Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8]2.[NH2:17][NH2:18]>CO>[Cl:15][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([CH2:4][C:3]([NH:17][NH2:18])=[O:2])[CH:6]=2)[N:11]=1
Reactant: COC(=O)Cc1ccc2nc(Cl)ccc2c1
Reactant: NN
Solvent: CO
Product: NNC(=O)Cc1ccc2nc(Cl)ccc2c1

Procedure:
(2-Chloro-quinolin-6-yl)-acetic acid methyl ester (0.160 g, 0.679 mmol), hydrazine (0.218 g, 6.79 mmol) and methanol (3 mL) were stirred at room temperature. The reaction was evaporated to give (2-chloro-quinolin-6-yl)-acetic acid hydrazide. This compound was not purified and was used directly in the next step. 1H NMR (400 MHz, DMSO-d6) δ 9.39 (m, 1H), 8.43 (d, 1H, J=9.2 Hz), 7.91 (m, 2H), 7.75 (m, 1H), 7.58 (m, 1H), 4.30 (bs, 2H), 3.57 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:42])[CH2:21][NH:22][C:23]([CH3:41])([CH3:40])[CH2:24][C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:42])[CH2:21][NH:22][C:23]([CH3:40])([CH3:41])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:38][CH:39]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCOc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Cc1ccc(OCCCC(=O)O)cc1)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
A solution of 1.00 g (1.73 mmol) of ethyl 4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo [1,4]oxazin-8-yl)-2-hydroxyethylamino]-2-methylpropyl}phenoxy)butyrate in 25 mL methanol is combined with 2.5 mL of 1 N sodium hydroxide solution, refluxed for 30 minutes, and then neutralized with 1 N hydrochloric acid. The solution is evaporated down and the residual oil is dissolved by heating in 5 mL of n-butanol. After the addition of a crystallization aid, a solid is precipitated out which is suction filtered and washed with acetone and diethyl ether. Yield: 0.75 g (79%); melting point: 216° C.-218° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:16])[O:8][C:7]2[C:9]([CH3:15])=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[C:6]=2[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].CN(C)C=[O:34]>O>[Si:23]([O:1][CH2:2][C:3]1([CH3:16])[O:8][C:7]2[C:9]([CH3:15])=[C:10]([CH3:14])[C:11]([OH:34])=[C:12]([CH3:13])[C:6]=2[CH2:5][CH2:4]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CO)CC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CO[Si](C)(C)C(C)(C)C)O2
Temperature: 25 °C
Reaction time: 23 h
Yield: 83.8 %

