Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:5][CH2:4]1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>O.C(O)C>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH:17]3[CH2:18][O:19]3)=[CH:12][CH:13]=2)[CH2:4][CH2:5]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(OCC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1cc(OCC2CO2)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.46 g of sodium hydroxide in 1.8 ml water and 14 ml ethanol, 1.64 g of p-(cyclopropylmethoxy)-phenol and 5.54 g of epichlorohydrin is stirred at room temperature in a nitrogen atmosphere for 24 hours and left at room temperature for 21/2 days. The solvent is evaporated in vacuo and the residue is taken up in ether, washed with water and sodium chloride solution. After drying over anhydrous magnesium sulfate, the solution is filtered and concentrated under reduced pressure to yield p-(cyclopropylmethoxy)-phenoxymethyloxirane which is used directly in the condensation.
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:20]([OH:22])=O)[CH:17]([CH3:19])[CH3:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:44])[C:39](=[O:43])[CH:40]([CH3:42])[NH2:41])=[CH:34][CH:33]=1>C(Cl)Cl.O>[C:8]([O:12][C:13]([NH:15][C@H:16]([C:20]([NH:41][CH:40]([C:39]([N:38]([C:35]1[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][CH:36]=1)[CH3:44])=[O:43])[CH3:42])=[O:22])[CH:17]([CH3:18])[CH3:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(N)C(=O)N(C)c1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N(C)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
0.9 g of N-methylpiperidine was added to a solution containing 2.0 g of N-tert-butoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 1.3 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 2.0 g of N1 -(4-chlorophenyl)-N1 -methyl-DL-alaninamide was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 3.4 g of the desired product in the form of a colorless needle crystal (yield: 87%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[NH2:1][C:2]1[C:3]([C:9](=[NH:10])[NH:12][OH:13])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NO
Reactant: N#Cc1nc(Br)cnc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(NO)c1nc(Br)cnc1N
Temperature: 0 °C
Yield: 77 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carbonitrile (1 g, 5.025 mmol) was dissolved in MeOH (20.00 mL) and cooled to 0° C. Hydroxylamine hydrochloride (349.2 mg, 5.025 mmol) and triethylamine (508.5 mg, 700.4 μL, 5.025 mmol) were added and the reaction allowed to warm to ambient temperature. After 2 hours the resultant precipitate was filtered off and dried (898 mg, 77% Yield). MS (ES+) 234.89
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:6]=1)(=O)=O.[C-:25]#[N:26].[Na+]>CS(C)=O.C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][NH:11][C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:6]=[C:5]([C:25]#[N:26])[N:10]=1
Reactant: CS(=O)(=O)c1nc(NCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1nc(NCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.4 %

Procedure:
To a stirring solution of 2-[2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl-amino]-ethanol (493 mg) in dimethyl sulfoxide (15 ml) was added sodium cyanide (100 mg). The resulting solution was stirred at room temperature for 72 hrs. After diluting with ethyl acetate (100 ml) and washed with water (100 ml), brine (100 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a pale yellow solid (380 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[CH2:56]([C:59]1[S:60][C:61]([CH2:64]O)=[CH:62][N:63]=1)[CH2:57][CH3:58]>C1COCC1>[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:64][C:61]3[S:60][C:59]([CH2:56][CH2:57][CH3:58])=[N:63][CH:62]=3)=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCc1ncc(CO)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCc3cnc(CCC)s3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecyl-pyrimidin-2-yl)phenol and 2-propylthiazol-5-yl-methanol (prepared by LiAlH4 reduction of methyl 2-propylthiazole-5-carboxylate). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[OH2:6].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].Cl>C1C=CC=CC=1>[OH:17][C:12]1[CH:13]=[CH:14][C:15]([CH:2]([C:13]2[CH:14]=[CH:15][C:16]([OH:6])=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=2)[C:1]([OH:5])=[O:4])=[CH:16][C:11]=1[C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: O=CC(=O)O
