Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[CH2:11]([O:13][C:14](=[O:17])[CH:15]=O)[CH3:12].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:1][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:17])=[C:3]([OH:10])[CH:4]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1cc(Cl)c(Cl)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CNc1cc(Cl)c(Cl)cc1O
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 2-amino-4,5-dichlorophenol (2.0 g, 11.3 mmol) and ethyl-2-oxoacetate (2.26 g, 12.42 mmol) in DCM (50 mL) at room temperature, AcOH (1 mL) was added and the resulting mixture was stirred for 1 h. To this mixture, NaBH(OAc)3 (7.2 g, 33.9 mmol) was added and then stirred for 16 h. The mixture was concentrated in vacuo and the residue was suspended in DCM. The mixture was filtered through a pad of Celite and the filtrate was washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product (2.4 g, 81% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18]C)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1.[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[CH3:8]
Reactant: Fc1ccccn1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C[n+]1ccccc1F
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
10 mmol of 2-fluoropyridine and 10 mmol of methyl 4-methylbenzenesulphonate are mixed in a 50 ml round-bottomed flask and stirred for 6 hours at 70° C. under a nitrogen atmosphere. The salt obtained in the form of a white solid is used without additional purification in the following step.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.CO>CN1CCCC1=O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12]([NH:30][C:29]4[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=4)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(S(C)(=O)=O)nc21
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl) pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8 replacing methyl 2-fluorophenoxyacetate with methyl 4-fluorophenoxyacetate—Step A–B, 0.35 g, 1 mmol) and 4-fluoroaniline (0.284 mL, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the crude product which was purified by column chromatography (SiO2, CH2Cl2/MeOH—95/5). The column fractions were combined and concentrated under reduced pressure to provide the free amine. This was suspended in ethyl acetate (1–2 mL) and hydrochloric acid in ether (1M, 1.2 eq) was added. Isolation of the solid via filtration and drying provided 0.101 g of the hydrochloride salt (Mass spec. M+1=381, MP=242.3–242.6° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][CH:8]=1)[CH3:2].[Sn].Cl.C(Cl)Cl>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([SH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(S)cc1

Procedure:
To a mixture of (4-chlorosulfonyl-phenoxy)-acetic acid ethyl ester (0.98 g, 3.5 mmol) and tin powder (2.1 g) in ethanol (4.4 mL) is added HCl in dioxane (1.0 M, 4.4 mL) under nitrogen. The mixture is heated to reflux for 2 hrs, it is poured into ice and methylene chloride and filtered. The layers are separated and extracted with methylene chloride, dried and concentrated. The crude product is used for next step without purification.
Reaction SMILES: [O:1]1[C:5]([C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[O:1]1[C:5]([C:6]2[S:10][C:9]([S:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:17]=3)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccno2)s1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccno2)s1

Procedure:
The title compound was prepared according to General Procedure 1, described in Example 1, with 5-isoxazol-5-ylthiophene-2-sulfonyl chloride (13.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). MS (ESI+) calcd mass for C14H10N6O3S2 374.025580, found 374.025420.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[S:16][C@H:15]([N-]C)[C@@H:14]([O:19][Si](C(C)(C)C)(C)C)[C@H:13]1[O:27][Si](C(C)(C)C)(C)C.[F-].[CH2:36]([N+:40]([CH2:49]CCC)(CCCC)CCCC)CCC.[O:53]1CCCC1>>[CH3:36][NH:40][C:49]([C@@H:15]1[C@@H:14]([OH:19])[C@@H:13]([OH:27])[C@H:12]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][C:9]([Cl:11])=[N:10][C:2]=3[NH2:1])[S:16]1)=[O:53]
Reactant: C1CCOC1
Reactant: C[N-][C@H]1S[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CNC(=O)[C@H]1S[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
140 mg (0.24 mmol) of (2S,3S,4R,5R)-[5-(6-amino-2-chloro-purin-9-yl)-3,4-bis(tert-butyldimethylsilanyloxy)tetrahydrothiophen-2-yl]-methyl amide from the aforementioned Experimental Example 28 were dissolved in 10 mL of anhydrous tetrahydrofuran to which 0.67 mL (0.67 mmol, 1M tetrahydrofuran solution) of tetrabutylammonium fluoride was added. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was distilled under reduced pressure and the concentrate was purified by silica gel column chromatography using the eluant (dichloromethane:methanol=4:1) to obtain 58 mg (yield: 69%) of (2S,3S,4R,5R)-5-(6-amino-2-chloro-purin-9-yl)-3,4-dihydroxytetrahydrothiophene-2-carboxylic acid methyl amide as white solids (see Table 3).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C@@H:4]2[CH2:16][C:15](=[O:17])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8].[BH4-].C[N+](C)(C)C.C(O)(=O)C>C(Cl)Cl>[OH:18][CH:3]1[C@@H:4]2[CH2:16][C:15](=[O:17])[N:5]2[C:6]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:12])[Cl:13])=[O:8])=[C:2]1[CH3:1]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@H]2C1=O
Agent: C[N+](C)(C)C
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@H]2C1O
Reaction time: 0.5 h