Procedure:
A solution of 6-hydroxy,-2-hydroxymethyl-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran, (3.14 g, 46.1 mmol), prepared by the reduction of the commercially available acid (Aldrich) using lithium aluminum hydride, and t-butyldimethylsilyl chloride (3.06 g, 20.3 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 23 hours. The reaction mixture was diluted with water (200 mL) and the product extracted with ethyl acetate (4×50 mL). The combined organic extracts were dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with a gradient elution of hexane/ethyl acetate to give 5.38 g (83.8% yield) of 2-(t-butyldimethylsilyloxymethyl)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran as an oil.
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19]1=[O:36].C(N(CC)CC)C>C(Cl)Cl>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19]1=[O:36])([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCc2ccccc2)OCC)CS[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the crude chloro(4-phenylbutyl)phosphinic acid, ethyl ester (2.6 mmole), dry methylene chloride (9.0 ml.) and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (0.72 g., 2.4 mmole) at 0° (ice bath) in an argon atmosphere is treated dropwise with triethylamine (0.44 ml., 1.3 eq.) in methylene chloride (2 ml.) over 5 minutes. After 30 minutes, the ice bath is removed and the reaction mixture is stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, brine, dried (MgSO4), and evaporated. The residue (1.5 g.) is chromatographed on silica (80 g.) eluting with hexane/acetone (2:1) to give 1.0 g. of (R)-dihydro-5-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester as an oil after evaporation. TLC (hexane/acetone, 2:1) single spot at Rf =0.5.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#N)=[CH:6][CH:5]=1.I[CH3:14].C[N:16]([CH3:19])C=O>O>[CH3:14][C:10]([C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)([CH3:11])[C:19]#[N:16]
Reactant: N#CCc1ccc(Br)cc1
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C#N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 50 g, 1.25 m) in dry N,N-dimethylformamide (400 ml under nitrogen was added with stirring a solution of 4-bromophenylacetonitrile in N,N-dimethylformamide (400 ml) keeping the temperature between 30° and 40° C. A solution of iodomethane (213 g, 1.50 m) in N,N-dimethylformamide was then added gradually keeping the temperatue between 35° C. and the mixture then stirred at ambient temperature overnight. With ice cooling 2N aqueous hydrochloric acid (800 ml) was gradually added and then the mixture was diluted with water (1200 ml). The product was extracted with ether and the extract washed with water, saturated sodium bicarbonate, aqueous sodium sulphite, water again and finally brine. After drying and concentration on vacuo an orange oil was obtained which was distilled in vacuo to give the title compound as a colourless liquid (98.05 g, 87.5%) b.pt. 98°-100°/0.4 mm.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:49]1([S:52](Cl)(=[O:54])=[O:53])[CH2:51][CH2:50]1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:52]([CH:49]1[CH2:51][CH2:50]1)(=[O:54])=[O:53])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)C3CC3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 75 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step6, Example 1) was added cyclopropanesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18]OCC)[C:6]=2[CH:22]=1.C(OC(=O)C)(=O)C.[IH:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][I:30])[C:6]=2[CH:22]=1
Reactant: I
Reactant: CCOCCCC1c2ccccc2C=Cc2ccc(Cl)cc21
Solvent: CC(=O)OC(C)=O
Product: Clc1ccc2c(c1)C(CCCI)c1ccccc1C=C2
Temperature: 65 °C

