Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:45])([F:44])[C:10]1[CH:11]=[C:12]([C:20]2[N:24]=[CH:23][N:22](/[CH:25]=[CH:26]\[C:27]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)=[O:28])[N:21]=2)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl.CO>[F:19][C:16]([F:17])([F:18])[C:14]1[CH:13]=[C:12]([C:20]2[N:24]=[CH:23][N:22](/[CH:25]=[CH:26]\[C:27]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)=[O:28])[N:21]=2)[CH:11]=[C:10]([C:9]([F:8])([F:44])[F:45])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NCC1CCCNC1
Yield: 146.9 %

Procedure:
In a 25 mL single neck round-bottomed flask (Z)-tert-butyl 3-((3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamido)methyl)piperidine-1-carboxylate (1) (0.1 g) was dissolved in dichloromethane (5 mL) and TFA (1.0 mL) dissolved in dichloromethane added dropwise. The progress of the reaction was followed by TLC on silica gel in 10% methanol in dichloromethane as a mobile phase in UV visualization. Reaction mixture was concentrated by rotary evaporation (40° C., 20 mmHg) to afford 0.12 g of compound. The resulting crude compound was purified by ‘SAEx’ column chromatography. Fraction collected together to obtain compound (40 mg) yield 49%.
Reaction SMILES: C([O:3][P:4]([C:9]1([P:18](=[O:25])([O:22]CC)[O:19]CC)[CH2:13][C:12]([C:14](=[O:17])[CH2:15][CH3:16])=[N:11][NH:10]1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(Cl)(Cl)Cl>[O:17]=[C:14]([C:12]1[CH2:13][C:9]([P:18](=[O:19])([OH:25])[OH:22])([P:4](=[O:3])([OH:8])[OH:5])[NH:10][N:11]=1)[CH2:15][CH3:16]
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)CC(C(=O)CC)=NN1
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: CCC(=O)C1=NNC(P(=O)(O)O)(P(=O)(O)O)C1

Procedure:
[2,4-Dihydro-5-(1-oxopropyl)-3H-pyrazol-3-ylidene]bisphosphonic acid tetraethyl ester (III, EXAMPLE 12, 1.56 g) and bromotrimethylsilane (2.6 ml) in chloroform (20 ml) are stirred at 50° for 4 hrs, then concentrated. The concentrate is diluted with water and ethyl acetate, shaken, and the aqueous layer separated and freeze dried to give the title compound, mp 148° foamed, IR (mineral oil mull) 3325, 1597, 1532, 1430, 1189, 1173, 1060, 1019 and 937 cm-1 ; NMR (D2O) 3.40, 2.84 and 1.07 δ.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]([CH3:41])[CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=2)=[C:34]([CH3:41])[CH:33]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCCC(Oc1ccc(-c2ccc(F)cc2C)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
This compound is made in a substantially similar manner as Example 117 using isomer 1 of 3-{4-[1-(4-bromo-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl ester and 4-fluoro-2-methyl-phenylboronic acid as starting materials in step D. MS (ES): 492.3 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17]O)[CH2:3][CH2:2]1.P(Br)(Br)[Br:20].C(=O)(O)[O-].[Na+]>ClCCl>[Br:20][CH2:17][C:5]1[C:6]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Alternate procedure: Cool a solution of (5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl)-methanol (100 g, 0.35 mol) in dichloromethane (1200 mL) to −10° C. Add phosphorous tribromide (105 g, 0.39 mol) dropwise while maintaining the internal temperature between −5° C. and 0° C. Stir at −5° C. to 0° C. for 30 min. Allow to warm to between 20° C. and 25° C. and stir at 20° C. to 35° C. for 2 h. Cool the reaction mixture to 0° C. to 5° C. Add an aqueous solution of sodium bicarbonate (775 mL) dropwise. Separate the phases. Extract the aqueous phase with dichloromethane (2×350 mL). Wash the combined organic phases with water (3×500 mL). Concentrate the organic phase to afford 115 g (94%) of the title compound as a solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21]I>O1CCCC1.CN(C)C=O.O.CCCCCC.C(OCC)(=O)C>[CH2:3]([O:10][C:11]([N:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:21])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: CCOC(=O)CCNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(C)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (1.92 g, 60% in Oil) in a mixture of tetrahydrofuran (200 ml) and N,N-dimethylformamide (50 ml) was added dropwise ethyl 3-(benzyloxycarbonylamino)propionate (10 g) at 30° C. under nitrogen atmosphere, which was stirred for 30 minutes. To the reaction mixture was added methyl iodide (3 ml) and stirred for additional 6 hours. To the resulting mixture was added carefully water (5 ml), which was poured into a mixture of ethyl acetate (500 ml), n-hexane (150 ml) and water (100 ml). Organic layer was separated, washed n turn with water (100 ml×3), 1N-aqueous hydrochloric acid (100 ml), brine (100 ml), saturated sodium hydrogen carbonate in water (100 ml) and brine (100 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting In turn with n-hexane, 10%, 50% ethyl acetate in n-hexane to give ethyl 3-(N-benzyloxycarbonyl-N-methylamino)propionate (8.32 g).
