Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:11]2[C:15]([S:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:14]([Si:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([N:11]2[C:15]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([Si:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CSc1c([Si](C)(C)C)nnn1-c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[Si](C)(C)c1nnn(-c2cccc3ccccc23)c1SCC(=O)O
Temperature: 25 °C

Procedure:
A mixture of compound ethyl 2-(1-(naphthalen-1-yl)-4-(trimethylsilyl)-1H-1,2,3-triazol-5-ylthio)acetate (1 g, 2.6 mmol), aqueous sodium hydroxide solution (10%, 12 mL) and methanol (20 mL) was stirred at reflux for 2 hours. The reaction mixture was then cooled to room temperature and concentrated to a reduced volume. Water was added, the reaction neutralized with aqueous HCl solution (1N) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 2-(1-(naphthalen-1-yl)-4-(trimethylsilyl)-1H-1,2,3-triazol-5-ylthio)acetic acid as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].Cl.[N:47]1[CH:52]=[CH:51][C:50]([CH2:53]Cl)=[CH:49][CH:48]=1>>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:53][C:50]4[CH:51]=[CH:52][N:47]=[CH:48][CH:49]=4)[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: ClCc1ccncc1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccncc4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine (5 mmol) and 4-picolyl chloride hydrochloride to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Product: Nc1cccc(-c2ccc3nc(NC(=O)c4cccnc4)nn3c2)c1
Yield: 39.1 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a) but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-aminobenzeneboronic acid (64 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/DCM, gradient from 0:100 to 10:90) gave the title compound as a dark red solid (31 mg, 40%). HPLC, Rt: 1.07 min. (purity 96.3%). LC/MS, M+(ESI): 331.4, M−(ESI): 329.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=1.CC([O-])(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.CC(N(C)C)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:12]=[C:11]([O:10][CH3:9])[CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccnc(Cl)c1
Reactant: Nc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccnc(Oc2ccc(N)cc2)c1

Procedure:
4-Aminophenol was reacted with 4-methoxy-2-chloropyridine in the presence of KOtBu/18-Crown-6/DMA at 150° C. for 5 hrs to give 2-(4-aminophenoxy)-4-methoxypyridine. The product was purified by chromatography.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10].C([C:17]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:18]=1[S:19](Cl)(=[O:21])=[O:20])(=O)C>O>[OH:10][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][OH:13])[S:19](=[O:21])([C:18]1[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][CH:17]=1)=[O:20]
Reactant: OCCNCCO
Reactant: CC(=O)c1cc(N)ccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N1,N1 -bis(2-hydroxyethyl) sulfanilamide was prepared as follows. (This method was taken in part from G. DiModica and E. Angeletti, Gazz. chim. ital., 1960, 90, 434-9 [CA 55:11344d].) A mixture of sodium carbonate (55.6 g), D.I. water (120 mL), and diethanolamine (57.8 g) was stirred and heated to 60°-70° C. Acetylsulfanilyl chloride (116.8 g) was added as a solid over an hour. D.I. water (225 mL) was added in portions during the acetylsulfanilyl chloride addition to keep the mixture stirrable. The mixture was stirred for an additional 3 hours at 60°-70° C., then allowed to cool to room temperature for about 16 hours. The solids were isolated by filtration and washed with 200 mL cold D.I. water.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:46]1[CH2:51][CH2:50][CH2:49][C@@H:48]([NH:52][C:53]2[CH:58]=[N:57][CH:56]=[C:55]([C:59]3[CH:60]=[N:61][N:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=34)[N:54]=2)[CH2:47]1>CN(C=O)C>[O:12]=[C:10]([N:46]1[CH2:51][CH2:50][CH2:49][C@@H:48]([NH:52][C:53]2[CH:58]=[N:57][CH:56]=[C:55]([C:59]3[CH:60]=[N:61][N:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=34)[N:54]=2)[CH2:47]1)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccn2ncc(-c3cncc(N[C@@H]4CCCNC4)n3)c2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
[(Tert-Butoxycarbonyl)amino]acetic acid (65 mg, 0.37 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (142 mg, 0.37 mmol) and diisopropylethylamine (65 mL, 0.37 mmol) were added to a solution of (R)—N-(piperidin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-amine (Preparation 28b, 100 mg, 0.34 mmol) in N,N′-dimethylformamide (2 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water and the organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by reverse phase chromatography (C-18 silica from Waters, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to yield the title compound (88 mg, 57%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COCC(=O)Nc1ccccc1
Reactant: Brc1ccccn1
Product: COCC(=O)N(c1ccccc1)c1ccccn1
Yield: 58.6 %