Procedure:
3-Chloro-5-(3-ethoxypropyl)-5H-dibenzo[a,d]cycloheptene (0.03 mole) is dissolved in 45 ml. of acetic anhydride. The solution is heated to 65° C. and nitrogen is passed through while 30 ml. of hydriodic acid (sp. gr., 1.5) is added gradually, keeping the temperature below 90° C. The solution is heated to approximately 80° C. for 30 minutes, then cooled and poured into ice-water. The product is extracted into ether, the extract washed with dilute sodium thiosulfate solution, followed by dilute sodium bicarbonate solution and finally with water. The product is isolated by evaporation of the ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH3:46])[C:33](B2OC(C)(C)C(C)(C)O2)=[C:34]([NH2:36])[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:33]3[C:32]([CH3:46])=[CH:31][C:30]([O:29][CH3:28])=[CH:35][C:34]=3[NH2:36])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)c(N)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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(N)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
A solution of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27: step c) 1.50 g, 3.05 mmol) in toluene:EtOH (2:1, 45 mL) was treated with 5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (((Example 198: step d) 1.61 g, 6.11 mmol), aqueous Na2CO3 (2 M, 12.2 mL, 24.4 mmol) and Pd(PPh3)4 (0.706 g, 0.611 mmol). The mixture was heated to 80° C. 4 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with brine (1×75 mL) and water (2×75 mL), dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (25% then 35% then 50% EtOAc in hexanes) afforded the product {[4-(2′-amino-4′-methoxy-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.680 g, 40%) as a yellow-brown solid. 1H NMR (MeOD): δ 8.223 (s, 1H), 8.001 (d, 1H, J=7.2 Hz), 7.879 (t, 1H, J=1.6 Hz), 7.698 (t, 1H, J=8.0 Hz), 7.549 (d, 1H, J=8.0 Hz), 6.287 (dd, 2H, J=7.2 Hz, J=2.4 Hz), 3.770 (s, 3H), 2.669 (s, 3H), 1.900 (s, 3H), 1.510 (s, 9H). C25H29N3O5S3: 548.13 (M+1) found 547.70.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[CH2:13]1[O:15][C@H:14]1[C:16]([F:19])([F:18])[F:17]>C1COCC1.O>[F:17][C:16]([F:19])([F:18])[C@H:14]([OH:15])[CH2:13][O:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: FC(F)(F)[C@H]1CO1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COC[C@@H](O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (390 mg, 8.9 mmol, 55% in mineral oil) in THF (10 mL) at 0° C. was added 4-methoxybenzylalcohol (1.27 g, 8.92 mmol) in THF (5 mL). After 1 h stirring at 0° C. R-(+)-3,3,3-trifluoro-1,2-epoxypropane (500 mg, 4.46 mmol) was added to a 20 mL microwave vial via syringe. The closed vial was heated at 100° C. for 18 h. The reaction mixture was diluted with water and extracted twice with Et2O. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. Chromatography over silica (cyclohexane-EtOAc 95:5 to cyclohexane-EtOAc 75:25) afforded the title compound: ESIMS [M+NH4]+=268; 1H NMR (360 MHz, CDCl3): δ 7.29 (d, 2H), 6.94 (d, 2H), 4.56 (s, 2H), 4.15 (m, 1H), 3.87 (s, 3H), 3.74 (dd, 1H), 3.66 (dd, 1H), 2.88 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([O:23][CH3:24])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][C:8]=1[O:21][CH3:22])O.S(Cl)(C)(=O)=O>CN(C1C=CN=CC=1)C.ClCCl.CCOCC.CO>[CH3:1][O:2][C:3](=[O:25])[CH:4]([O:23][CH3:24])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:15])[CH3:16])=[CH:9][C:8]=1[O:21][CH3:22]
Reactant: COC(=O)C(OC)C(O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1OC)OC
Temperature: 0 °C

Procedure:
A mixture of 3-[4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-phenyl]-3-hydroxy-2-methoxy-propionic acid methyl ester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq) and a catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at room temperature over night. The reaction mixture was diluted with ether and washed with HCl 1N. Dried and concentrated in vacuo to give a residue which was chromatographed in silica gel to yield a compound which was dissolved in methanol was treated with Mg (20 eq) and stirred until gas evolution was observed. Cooled to 0° C. and stirred for 4 hours. The solvent was removed and the residue reconstituted in ether washed with HCl 1N and brine and concentrated to give the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][Cl:33])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CN([CH:37]=[O:38])C>>[Cl:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][Cl:33])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:37](=[O:38])[NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: CN(C)C=O
Reactant: Nc1cccc(NC(=O)CCN2CCCCC2)c1
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Product: O=C(CCN1CCCCC1)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1

Procedure:
By following the same procedure as that for BO-2091, BO-2147 was prepared from N-(3-aminophenyl)-3-(piperidin-1-yl)propanamide (2.47 g, 10.0 mmol) and N-mustard isocyanate [19, freshly prepared from N-mustard amine hydrochloride 18 (6.1 g, 20 mmol)] in dry DMF. Yield: 4.2 g (82%); mp 108-110° C. The HCl salt of compound BO-2147 was prepared by following the same procedure as that for compound BO-2091. 1H NMR (DMSO-d6) δ: 1.33-1.42 (1H, m, CH), 1.67-1.79 (5H, m, CH), 2.90-2.94 (4H, m, CH2), 3.30-3.33 (2H, m, CH2), 3.38-3.42 (2H, m, CH2), 3.69-3.74 (8H, m, CH2), 6.73-6.75 (2H, m, Ar—H), 7.16-7.18 (2H, m, Ar—H), 7.26-7.27 (3H, m, Ar—H), 7.72 (1H, s, Ar—H), 8.95 (1H, brs, NH), 9.14 (1H, brs, NH), 10.33 (1H, brs, NH). 13C NMR (CDCl3, 125 MHz) δ: 21.32, 22.37, 30.53, 40.89, 51.79, 52.13, 53.14, 108.79, 112.57, 113.03, 113.97, 119.99, 128.88, 139.31, 140.50, 152.87, 167.79. HRMS [ES+]: calcd for C25H33Cl2N5O2, 506.4678 [M+H]+. found 506.2090. HPLC 98.8%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C:13]2=[N:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC[C@@H]1OC[C@]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=3[F:45])NOC[C@@H]2C1)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C@:13]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=3[F:45])[NH:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1ON=C2CO[C@@H](COCc3ccccc3)C[C@H]21
Reactant: Fc1ccc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CON3)c(F)c1
Product: C[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@@H]12