Procedure:
Freshly prepared 2,2,2-trichloroethyl 2-methyloxocarbapen-2-em-3-carboxylate, made from 100 mg. (0.317 mmole) of the precursor oxide according to Example 11, was taken up in 2 ml. of methylene chloride and cooled to -78° C. Tetramethylammonium borohydride (23 mg., 0.079 mmole) was added. After 30 minutes, ir spectral analysis (1775 cm-1) indicated a satisfactory reduction. The reaction was quenched with acetic acid (0.58 equivalent, 10 microl.), extracted twice with aqueous buffer solution (pH 7), dried over anhydrous magnesium sulfate and filtered to yield a solution of 2,2,2-trichloroethyl 1-hydroxy-2-methylcarbapen-2-em-3-carboxylate. If desired, this product is further isolated by evaporation to dryness in vacuo at reduced temperature.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])=[CH:7]2.C([O-])(=O)C.[Na+].[H][H]>O.[Pd].C(O)(C)C>[CH3:17][C:16]([CH2:15][CH2:14][C:6]1[CH:5]=[CH:4][C:3]2[CH:2]=[C:11]([O:12][CH3:13])[CH:10]=[CH:9][C:8]=2[CH:7]=1)=[O:18]
Reactant: [H][H]
Reactant: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
49.44 Grams (0.154 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one, 12.24 g (0.149 moles) of anhydrous sodium acetate, 4 g of a 50% suspension in water of 5% palladium on carbon, equivalent to 0.00094 moles of palladium and 400 ml of isopropanol are put into a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2.5 atmospheres. For a period of time of 9 hours the temperature of reaction is kept at 50° C., then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered in order to eliminate the catalyst. The solution is concentrated to 130 ml, diluted with 45 ml of water, heated to 60° C. and added with 18.2 g of sodium metabisulfite. The reaction mixture is kept for one hour at 60° C. and then is cooled to 0° C. The so obtained suspension is kept at 0° C. for two hours and then is filtered; the solid is washed with 60 ml of isopropanol cooled to 0° C. and then is suspended in a mixture made by 70 ml of a 10% aqueous solution of sodium hydroxide and 270 ml of toluene. The reaction mixture is stirred for one hour and half at room temperature, then is heated at 60° C. and the layers are separated. The organic phase is washed with 60 ml of water and is concentrated under vacuum at 60° C. until an oil is obtained which solidifies by cooling. The solid is dissolved at 60° C. in 40 ml of isopropanol and the resulting solution is cooled to 0° C. in two hours. The obtained suspension is kept for one hour at this temperature, filtered, washed with 10 ml of cold isopropanol and dried in oven under vacuum until constant weight. 26.3 Grams of nabumetone are obtained with a yield equal to 74.8%.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:53][CH2:54][C:55]1[C:56]([OH:63])=[N:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>ClCCl.O>[OH:63][C:56]1[C:55]([CH2:54][NH:53][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([CH:4]([O:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:3][CH:2]([CH3:1])[CH3:21])=[CH:20][CH:19]=2)=[C:60]([CH3:61])[CH:59]=[C:58]([CH3:62])[N:57]=1
Reactant: CC(C)CC(Oc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(CC(C)C)Oc3ccccc3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of 4-(3-Methyl-1-phenoxybutyl)benzoic acid (20 mg, 0.07 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (59 mg, 0.15 mmol) and triethylamine (2 mL) was dissolved in dichloromethane (20 mL). The mixture was stirred for 0.5 hour. And then added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol) was added to the mixture and the resultant mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the reaction mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(3-methyl-1-phenoxybutyl)benzamide (Compound I-49) (15 mg, 52%). LRMS (M+H+) m/z: calcd 418.23. found 418. HPLC purity (214 nm): 95%. 1H NMR (300 MHz, CD3OD): δ 7.73 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.13 (t, J=7.5 Hz, 2H), 6.83-6.79 (m, 3H), 6.09 (s, 1H), 5.26-5.21 (m, 1H), 4.47 (s, 2H) 2.34 (s, 3H), 2.23 (s, 3H), 1.95-1.82 (m, 2H), 1.61-1.56 (m, 1H), 1.02-0.95 (m, 6H).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:27]([NH:29][C@H:30]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:22][CH2:23][CH:24](C)C.Cl.Cl[C:40](OCC(C)C)=O>>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([NH:20][C@H:21]([C:27]([NH:29][C@H:30]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:22][CH:23]([CH3:24])[CH3:40])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)CCC(C)C)C(N)=O
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Yield: 57 %