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:53]([O:55][C:56](=[O:61])[C@H:57]([CH2:59][NH2:60])N)[CH3:54]>CN(C=O)C.C(Cl)CCl>[CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:60][CH2:59][CH2:57][C:56]([O:55][CH2:53][CH3:54])=[O:61])=[O:18])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@@H](N)CN
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of 177.8 mg product from Step D Example 1, 92.0 mg EDC, 64.9 mg HOBt in 1.5 mL DMF was stirred at room temperature for 30 minutes. Diisopropylethylamine (DIEA, 84 μL) and β-amino-alanine ethyl ester hydrochloride (73.7 mg) were added and the mixture stirred for additional 16 hours. The solvent was removed under reduced pressure. Some crystalline product precipitated after dissolving the residue in 14 mL 3:2 MeCN and water with 0.1% TFA. More title compound was isolated by preparative HPLC of the filtrate using 60˜80% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA on a 9.4×250 mm SB-C18 Zorbax column. 1H NMR (CD3OD, 600 MHz) δ 7.84˜7.87 (m, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H), 6.56 (s, 1H), 5.46 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.60 (t, J=6.8 Hz, 2H), 2.62 (t, J=6.8 Hz, 2H), 2.60 (tt, J=11.7 & 3.3 Hz, 1H), 1.73˜1.77 (m, 4H), 1.68˜1.71 (m, 1H), 1.37˜1.43 (m, 2H), 1.24˜1.35 (m, 3H), 1.21 (t, J=7.1 Hz, 3H). LC-MS: 2.47 min. (M+H=544.4).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[C:4]([CH:24]2[CH2:27][O:26][CH2:25]2)[CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34]C(=O)OC(C)(C)C)[CH2:29]1.CN1CCOCC1>CN1CCCC1=O>[CH3:23][C:19]1[N:18]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:28]5[CH2:33][CH2:32][CH2:31][C@H:30]([NH2:34])[CH2:29]5)[CH:3]=[C:4]([CH:24]5[CH2:27][O:26][CH2:25]5)[CH:5]=4)[C:16]=3[CH:15]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(C3COC3)cc(F)n2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(C3COC3)cc(N3CCC[C@H](N)C3)n2)n1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
A mixture of 1-[6-fluoro-4-(oxetan-3-yl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.1443 mmol; 63 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.4329 mmol, 80.7 mg), and N-Methylmorpholine (0.3607 mmol; 36.9 mg; 0.0401 mL) in 1-Methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was cooled to room temperature. The solvents were removed. The residue was treated with 20% TFA in DCM at room temperature for 2 h. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 250 as an off-white solid (17.5 mg, 26%). 1H NMR (400 MHz, DMSO) δ 9.61-9.57 (s, 1H), 9.49-9.43 (s, 1H), 9.36-9.29 (s, 1H), 8.69-8.66 (s, 1H), 8.65-8.61 (s, 1H), 7.33-7.30 (s, 1H), 6.82-6.76 (s, 1H), 5.02-4.95 (m, 2H), 4.73-4.66 (t, J=6.3 Hz, 2H), 4.42-4.35 (d, J=13.2 Hz, 1H), 4.35-4.27 (dd, J=15.0, 7.2 Hz, 1H), 4.20-4.13 (d, J=10.7 Hz, 1H), 3.29-3.21 (m, 2H), 3.08-3.01 (m, 1H), 2.98-2.91 (s, 1H), 2.66-2.61 (s, 3H), 2.01-1.83 (m, 3H), 1.71-1.58 (d, J=13.4 Hz, 1H), 1.51-1.40 (d, J=10.8 Hz, 1H), 0.99-0.92 (t, J=7.3 Hz, 1H); MS (ESI) m/z: 443.2 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:46][CH2:47][CH2:48][CH3:49])[C:35]([N:37]3[CH:41]([C:42]([O:44][CH3:45])=[O:43])[CH2:40][S:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:46][CH2:47][CH2:48][CH3:49])[C:35]([N:37]3[CH:41]([C:42]([O:44][CH3:45])=[O:43])[CH2:40][S:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCCC)C(=O)N3CSCC3C(=O)OC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(CCCC)C(=O)N3CSCC3C(=O)OC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(4-methoxycarbonyl-thiazolidin-3-ylcarbonyl)-n-butylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(C2(CN)CCCCC2)cc1OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
(3,4-Dimethoxy-phenyl)-acetonitrile (5.00 g, 28.2 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran in a 250 mL round bottom flask. Sodium hydride (2.03 g, 84.6 mmol) was slowly added and the reaction mixture was warmed to 50-60° C. 1,4-Dichloropentane (4.78 g, 33.9 mmol) was then added and the reaction mixture was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and quenched with the slow addition of methanol. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel to yield a pale yellow oil (3.65 g, 14.9 mmol, 52.8%). The resulting 1-(3,4-dimethoxy-phenyl)-cyclohexanecarbonitrile (2.00 g, 8.15 mmol) was dissolved in dry ether (40 mL) and cooled to 0° C. under an atmosphere of nitrogen. Lithium aluminum hydride (8.15 mL, 1M in ether) was slowly added and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0° C. and quenched with 0.34 mL water, 0.34 mL of 15% sodium hydroxide, and then an additional 1.4 mL of water. The reaction mixture was then filtered through celite, washed with water and a saturated aqueous sodium chloride solution. The filtrate was evaporated to dryness to give a colorless oil (1.91 g, 7.66 mmol, 94.0%). ESI-MS m/z calc. 249.2, found 250.2 (M+1)+. Retention time of 1.76 minutes.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:3])[CH3:2].CI.[C:26](=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]([N:4]([CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH3:26])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2=C(CC(C)NC(C)C)C(=O)NCCC2)cc1
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: COc1ccc(C2=C(CC(C)N(C)C(C)C)C(=O)NCCC2)cc1

Procedure:
The mixture of 8.23 g of 3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 2.25 ml of methyl iodide, 3.59 g of potassium carbonate and 100 ml of absolute ethanol is refluxed for five hours and evaporated. The residue is suspended in 100 ml of water and the suspension extracted with diethyl ether. The extract is dried, evaporated and the residue crystallized from ethanol-water to yield the 3-[2-(N-isopropyl-N-methylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 86°-88°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: OCC1CCCO1
Product: Fc1cc(OCC2CCCO2)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and rac-2-hydroxymethyl-tetrahydrofuran in analogy to Example 9c): MS (EI): 274 and 276 M+.
Reaction SMILES: [Br:1][C:2]1[CH:33]=[C:32]([OH:34])[C:31]([OH:35])=[CH:30][C:3]=1[C:4]([NH:6][NH:7][S:8]([NH:11][C:12]([N:14]1[CH2:17][C@H:16]([NH:18]C(=O)OCC2C=CC=CC=2)[C:15]1=[O:29])=[O:13])(=[O:10])=[O:9])=[O:5].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].C1(SC)C=CC=CC=1>CCOCC>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:18][C@H:16]1[CH2:17][N:14]([C:12]([NH:11][S:8]([NH:7][NH:6][C:4](=[O:5])[C:3]2[CH:30]=[C:31]([OH:35])[C:32]([OH:34])=[CH:33][C:2]=2[Br:1])(=[O:10])=[O:9])=[O:13])[C:15]1=[O:29]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2cc(O)c(O)cc2Br)C1=O)OCc1ccccc1
Solvent: CCOCC
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2cc(O)c(O)cc2Br)C1=O
Reaction time: 8 h

Procedure:
At room temperature, 2.29 g (4 mmol) of (S)-[1-[[[[2-(2-bromo-4,5-dihydroxybenzoyl)hydrazino]sulfonyl]amino]carbonyl]-2-oxoazetidinyl]carbamic acid, phenylmethyl ester was added to a mixture of 4.5 ml of trifluoroacetic acid and 1.6 g of thioanisole. After stirring overnight, 50 ml of ether was added and the resulting crystals were filtered off by suction, dried and triturated with 40 ml of dichloromethane. The crystals were filtered off again and dried in vacuo; yield: 1.9 g, melting point 157° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14]C1C=CC=CC=1)=[O:12])C1C=CC=CC=1.[C:49]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)([OH:51])=[O:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([C:55]3[CH:56]=[CH:57][C:52]([C:49]([OH:51])=[O:50])=[CH:53][CH:54]=3)=[CH:46][CH:47]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])[C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:10]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 4-carboxyphenylboronic acid to give 32 on a 0.1 mmol scale via General Procedure H. 32 was not purified at this stage and was deprotected without purification.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:6][C@@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+:24]=[N-:25]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])CC1CCCCC1
Temperature: 50 °C