Procedure:
The product, obtained as a yellow oil, was prepared from (3S,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C13) according to the general procedure for the synthesis of (3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C5) in Preparation P1. Yield: 21.5 g, 57.2 mmol, 48%. LCMS m/z 376.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.98 (ddd, J=9.1, 9.1, 6.8 Hz, 1H), 7.28-7.40 (m, 5H), 6.87-6.93 (m, 1H), 6.80 (ddd, J=11.9, 8.6, 2.6 Hz, 1H), 4.60 (AB quartet, JAB=12.1 Hz, ΔνAB=19.9 Hz, 2H), 3.99-4.06 (m, 1H), 3.97 (dd, half of ABX pattern, J=12.9, 2.0 Hz, 1H), 3.80-3.88 (m, 2H), 3.56 (dd, half of ABX pattern, J=10.2, 6.3 Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.2, 4.1 Hz, 1H), 2.81-2.87 (m, 1H), 2.04 (ddd, J=14.2, 7.6, 2.8 Hz, 1H), 1.48-1.59 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:33][CH2:34][O:35][CH3:36])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=4)[S:17][C:10]=23)=[CH:4][CH:3]=1.[N:37]1[CH:42]=[CH:41][CH:40]=C[CH:38]=1.ClC(OC1C=CC=CC=1)=[O:45].C1(N)CC1>CN(C=O)C>[CH:42]1([NH:37][C:38](=[O:45])[NH:1][C:2]2[N:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:18]5[N:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:33][CH2:34][O:35][CH3:36])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:20][CH:19]=5)[S:17][C:10]=34)=[CH:4][CH:3]=2)[CH2:40][CH2:41]1
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)nc4)c3s2)nc1)C(=O)OC(C)(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
To a stirred solution of aniline 27 (634 mg, 1.249 mmol) and pyridine (303 μL, 3.746 mmol) in DMF (15 mL) at 0° C. under nitrogen was added dropwise phenyl chloroformate (415 μL, 3.308 mmol). The reaction mixture was stirred at 0° C. for 2 hrs and cyclopropylamine (433 μL, 6.250 mmol) was slowly added. The reaction mixture was allowed to warm-up to RT over 30 min and was heated at 55° C. for 5 hr then cooled to RT. The reaction mixture was partitioned between AcOEt and a saturated aqueous solution of sodium bicarbonate. The organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate, 1N NaOH, a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SiliaFlash 40 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV). The desired fractions were collected, concentrated and dried under high vacuum to afford the title compound 28 (754 mg, 1.27 mmol, quant. yield) as a pale yellow sticky oil. MS (m/z): 591.6 (M+H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)[N:10]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:9]=1)=[O:7])C.Cl>CO.O1CCCC1>[CH3:28][O:27][C:24]1[N:23]=[CH:22][C:21]([N:10]2[C:11]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=3)=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[N:9]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(-c2cc(OC)ccn2)n(-c2ccc(OC)nc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccnc(-c2cc(C(=O)O)nn2-c2ccc(OC)nc2)c1
Reaction time: 5 h