Procedure:
Condensation of BocDPheOH (2.65 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 2.98 g.) by the mixed anhydride method using isobutyl chloroformate gave BocDPhe-Leu-MetNH2 in 57% yield. De-t-butoxycarbonylation of BocDPhe-Leu-MetNH2 (2.7 g.) using hydrogen chloride in ethyl acetate gave HDPhe-Leu-MetNH2 hydrochloride salt in 82% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:3]=[C:2]([C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=2)[CH:7]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(Br)c2)c1
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: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1

Procedure:
N-[(3-Bromo-5-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (300 mg, 0.459 mmol), (3-formylphenyl)boronic acid (68.8 mg, 0.459 mmol), potassium carbonate (190 mg, 1.376 mmol), and tetrakis(triphenylphosphine)palladium(0) (26.5 mg, 0.023 mmol) were placed in a 2-5 mL Biotage microwave vial along with a stir bar. Then 1,4-dioxane (3 mL) and water (1 mL) were added. The vial was capped and microwaved for 15 min at normal power in the SmithCreator microwave at 100° C. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (10 mL). The organic phase was washed 3× with water (10 mL), 1× with brine (10 mL), and dried over anhydrous Na2SO4. The crude product was taken up in dichloromethane and absorbed on Isolute® Sorbent and purified using CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH to afford the title compound as a pale yellow solid. LC-MS m/z 679.0 (M+H)+, 2.21 min (ret time); mp 123-127° C.; analytical HPLC shows 96.2% purity, (ret time 14.171 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:38]1[CH2:47][C@H:46]([OH:48])[CH2:45][C@H:39]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:28]1[CH:33]=[C:32]([CH:34]=O)[CH:31]=[CH:30][C:29]=1[O:36][CH3:37].[NH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:24])[F:25])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:38]1[CH2:47][C@H:46]([OH:48])[CH2:45][C@H:39]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:28]1[CH:33]=[C:32]([CH2:34][N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[CH:31]=[CH:30][C:29]=1[O:36][CH3:37]
Reactant: C1CCNCC1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CN4CCCCC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg of the compound obtained in Step 198-3 in CHCl3 (3.5 ml) was added piperidine (0.14 ml) and acetic acid (0.24 ml), and the reaction mixture was stirred for 30 minutes. To the solution was added 327 mg of sodium triacetoxy borohydride, and the reaction mixture was further stirred for 15 hours. After the end of the reaction, water was added to the solution and the resulting mixture was extracted with CHCl3. The organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: MeOH/CHCl3=1/99; v/v) to obtain respectively 94 mg (Isomer A: colorless amorphous) and 217 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCCC1.O[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:29])[CH3:28]>CO.CCCCCC>[O:29]=[C:27]1[C:22]2[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:1][C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:28]1
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCCCCC
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 70.7 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (93.7 g, 470 mmol) in pyrrolidine (56.0 mL, 673 mmol) and anhydrous MeOH (112 mL) was added 1-(2-hydroxyphenyl)ethanone (56 mL, 468 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. Methanol was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 mL), washed with 1 M aqueous HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. This oil was diluted with hexane (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. Crystals were collected via vacuum filtration and rinsed with hexane to obtain tert-butyl 4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (105 g, 70%) as a light yellow solid. ESI-MS m/z calc. 317.2, found 318.2 (M+1)+; Retention time: 1.78 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=7.8, 1.5 Hz, 1H), 7.55-7.45 (m, 1H), 7.10-6.90 (m, 2H), 3.95-3.80 (m, 2H), 3.26-3.17 (m, 2H), 2.72 (s, 2H), 2.03 (d, J=13.0 Hz, 2H), 1.68-1.58 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][C:13]=2[N:14]=1.[N:22]1([CH2:28][C:29]2[C:37]3[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=3)[NH:31][N:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:22]1([CH2:28][C:29]2[C:37]3[C:32](=[CH:33][C:34]([NH:38][C:19]([C:17]4[CH:16]=[CH:15][C:13]5[N:14]=[C:10]([NH:9][C:3]6[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=6[Cl:1])[NH:11][C:12]=5[CH:18]=4)=[O:21])=[CH:35][CH:36]=3)[NH:31][N:30]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: Nc1ccc2c(CN3CCOCC3)n[nH]c2c1
Reactant: O=C(O)c1ccc2nc(Nc3ccc(Cl)cc3Cl)[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ccc2c(CN3CCOCC3)n[nH]c2c1)c1ccc2nc(Nc3ccc(Cl)cc3Cl)[nH]c2c1