Yield: 65 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (13.3 g, 39.3 mmol) from Step 1 was dissolved in anhydrous DMF (140 mL). Solid NaN3 (5.18 g, 79.7 mmol) was added and the reaction was warmed to 50° C. for 5 h. The reaction mixture was permitted to cool to rt and the solvent was removed under reduced pressure (150 Torr, 55° C.). This material was taken up into Et2O (150 mL), washed with water (3×10 mL) and brine (3×10 mL), dried (Na2SO4), decanted, and stripped to give 13.9 g crude product. This was separated on a silica column using a gradient from 0-100% EtOAc in hexanes. Solvent was stripped from appropriate fractions to give (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate (7.21 g, 65%) as a clear oil. 1H NMR (CDCl3) δ 0.60-1.80 (m 12H), 1.40 (s, 9H), 2.86 (d, 1H), 3.29 (d, 1H), 4.85 (d, 1H), 4.51 (m, 1H), 8.00 (s, 1H). MS ESI+ve m/z 183 (M(−BOC)+1).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:51]=[CH:50][C:16]([CH2:17][N:18]([CH3:49])[CH2:19][C:20]([O:22][C@H:23]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]3[CH2:48][CH2:47]3)[CH:35]=2)[CH2:24][C:25]2[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=2[Cl:33])=[O:21])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl.Cl>[Cl:33][C:26]1[CH:27]=[N+:28]([O-:32])[CH:29]=[C:30]([Cl:31])[C:25]=1[CH2:24][C@@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[O:22][C:20](=[O:21])[CH2:19][N:18]([CH3:49])[CH2:17][C:16]1[CH:15]=[CH:14][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:51][CH:50]=1
Reactant: CN(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)Cc1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-4-(2-(2-((4-(N-(tert-butoxycarbonyl)methylsulfonamido)benzyl)(methyl)amino)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.250 g, 0.323 mmol) in DCM (15 ml), HCl 4M in dioxane (2 ml, 8.00 mmol) was added, and the solution was stirred at RT overnight. The mixture was portioned between DCM and 5% NaHCO3, and the organic layer was dried over sodium sulfate. The solvent was removed, and the crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1 to 97:3) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(methyl(4-(methylsulfonamido)benzyl)amino)-acetoxy)ethyl)pyridine 1-oxide, free base (0.120 g, 0.178 mmol, 55.1% yield), as a colorless amorphous solid. This product was dissolved in DCM (12 ml) and HCl 4M in dioxane (0.089 ml, 0.356 mmol) was added; the mixture was stirred at RT for 2 hours, and volatiles were removed under vacuum. The product was further dissolved in DCM and washed with 5% NaHCO3. The organic phase was dried over Na2SO4, and the crude was purified by chromatography on silica gel cartridge (DCM/EtOAc 90/10 to EtOAc 100%) followed by a further filtration through a silica gel cartridge (DCM/MeOH 99/1 to 98/2) to give 0.090 g of free base. This product was dissolved in 5 ml of DCM, and HCl 4M in dioxane (0.044 ml, 0.177 mmol) was added. The mixture was stirred at RT for 1 hour. The solvent was removed to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(methyl-(4-(methylsulfonamido)benzyl)amino)acetoxy)ethyl)pyridine 1-oxide hydrochloride (0.095 g, 0.134 mmol, 41.5% yield, MS/ESI+ 673.99 [MH]+)
Reaction SMILES: [N+]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1)([O-])=O.[I:13]I>>[I:13][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1
Reactant: O=[N+]([O-])c1n[nH]c2ccccc12
Reactant: II
Product: Ic1n[nH]c2ccccc12

Procedure:
In step 1 of Scheme A, nitroindazole compound a is treated with iodine or iodine equivalent to form 3-iodo indazole compound b. The amine functionality at the 1-position may be protected (not shown) prior to carrying out this step, and then subsequently deprotected. In step 2 the iodoindazole b is reacted with aryl boronic acid c in the presence of suitable palladium catalyst to afford 3-aryl indazole d. Aryl boronic acid c may in certain embodiments be replaced with a corresponding heteroaryl boronic acid. In step 3 the nitro group on indazole compound d is reduced to yield amino-substituted indazole e. Indazole e in step 4 is then treated with arylsulfonyl chloride f to form the sulfonamide compound g, Compound g is a compound of formula Ia in accordance with the invention.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][NH:21][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(C)(CN)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(NCC(C)(C)c2ccc(F)cc2)nc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 76.5 %

Procedure:
To a 20 dram vial was added methyl 2-chloropyrimidine-5-carboxylate (250 mg, 1.4 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (468 mg, 2.8 mmol, 2.0 equiv), DIPEA (1.0 mL, 5.6 mmol, 4.0 equiv), and toluene (5 mL). The vial was heated in an oil bath to 60° C. and stirred for 20 min, concentrated, and purified by silica gel column chromatography (0-50% EtOAc/hexanes) to give 325 mg (77%) of methyl 2-(2-(4-fluorophenyl)-2-methylpropylamino)pyrimidine-5-carboxylate as a white solid (m/z [M+H]=304.1).