Procedure:
1N Aqueous solution of sodium hydroxide (2.23 mL) was added to 1-(6-Methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid ethyl ester (0.416 g) obtained from Referential Example 18 in a mixture of methanol (6.3 mL) and tetrahydrofuran (6.3 mL) at room temperature, followed by stirring for 5 hours. The reaction mixture was neutralized with 1N aqueous solution of hydrochloric acid (2.23 mL), and then partitioned between water and chloroform. Subsequently, the aqueous layer was extracted with chloroform twice. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound as a solid substance (0.353 g, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]3[N:16]=[N:17][N:18]([CH3:19])[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].CS(O[CH2:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:31]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C(OCC)(=O)C>[CH3:19][N:18]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:29][C@H:30]4[CH2:34][CH2:33][N:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH2:31]4)=[C:3]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[N:13]=[C:12]([C:14]#[N:15])[C:11]=2[N:16]=[N:17]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Reactant: CS(=O)(=O)OC[C@H]1CCN(c2ccccn2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OC[C@H]4CCN(c5ccccn5)C4)c(C(F)(F)F)c3)cc21

Procedure:
6-(4-Hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.313 mmol, 0.1 g), (S)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methyl methanesulfonate (0.376 mmol, 0.096 g), cesium carbonate (0.470 mmol, 0.153 g) and tetrabutylammonium idodide (0.157 mmol, 0.058 g) were stirred in DMF (1 ml) at 50° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and dried over Na2SO4. The resulting residue was triturated with ether and filtered. The solid was sonicated in methanol, filtered and dried to afford (S)-1-methyl-6-(4-((1-(pyridin-2-yl)pyrrolidin-3-yl)methoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile. (0.032 g)
Reaction SMILES: CO.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([NH:12][CH2:13][CH2:14]CO)=[O:11])[NH:7][C:8]=1[Br:9].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>C1COCC1>[Br:9][C:8]1[NH:7][C:6]([C:10]2[O:11][CH2:14][CH2:13][N:12]=2)=[CH:5][C:4]=1[Br:3]
Reactant: O=C(NCCCO)c1cc(Br)c(Br)[nH]1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: Brc1cc(C2=NCCO2)[nH]c1Br
Temperature: 80 °C
Yield: 66.3 %

Procedure:
Method A. A solution of 10 (0.25 g, 0.77 mmol) in 2 mL of methanesulfonic acid was heated at 60° C. for 3 d. The reaction mixture was diluted with ether (100 mL) and washed with sat. NaHCO3 (20 mL×3) and sat. NaCl (20 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (EtOAc/hexanes 1:1) to give 14 (0.14 g, 59%) as a colorless solid: 1H NMR (CDCl3) d 2.00 (p, 2H, J=5.7), 3.52 (t, 2H, J=5.7), 4.32 (t, 2H, J=5.7), 6.58 (s, 1H), 10.10 (br, 1H); 13C NMR (CD3COCD3) d 22.2 (e), 41.3 (e), 66.6 (e), 99.1 (e), 109.4 (e), 115.0 (o), 127.7 (e), 153.8 (e); UV (CH3OH) 1max 329, 275 nm; MS m/z (relative intensity) 311 (M++5, 50), 309 (M++3, 100), 307 (M++1, 50); Anal. Calcd for C8H8N2OBr2: C, 31.20; H, 2.62; N, 9.10; Found: C, 31.17; H, 2.51; N, 9.29. Method B. To a stirred mixture of 10 (0.25 g, 0.77 mmol) and p-toluenesulfonyl chloride (0.16 g, 0.77 mmol) in 10 mL of THF was added triethylamine (0.6 mL, 4.27 mmol) at room temperature. The mixture was heated at 80° C. overnight. The solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography (CH2Cl2/MeOH 19:1) to give 14 (0.15 g, 63%) as a colorless solid.