min. Quinidine (10.9 g, 33.5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred at −55° C. for 16 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (400 mL). The layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), saturated aqueous brine solution (100 mL) and dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1R,2R,3S,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.92 g, 30.2 mmol, 99%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (1H, d, J=10.2 Hz), 1.96 (1H, d, J=8.6 Hz), 2.47-2.49 (2H, m), 2.93-2.94 (2H, m), 3.51 (3H, s), 6.15-6.20 (2H, m), 12.15 (1H, s).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[CH2:2][CH:3]([CH3:5])C.OC1C=CC2C(=CC=CC=2)C=1C=O.BrCC1C=C[C:37]([C:38]#[N:39])=[CH:36][CH:35]=1>>[CH:17]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:1][C:2]1[CH:3]=[CH:5][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1)=[O:18]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Agent: O=Cc1c(O)ccc2ccccc12
Product: N#Cc1ccc(COc2ccc3ccccc3c2C=O)cc1

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 2-hydroxy-1-naphthaldehyde and 4-(bromomethyl)benzonitrile.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[C:17]([F:24])[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([F:24])[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1nc(F)ccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CN(c1nc(F)ccc1N)C1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[N-methyl-N-(3-nitro-6-fluoro-2-pyridinyl)amino]piperidine (EXAMPLE 151, 5.81 g, 16.87 mmol) and platinum oxide (2.5 g) in ethanol (150 ml) is hydrogenated at 10 p.s.i. of hydrogen for one hr. Filtration and removal of the solvent gives 1-benzyl-4-[N-methyl-N-(3-amino-6-fluoro-2-pyridinyl)amino]piperidine. Without further purification, this material is dissolved in 85 ml acetonitrile and cooled to 0°. Acetone (3.76 ml, 51.2 mmol) and fused zinc chloride (465 mg, 3.4 mmol) are added and the mixture refluxed for 8 hrs. It is then poured into water and extracted with chloroform. The extract is dried over sodium sulfate, filtered and concentrated. Chromatography of the concentrate (silica gel, 300 g; ethyl acetate/hexane (50/50)) gives the title compound, NMR (300 MHz, CD3OD) 7.64, 7.36-7.41, 6.73, 3.60, 3.35, 3.00, 2.74, 2.10-2.20, 1.81 and 1.77δ.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Cl.[C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:12]=[CH:11][C:10]([CH2:13][C@@H:14]([NH:23]C(OC(C)(C)C)=O)[CH2:15][C@:16]([CH2:21][OH:22])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1.CCN(CC)CC>CC(C)=O>[CH3:1][O:2][C:3]([CH2:4][O:19][C:17](=[O:18])[C@@:16]([CH2:21][OH:22])([CH3:20])[CH2:15][C@H:14]([NH2:23])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][CH:9]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: COC(=O)CCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Chloroacetic acid methyl ester (34 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid methoxycarbonylmethyl ester.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:11][OH:12].[CH2:17]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH2:17]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[N:34][C:35]([O:12][CH2:11][CH:10]([O:9][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][O:3]3)[C:13]([F:14])([F:15])[F:16])=[CH:36][CH:37]=2)=[CH:30][CH:31]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: OCC(OC1CCCCO1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccc(-c2ccc(OCC(OC3CCCCO3)C(F)(F)F)nn2)cc1

Procedure:
A mixture of sodium hydride (100 mg) with toluene (10 ml) was stirred under ice cooling, followed by gradually dropwise dropping a mixed solution of optically active 2-(2-tetrahydropyranyloxy)-3,3,3-trifluoro-1-propanol obtained in Example 3 (450 mg) with toluene (4 ml), stirring the mixture at room temperature for one hour, pouring a solution of 3-(4-nonylphenyl)-6-chloropyridazine (540 mg) in toluene (10 ml) in the mixture, stirring at 80° C. for 2 hours, extracting the reaction mixture with toluene, washing till the washing liquid became neutral, removing the solvent, purifying according to silica gel chromatography, and drying the residue by a vacuum pump, to obtain 3-(4-nonylphenyl)-6-(2-(2-tetrahydropyranyloxy)-3,3,3-trifluoropropoxy)pyridazine. Yield: 700 mg. m.p. 96.1° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[CH2:12]([N:20]=[C:21]=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[CH2:12]([NH:20][C:21](=[O:22])[O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCN=C=O
Reactant: O=[N+]([O-])c1ccccc1CO
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)OCc1ccccc1[N+](=O)[O-]

Procedure:
100 mL toluene, 10 g 2-nitrobenzyl alcohol and 11.4 mL octyl isocyanate were introduced into a 200-mL roundbottom flask and heated under reflux for 2 hours under a nitrogen blanket. After cooling, the reaction solution was washed several times with water, and the toluene solution thereby afforded was then dried over sodium sulfate. The sodium sulfate was thereafter filtered off and the solvent was eliminated from the filtrate using a rotary evaporator. The resulting solid was recrystallized twice from hexane to yield 12.5 g ortho-nitrobenzyl n-octylcarbamate as light-yellow, needle-like crystals. mp=70°-71° C. Infrared absorption=3331 cm-1, 1691 cm-1.
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[Cl:11][C:12]1[CH:19]=[C:18]([N:1]2[CH:10]3[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:4][CH2:3][CH2:2]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C1CC[C@@H]2NCCC[C@@H]2C1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCCC3CCCCC32)cc1Cl
Yield: 68 %

Procedure:
A solution (2 mL) of cis-decahydroquinoline (447 mg), 2-chloro-4-fluorobenzonitrile (500 mg) and lithium carbonate (237 mg) in dimethyl sulfoxide was reacted at 140° C. for 10 min in a microwave reaction apparatus. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) to give the title compound as a colorless oil (yield: 600 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(C)C.[Pd]>[NH:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC3(CC2)Cc2ccccc2O3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: c1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C

Procedure:
A solution of 5.3 g of 2,3-dihydro-1'-benzylspiro[benzofuran-2,4'-piperidine], free base of B, in 250 ml of isopropyl alcohol is hydrogenated with a Paar shaker, 50 psig, 65°-70° C. and 1 g of a 10% palladium/carbon catalyst until the uptake of hydrogen is completed. Thereafter, the solution is successively permitted to cool to ambient temperature, filtered and concentrated to dryness, leaving a white solid. The solid is dissolved in a benzene-ether mixture, the solution filtered through celite and then concentrated again providing a white solid, which upon trituration with ether, provides the product, 2,3-dihydrospiro[benzofuran-2,4'-piperidine], mp 56°-58.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:19]([F:22])=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:16]([O:17][CH3:18])=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:6].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:23][C:3]1[C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[CH:21][CH:20]=[C:19]([F:22])[C:4]=1[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:16]([O:17][CH3:18])=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:6]
Reactant: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc(N)c3F)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)c4ccccc4)c3F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
3-Amino-2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.005 g, 0.0157 mmol) was taken up as a slurry in CHCl3 (1.0 mL). Three drops of pyridine were added, followed by the addition of benzenesulfonyl chloride (0.00600 mL, 0.0470 mmol). The slurry was stirred overnight at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography to provide 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(phenylsulfonamido)benzamide (5.7 mg, 79%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.59 (s, 1H), 11.01 (s, 1H), 10.39 (br s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.76-7.78 (m, 2H), 7.64-7.68 (m, 1H), 7.57-7.61 (m, 1H), 7.31-7.37 (m, 1H), 7.17-7.21 (m, 1H), 4.01 (s, 3H); m/z (APCI-neg) M−1=458.2.