Procedure:
Using 2-methoxy-acetanilide (5.0 g) and 2-bromopyridine (9.5 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate: hexane=1:1) produced 2-methoxy-N-(2-pyridyl)acetanilide (4.3 g, crude product) as a yellow oil.
Reaction SMILES: C[CH:2]([CH2:11][CH2:12]C=C(C)C)[CH2:3][CH2:4][CH2:5][C:6](=[O:10])[C:7]([O-:9])=[O:8].O=C(CCC)C(O[CH2:22][CH2:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=O.O=C(CCCCCCCCCCCCCC)C(OCCC(C)CCC=C(C)C)=O.CC(CCC=C(C)C)CCC(C)C(=O)C([O-])=O.C1(C(=O)C(OCCC(C)CCC=C(C)C)=O)CCCCC1.O=C(C1C=CC=CC=1)C(OCCC(C)CCC=C(C)C)=O.CC(CCCCCCCCCCCC)C(=O)C(OCCC(C)CCC=C(C)C)=O.C1(C(=O)C(OCC2C=CC(OC)=CC=2)=O)CCCCC1.CC(CC)C(=O)C(OCCC(C)CCC=C(C)C)=O.C1(C(=O)C(OCC(C)CC2C=CC(C(C)(C)C)=CC=2)=O)CCCCC1.C1(C(=O)C(OCCCCCCCCCC)=O)CCCCC1>>[CH:5]1([C:6](=[O:10])[C:7]([O:9][C@H:26]2[C@H:27]([CH:28]([CH3:29])[CH3:30])[CH2:22][CH2:23][C@@H:24]([CH3:31])[CH2:25]2)=[O:8])[CH2:4][CH2:3][CH2:2][CH2:11][CH2:12]1
Reactant: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Reactant: CCCC(=O)C(=O)OCCC(C)CCC=C(C)C
Agent: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCOC(=O)C(=O)C1CCCCC1
Agent: CC(C)=CCCC(C)CCOC(=O)C(=O)c1ccccc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)C1CCCCC1

Procedure:
MS (EI): 294 (M+, 1); 250 (1); 167 (1); 154 (4); 140 (4); 139 (33); 138 (8); 137 (1); 123 (2); 112 (1); 111 (9); 110 (1); 109 (1); 98 (1); 97 (16); 96 (1); 95 (5); 84 (7); 83 (100); 82 (2); 81 (12); 80 (1); 79 (2); 71 (3); 70 (1); 69 (19); 68 (1); 67 (5); 57 (13); 56 (2); 55 (33); 54 (2); 53 (2); 43 (5); 42 (1); 41 (11); 39 (2); 29 (2); 27 (1).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:22][O:23][CH3:24])[C:11]=2[CH2:10]1)=O)(C)(C)C.[OH-].[Na+]>CO>[CH3:24][O:23][CH2:22][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH2:20][CH2:21][NH:9][CH2:10][C:11]1=2
Reactant: COCn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCn1c2c(c3ccccc31)CCNC2
Reaction time: 72 h

Procedure:
A 1.8 ml portion of 5 N hydrochloric acid was added to 9 ml of methanol solution containing 395 mg (1.25 mmol) of 2-t-butoxycarbonyl-9-methoxymethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and allowed to stand at room temperature for 3 days. This was adjusted to pH 8 with 5 N sodium hydroxide solution. Methanol was removed by evaporation under a reduced pressure and the resulting residue was extracted with chloroform. The extract was washed with water, dried (Na2SO4) and then concentrated under a reduced pressure to obtain 9-methoxymethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole quantitatively.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2.CN(C)C=O.[OH-].[Na+]>O1CCCC1>[O:22]=[C:16]1[CH2:15][C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][CH2:11][O:10][C:8](=[S:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:17]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: S=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1Cc2c(CCOC(=S)Nc3ccccc3)cccc2N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.9 %