Reactant: O
Reactant: CC(C)(C)c1ccccc1O
Agent: Cl
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(C(=O)O)c2ccc(O)c(C(C)(C)C)c2)ccc1O
Reaction time: 40 h

Procedure:
A solution of 82 g of glyoxylic acid . 1/2 H2O (1 mol) and 375 g of o-tert.-butyl-phenol (2.5 mols) in 300 ml of benzene was saturated at 40° C wtih gaseous hydrogen chloride and condensed at this temperature. From time to time, saturation was completed by adding a small amount of gaseous hydrogen chloride. After about 40 hours, condensation was complete. The precipitate which had separated upon cooling was suction-filtered and recrystallized from methylene chloride. The yield was 190 g (52 %, calculated on glyoxylic acid), m.p. 173° C.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:25])[N:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].CI.[C:28](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:28][O:1][C:2]1[C:3](=[O:25])[N:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C3CCCCO3)c(=O)c1O)C2(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1c(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)cnn(C2CCCCO2)c1=O
Temperature: 65 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
4-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (250 mg, 0.72 mmol) in N,N-dimethylformamide (2.5 mL) was mixed with methyl iodide (70 μL, 0.76 mmol) and potassium carbonate (104 mg, 0.76 mmol) at room temperature and stirred at 65° C. for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to give the desired product (154 mg, 59% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14].[CH2:16]([Sn](CCCC)(CCCC)C=CC)[CH2:17][CH2:18]C.[F-].[K+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH:16]=[CH:17][CH3:18])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Reactant: CC=C[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC=Cc1cc(C(=O)OC)c(N)c([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 77 %

Procedure:
A solution of 0.5 g (1.8 mmol) of the above ester 0.9 g (2.7 mmol) of tributyl-propenyl-stannane, 0.18 g (0.18 mmol) of (tetrakistriphenyl phosphine) palladium (0) in 25 mL of dioxane was degassed with nitrogen for 20 min then refluxed under nitrogen for 12 h. The reaction mixture was cooled, 20 mL of 2 M KF solution was added. The mixture was stirred for 20 min, extracted with ethyl acetate washed with water and brine. The residue was purified by column chromatography using 8:2 hexane and ethyl acetate to afford 0.35 g (77%) of the 2-amino-3-nitro-5-propenyl-benzoic acid methyl ester as a solid LCMS: 239 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][C:14]=1[F:20])[CH2:29]2
Reactant: Clc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4ccc(Cl)cc4C3)c(F)cc2c1=O
Yield: 64.9 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4dihydro-4-oxoquinoline-3-carboxylic acid, 260 mg of 5-chloroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 154 mg of the target compound.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][C:38]1([C:43]2[CH:48]=[C:47]([NH:49][CH2:50][CH2:51][NH2:52])[CH:46]=[CH:45][N:44]=2)[O:42][CH2:41][CH2:40][O:39]1>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[F:12][C:2]([F:1])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([NH:52][CH2:51][CH2:50][NH:49][C:47]1[CH:46]=[CH:45][N:44]=[C:43]([C:38]2([CH3:37])[O:42][CH2:41][CH2:40][O:39]2)[CH:48]=1)=[O:7]
Reactant: O=C(O)/C=C/C(F)(F)C(F)(F)F