Procedure:
The ester obtained as above was hydrolyzed using general procedure C to yield 2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid. The carboxylic acid (0.25 mmol) was coupled with 3-(morpholin-4-yl)methyl-1H-indazol-6-ylamine (0.25 mmol) using HBTU employing general procedure D. The product, 2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid (3-morpholin-4-ylmethyl-1H-indazol-6-yl)-amide, was obtained as a light brown solid after purification by silica gel chromatography using DCM/methanol as eluent. MS: m/z 536 (M+H)+.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:26])=O>CN(C)C=O>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Yield: 100.7 %

Procedure:
To a round bottom flask of 100 ml was placed 1.5 g of 4'-octylbiphenyl-4-carboxylic acid, added 3 g of thionyl chloride, and further added a small amount of N,N-dimethyl formamide, and then the contents in the flask were subjected to reflux for 4 hours. An excess amount of thionyl chloride was distilled off to obtain 1.6 g of 4'-octylbiphenyl-4-carboxylic acid chloride. To this acid chloride was added a solution prepared by dissolving 0.6 g of optically active 4-hydroxy benzoic acid 2-octyl ester having an optical purity of 98% e.e., 0.4 g of triethylamine, and 0.15 g of dimethylamino pyridine in 50 ml of methylene chloride, and then the contents in the flask were stirred a whole day and night. After finishing the reaction, white insoluble matters produced were filtered off. After methylene chloride layer formed was washed sufficiently with a diluted hydrochloric acid and water, and dried, the organic solvent was separated under a reduced pressure. Crude products thus obtained were purified by column chromatography and recrystallization to obtain an objective compound having an optical purity of 98% e.e.
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].[CH3:7]/[C:8](/[CH2:16][OH:17])=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)C=C>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([O:17][CH2:16]/[C:8](/[CH3:7])=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: C/C(=C\c1ccccc1)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: C=CCCl
Solvent: C1CCOC1
Product: C=CCOC/C(C)=C/c1ccccc1
Temperature: 5 °C
Yield: 67.4 %

Procedure:
Solid potassium tert-butylate (110 g, 0.960 mol) was added portion-wise (1 hour) to a solution of trans-2-methyl-3-phenyl-2-propen-1-ol (100 g, 0.950 mol) in dry THF (1 liter) at room temperature under nitrogen. After 1 more hour at room temperature, the reaction was cooled to 5° C. and tetra butyl ammonium iodide (12.1 g, 0.032 mol) was added followed by allyl chloride (100 g, 1.280 mol) drop-wise. The reaction was warmed up to room temperature overnight and poured onto water (2 liters). The reaction was extracted twice with ethyl acetate. Each organic phase was washed with water and brine. Combined extracts are dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with diethyl ether and the solvents were removed under vacuum. The product was purified by distillation through a 20-cm Widmer column. 120.5 g of the desired compound was obtained (97% pure, 0.620 mol, 97%). B.P.=70° C./0.067 mbar