Procedure:
Phenyl isothiocyanate (0.45 mL, 3.75 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (443 mg, 2.5 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 20 hours and then 70° C. for 8 hours. One mL of dimethylforamide was added to the mixture to make it homogenous and the heating was continued for another 42 hours. The reaction was cooled, poured into 1 N sodium hydroxide solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with 1 N hydrochloric acid (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from methanol/ethyl acetate/hexane to give 452 mg (58%) of phenyl-thiocarbamic acid O-[2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl]ester as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)O)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([CH2:4][C:6]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=S(=O)(c1ccccc1)n1cc(C(O)C2CC2)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(CC2CC2)c2cccnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
Cyclopropyl(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanol (0.285 g, 0.87 mmol) was dissolved in dry dichloromethane (9 mL) and chilled to 0° C. Triethylsilane (1.11 mL, 6.94 mmol, 8 eq.) and TFA (0.201 mL, 2.60 mmol, 3 eq.) were then added. The reaction mixture was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature. After about 1.5 hours, the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The extracts were dried over sodium sulfate and concentrated. Flash 40 Biotage (40M cartridge, DCM to 5% EtOAc/DCM) afforded 3-(cyclopropylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (159 mg, 59%). m/z (APCI-pos) M+1=313.1.
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2B2OC(C)(C)C(C)(C)O2)=[N:8]1.[Cl:25]C1C(C)=C(C=CC=1)N.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.N(OCCC(C)C)=O>>[Cl:25][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[N:7][NH:8]2
Reactant: CC1(C)OB(c2cccc3nn(C4CCCCO4)cc23)OC1(C)C
Reactant: Cc1c(N)cccc1Cl
Agent: CC(=O)[O-]
Agent: CC(C)CCON=O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: Clc1cccc2[nH]ncc12

Procedure:
Scheme 3 shows the synthesis of 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 10 starting by cyclization of 3-chloro-2-methylaniline 11 with potassium acetate, acetic anhydride, and isoamyl nitrite to yield 4-chloro-1H-indazole 12. The indazole nitrogen of 4-chloro-1H-indazole 12 was protected as tetrahydropyranyl (THP) with 3,4-dihydro-2H-pyran, and pyridinium p-toluenesulfonate in dichloromethane to yield 4-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole 13 and a minor amount (about 10%) of the THP regioisomer, 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. The mixture was reacted with PdCl2(PPh3)2, tricyclohexylphosphine, bis(pinacolato)diboron, and potassium acetate in DMSO and heated to 130° C. for 16 hours to give 10, containing a minor amount (about 10%) of the THP regioisomer, 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:16][CH2:17][CH2:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:16][CH2:17][CH2:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCCCC(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC(C(=O)OCC)c1ccc(N)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
5.5 g of ethyl 2-(4-nitrophenyl)hexanoate are dissolved in 55 ml of tetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added, and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. After aeration, the solid material is filtered off, and the filtrate is evaporated to dryness in vacuo. Yield: 4.8 g (99%) of ethyl 2-(4-aminophenyl)hexanoate (oil); LC-MS retention time: 1.73 min (“nonpolar” gradient).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[N:19]=2)=[C:9]1[CH3:39])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9]=2[CH3:39])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28]
Reactant: COc1cccc(CN2N=C(c3c(C)n(CC(=O)OC(C)(C)C)c4ccc(F)cc34)c3ccccc3S2(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(CN2N=C(c3c(C)n(CC(=O)O)c4ccc(F)cc34)c3ccccc3S2(=O)=O)c1

Procedure:
{3-[2-(3-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.13 (d, 1H), 7.91 (t, 1H), 7.84 (t, 1H), 7.48 (d, 1H), 7.38 (dd, 1H), 7.28 (t, 1H), 6.91 (m, 4H), 6.69 (dd, 1H), 5.06 (bs, 2H), 4.51 (s, 2H), 3.71 (s, 3H), 2.11 (s, 3H) ppm. MS calculated for C26H22FN3O5S—H: 506, observed: 506.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>CN(C=O)C.O>[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: Cc1cccc(CBr)c1
Reactant: c1ccc2[nH]nnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Cn2nnc3ccccc32)c1
Reaction time: 0.42 h

Procedure:
To a solution of benzotriazole (3 g) in DMF (38 mL) at r.t. was added a solution of 10N NaOH (2.75 mL). After stirring for 25 min., 3-methylbenzyl bromide (3.9 mL) was added. The mixture was further stirred for 30 min, diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed with brine (2×), water, brine, and was then dried (MgSO4) and concentrated. The residue was stirred in diethyl ether/hexane to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:23][C:24]1([CH2:28]O)[CH2:27][O:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]3([CH3:28])[CH2:27][O:26][CH2:25]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CC1(CO)COC1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: CC1(Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)COC1

Procedure:
Compound IIf was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and (3-methyloxetan-3-yl)methanol following the general procedure for the Mitsunobu reaction.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH:4]=[CH2:5].B1C2CCCC1CCC2.[CH2:16]([O:23][C:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][C:29](I)=[CH:30][CH:31]=2)[O:26][C:25]=1[C:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.[OH-].[Na+].Cl[Pd]Cl>[CH2:16]([O:23][C:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][C:29]([CH2:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])=[CH:30][CH:31]=2)[O:26][C:25]=1[C:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Reactant: C=CCC(C)C
Agent: Cl[Pd]Cl
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2oc3cc(CCCC(C)C)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirring solution of 4-methyl pent-1-ene (0.110 g, 1.3 mmol, 1.4 eq) in tetrahydrofuran (2 ml) under argon at 0° C. was added 9-BBN in tetrahydrofuran (0.5M, 2.7 ml, 1.4 mmol, 1.5 eq). The reaction was allowed to warm to room temperature then stirred for 6 hours then 34 (0.499 g, 0.9 mmol) (prepared as described in Example 2) in tetrahydrofuran (5 ml), 3M NaOH solution (1.1 ml) and dichloropalladium (dppf) (0.028 g, 0.03 mmol, 0.04 eq) were added and the reaction heated to reflux for 14 hours. The reaction was then quenched with water and diethyl ether. The organic layer was collected and the aqueous layer extracted with diethyl ether (2×). The combined organic layers were washed with 1M HCl and brine then dried (MgSO4) and concentrated in vacuo to give a yellow oil. A silica plug (dichloromethane) yielded 39e* (0.197 g, 49%) as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CS(Cl)(=O)=O.C(N(CC)CC)C.[CH3:26][NH:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[CH2:28]([N:27]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:26])[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CNCCC(C)C
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)cc(CN(C)CCC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 3-(hydroxymethyl)-5-methylbenzoate prepared by the method in EXAMPLE SP-198, Step 2 in anhydrous methylene chloride at −30° C. is added methanesulfonyl chloride (601 μL, 7.8 mmol), then triethylamine (1.5 mL, 11.1 mmol), and the reaction is stirred at 0° C. 15 min. The resulting precipitate is filtered, and the filtrate is added to N-methylisoamylamine (2.1 mL, 16.7 mmol). The reaction stirred at room temperature 16 h. The solution is concentrated under reduced pressure, redissolved in ethyl acetate and washed with saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20% ethyl acetate/hexanes) provides the title compound. ESI MS m/z 264.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2)=[C:20]([C:35]([F:36])([F:37])[F:38])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1cccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 15-3 (720 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (530 mg) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:27]3[CH2:26][CH2:25][N:24]([CH2:23][C:22]4[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=4[C:20]([F:34])([F:35])[F:19])[CH2:29][CH2:28]3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2cc(CCCN3CCN(Cc4ccccc4C(F)(F)F)CC3)on2)c1
Yield: 81.1 %

Procedure:
About 2 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-[2-(trifluoromethyl)benyl]piperazine (8.4, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (26 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.8 hr and followed the same processes as in Example 1 to obtain 15.4 mg (79.9%) of the target compound.