Reactant: CC1(c2cc(NCCN)ccn2)OCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2cc(NCCNC(=O)/C=C/C(F)(F)C(F)(F)F)ccn2)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,5,5,5-Pentafluoropent-2-enoic acid (133 mg, 0.7 mmol) and HBTU (265 mg, 0.7 mmol) were dissolved in a 2:1 mixture of anhydrous DMF and anhydrous THF (3 ml) and stirred at room temperature for 15 minutes. N-[2-(2-Methyl-1,3-dioxolan-2-yl)-4-pyridyl]ethane-1,2-diamine (100 mg, 0.45 mmol) was added and stirring was continued for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 47 mg (0.12 mmol, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)=O.CC(C)=O.[CH2:17]([Mg]Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCCC[Mg]Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCCCC(O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 3-bromobenzaldehyde (5.00 g, 27.02 mmol) in dry THF (100 mL), under nitrogen at −78° C. (dry ice/acetone bath) was added nBuMgCl (16.2 mL of a 2.0M solution in THF, 0.032 mol) and the reaction stirred for 1 hour at −78° C. and then allowed to warm to rt overnight. The reaction was then quenched with water, extracted with EtOAc and the layers separated. The organic layer was washed with water then brine, dried (Na2SO4) and reduced under vacuum to give a colourless oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with cyclohexane:EtOAc 9:1 afforded the title compound as a colourless oil (4.07 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].Br[C:31]1[S:35][C:34]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:33][CH:32]=1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:31]2[S:35][C:34]([C:36]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])=[CH:33][CH:32]=2)=[CH:17][CH:16]=1)=[O:14]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(c1ccc(Br)s1)N1CCCC1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C(=O)N3CCCC3)s2)cc1
Yield: 34 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (398 mg, 1.0 mmol) and (5-Bromo-thiophen-2-yl)-pyrrolidin-1-yl-methanone (CAS 326875-64-3) 261 mg, 1.0 mmol) to give 150 mg (34% yield). MS (ES+) 452.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.Cl.[S:46]1(=[O:52])(=[O:51])[CH2:50][CH2:49][NH:48][CH2:47]1.CN1CCOCC1>CN(C=O)C>[O:51]=[S:46]1(=[O:52])[CH2:50][CH2:49][N:48]([C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:17])[CH3:18])[CH2:47]1
Reactant: O=S1(=O)CCNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](C(=O)N1CCS(=O)(=O)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). Thiazolidine 1,1-dioxide hydrochloride (12.17 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-45% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (8.8 mg, 43%). 1H NMR (500 MHz, DMSO-d6) δ 0.76-0.81 (m, 3H), 0.95 (d, J=6.5 Hz, 3H), 2.41-2.50 (m, 1H), 3.35-3.45 (m, 2H), 3.80-3.89 (m, 2H), 4.49-4.91 (m, 4H), 5.18-5.42 (m, 1H), 8.01 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.43 (s, 1H). [M+H] calc'd for C17H19FN4O4S, 395; found, 395.
Reaction SMILES: Cl.Cl.[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[CH2:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13].[NH:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36](O)=[O:37])[N:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[NH:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36]([N:17]2[CH2:18][CH2:19][N:14]([C:9]3[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([O:6][CH2:5][CH2:4][F:3])[CH:8]=3)[CH2:15][C@@H:16]2[CH3:20])=[O:37])[N:27]=1
Reactant: C[C@H]1CN(c2ccc(Cl)c(OCCF)c2)CCN1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccc(Cl)c(OCCF)c2)CCN1C(=O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Temperature: 30 °C
Yield: 13.4 %

Procedure:
To a vial containing (S)-1-(3-(2-fluoroethoxy)-4-chlorophenyl)-3-methylpiperazine dihydrochloride (80 mg, 0.23 mmol) was added 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (51 mg, 0.21 mmol), HBTU (81 mg, 0.21 mmol), DMF (0.7 mL), and DIPEA (0.2 mL, 1.2 mmol). The reaction mixture was maintained at 30° C. for 24 h. The solution was diluted with EtOAc (30 mL) and washed with 1N HCl (2×10 mL) and sat. aq. NaCl (2×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resultant residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions were lyophilized to afford the indicated compound (14 mg, 13% yield): MS (ES) [M+H]+expected 498.2, found 498.4; 1H NMR (CDCl3, 400 MHz) δ 9.95 (br s, 1H), 8.79 (dd, J=1.6, 8.2, 1H), 8.55 (dd, J=1.6, 4.4, 1H), 7.19-7.26 (m, 4H), 6.44-6.50 (m, 2H), 5.40 (br s, 2H), 4.77 (dt, J=4.2, 47.2, 2H), 4.26 (dt, J=4.2, 27.2, 2H), 2.78-4.42 (m, 10H).
Reaction SMILES: [NH:1]([C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([OH:18])=O)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])C.CCOC(OC(O[CH2:35][CH3:36])=O)=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:2]1([NH:1][C:8]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[C:16]([N:21]2[C@@H:22]3[C@@H:23]([C@H:8]([C:36]4[CH:35]=[CH:15][CH:10]=[CH:11][CH:12]=4)[NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=43)[CH2:25][CH2:24]2)=[O:18])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)OC(=O)OCC
Reactant: O=C(O)[C@H]1CCCC[C@H]1C(=O)Nc1ccccc1
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)[C@H]1CCCC[C@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a mixture of the compound (242 mg, 0.75 mmol) synthesized in Reference Example 8, (1S*,2R*)-2-(anilinocarbonyl)cyclohexanecarboxylic acid (222 mg, 0.90 mmol) and triethylamine (0.313 ml, 2.25 mmol) in DMF (7.5 ml) was added DEPC (0.151 ml, 0.90 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The title compound (1R*,2S*,3aR*,4R*,9bR*) (163 mg, 45%) was obtained as a white solid from the first eluted fraction
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[C@:16]2([CH3:17])[C@H:11]([C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9][C@:8]1([OH:21])[CH3:20])(=O)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:30][CH2:6][C@@H:7]2[C@:16]3([CH3:17])[C@H:11]([C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15]3)[CH2:10][CH2:9][C@@:8]2([CH3:20])[OH:21])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(S)c1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cccc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Reaction time: 18 h
Yield: 69 %

Procedure:
A mixture of [(1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-1-yl]methyl methanesulfonate (12) (5.0 g, 16 mmol), 3-methoxybenzenethiol (1.9 mL, 16 mmol), cesium carbonate (15.3 g, 47.2 mmol) in anhydrous CH3CN (200 mL) was prepared under N2. The mixture was heated to reflux and stirred for 18 h. The reaction mixture was filtered and the filtrate concentrated to dryness. The crude product was purified by flash chromatography on silica gel (Hexanes/EtOAc, 10:1) to yield (1R,2R,4aS,8aS)-1-{[(3-methoxyphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (13-1) (4.0 g, 71% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.CCCCCC.[S:25](=[O:27])=[O:26].O.O.O.C([O-])(=O)C.[Na+].[NH2:36]OS(O)(=O)=O>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[S:10][C:11]([S:25]([NH2:36])(=[O:27])=[O:26])=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:1])[CH3:3]
Reactant: O=S=O
Reactant: NOS(=O)(=O)O
Reactant: CC(C)(C)NS(=O)(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(S(N)(=O)=O)s1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of the product from Step A (1.5 g, 6.85 mmol) in THF (10 mL) cooled to -60° C. was added n-butyllithium in hexane (2.5M, 6.0 mL, 15.1 mmol). The mixture was stirred for 15 min at -60° C. and for 30 min at -10° C. Sulfur dioxide gas was passed through the surface of the mixture for 10 min. The cooling bath was removed and the mixture was stirred for an additional 1 h. The volatiles were evaporated and the residue was dissolved in water (30 mL) and sodium acetate trihydrate (5.59 g, 41.1 mmol) was added. The mixture was cooled in an ice-water bath and hydroxylamine-O-sulfonic acid (2.71 g, 23.9 mmol) was added. The cooling bath was removed and the mixture was stirred for 2 h. The suspension was extracted with ethylacetate (3×50 mL) and the combined extracts were washed with 5% sodium bicarbonate solution, brine and dried over molecular sieves. The solvent was evaporated and the residue was chromatographed on silica eluting with 40% ethylacetatehexane, to yield 1.25 g (61%) of a liquid which solidified on standing: mp 116°-120° C.
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[C:6]([F:26])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:13]([F:25])[CH:12]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[S:27]1[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28]1.[N:35]1C=CC=CC=1>>[F:26][C:6]1[C:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])=[C:13]([F:25])[CH:12]=2)=[CH:8][CH:9]=[C:10]2[C:5]=1[NH:4][N:3]=[C:2]2[C:28]1[S:27][CH:31]=[CH:30][C:29]=1[C:32]([NH2:35])=[O:33]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1F
Reactant: O=C(Cl)c1ccsc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(-c4sccc4C(N)=O)n[nH]c3c2F)cc1F
Reaction time: 18 h

Procedure:
A solution of 1.5 g of tert-butyl [4-(3-amino-7-fluoro-1H-indazol-6-yl)-2-fluoro -phenyl]carbamate in 34 mL of pyridine is admixed at 15° C. with 0.61 g of thiophene-3-carbonyl chloride. The reaction mixture is stirred for 18 h and then poured into distilled water and extracted with ethyl acetate. The organic phase is washed a number of times with distilled water and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. This gives 1.58 g of (7-fluoro-6-{3-fluoro-4-tert-butyloxycarbonylaminophenyl}-1H-indazol-3-yl)thiophene-3-carboxamide in the form of a cream-colored solid, whose characteristics are as follows: