Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[NH:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([O:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][N:30]=3)[CH2:24]2)[C:20](=[O:39])[NH:19][C:18]2([C:40]([NH:42][S:43]([C:46]3([CH2:49][CH2:50][CH3:51])[CH2:48][CH2:47]3)(=[O:45])=[O:44])=[O:41])[CH:16]([CH2:17]2)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N(C([O-])=O)=NC([O-])=O.[K+].[K+].C(O)(=O)C>CO>[C:1]([O:5][C:6](=[O:52])[NH:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([O:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][N:30]=3)[CH2:24]2)[C:20](=[O:39])[NH:19][C:18]2([C:40]([NH:42][S:43]([C:46]3([CH2:49][CH2:50][CH3:51])[CH2:47][CH2:48]3)(=[O:44])=[O:45])=[O:41])[CH:16]([CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC1(S(=O)(=O)NC(=O)C23CC2C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N2CC(Oc4nccc5ccccc45)CC2C(=O)N3)CC1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCC1(S(=O)(=O)NC(=O)C23CC2CCCCCCCC(NC(=O)OC(C)(C)C)C(=O)N2CC(Oc4nccc5ccccc45)CC2C(=O)N3)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.8 %

Procedure:
To a mixture of 73 mg (0.1 mmol) of [18-(Isoquinolin-1-yloxy)-2,15-dioxo-4-(1-propylcyclopropanesulfonylamino-carbonyl)-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester in 3 mL of methanol was added 332 mg (2 mmol)of dipotassium azodicarboxylate. Glacial acetic acid (240 mg, 4 mmol) in 2 mL of methanol was added slowly by a syringe pump over 5 h. The mixture was stirred at rt. After 5 h, another 332 mg (2 mmol) of dipotassium azodicarboxylate and 240 mg (4 mmol) of glacial acetic acid was added over the course of 5 h and the stirring was continued overnight. This cycle was repeated twice. LC-MS showed about 40% starting material still remaining. The solvent was then removed on a rotary evaporator. Water was added to the residue and the mixture was extracted three times with ethyl acetate. It was then dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in methanol and purified by preparative HPLC (YMC ODS-A, S5, 20×100 mm, gradient: 80% B to 85% B, 15 min, hold 2 min, flow rate 25 mL/min) to isolate the product as a white powder (25 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:13]3[CH2:12][O:11]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[C:14]3([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH2:15][NH:16][CH2:17][CH:13]3[CH2:12][O:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2OCC3CN(C(=O)OC(C)(C)C)CC32c2cccnc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2OCC3CNCC32c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a stirred solution of tert-butyl 1-[(4-methoxyphenyl)methyl]-6a-(3-pyridyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (2.9 g, 7.05 mmol) in dichloromethane (80 mL) is added trifluoroacetic acid (16 mL). The reaction mixture is stirred for 1 hour 30 minutes at room temperature. The solvent is concentrated and the residue is partitioned between saturated aqueous sodium bicarbonate (30 mL) and dichloromethane (100 mL). The resulting solution is stirred for 30 minutes then the phases are separated. The aqueous phase is re-extracted with dichloromethane. The combined dichloromethane extracts are dried over magnesium sulfate, filtered, and concentrated under vacuum to give a residue. The residue is purified by silica gel chromatography using a 0-10% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (1.33 g, 43%). ES/MS (m/e): 312 (M+1).
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:7]1[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(Cl)Cl>O>[CH2:12]([C:11]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:33]2[CH:32]=[CH:31][S:30][C:29]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC(O)(CCCCCCCC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCC1(CCCCCCCC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (9.38 mL) was added dropwise to 9-([2,2′-bithiophen]-3-yl)heptadecan-9-ol (IIe) (6.32 g, 15 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (130 mL) and water (130 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Ie) (1.81 g, 30.0%). 1H-NMR (CDCl3): δ=7.14 (d, J=4.8 Hz, 2H), 6.93 (d, J=5.1 Hz, 2H), 1.87-1.79 (m, 4H), 1.40-1.06 (m, 24H), 0.95-0.82 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:17])[CH3:16])(=[O:12])=[O:11].S(=O)(=O)(O)O>C(O)(C)(C)C>[C:15]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:16])[CH3:17])(=[O:11])=[O:12])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(CCS(=O)(=O)CCOCCOCCO)NC(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: CC(C)(CCS(=O)(=O)CCOCCOCCOC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 106 %

Procedure:
To a solution of benzyl 4-(2-(2-(2-hydroxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (132.3 mg, 0.317 mmol) in tert-butanol (500 ul) was added conc. sulfuric acid (100 ul). The solution was stirred at RT for 6 d, concentrated in vacuo, and the residue purified by flash chromatography (30%→80% EtOAc in hexanes) to afford the title compound as a clear oil (79.5 mg, 0.168 mmol, 53%). 1H NMR (CDCl3, 400 MHz) δ 1.18 (s, 9H), 1.27 (s, 6H), 2.17-2.20 (m, 2H), 3.12-3.18 (m, 4H), 3.46-3.49 (m, 2H), 3.53-3.56 (m, 2H), 3.60 (s, 4H), 3.89 (t, J=6.8 Hz, 2H), 5.01-5.04 (m, 3H), 7.3-7.4 (m, 5H). LRMS (ESI/APCI): 496 [M+Na]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[N-:9]=[N+:10]=[N-:11].[Na+]>>[N:9]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCBr
Agent: [Na+]
Product: [N-]=[N+]=NCCCCC(=O)O

Procedure:
Reaction of 5-bromopentanoic acid and NaN3, as described for the synthesis of 6, gave 5-azidobutanoic acid 8. Saponification was not necessary. Used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[F:41])[O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:29]=[C:30]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[N:31]=2)[N:28]=1>CN(C)C=O.O1CCCC1.[OH-].[Na+]>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:40]([F:41])=[C:19]([NH:18][C:8]([C:6]5[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:20]=4)=[N:28][N:27]3[CH:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: CCn1cc(C(=O)O)c(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)c(C)n1
Yield: 51.6 %

Procedure:
To a solution of 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (2.00 g, 13.0 mmol) and N,N-dimethylformamide (3 drops) in tetrahydrofuran (30 mL) was added oxalyl chloride (2.23 mL, 26.0 mmol) with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (20 mL) with stirring under ice-cooling, N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (3.27 g, 10.0 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution (50 ml) and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1, 80 mL, 40 mL×2). The organic layer was washed with water (10 mL×3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and crystallized from ethyl acetate to give the title compound (2.39 g, yield 52%) as a white solid. melting point 199° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:14][C:8]1([CH3:13])[CH2:7][C:6](=[O:15])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=3)[CH:4]=2)[S:9]1
Reactant: C#Cc1ccc2c(c1)C(=O)CC(C)(C)S2
Reactant: CCOC(=O)c1ccc(I)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CC(C)(C)S3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A solution of 6-ethynyl-2,2-dimethylthiochroman-4-one (Compound 222, 510.0 mg, 2.36 mmol) and ethyl 6-iodonicotinate (654.0 mg, 2.36 mmol) in 20.0 mL Et3N was purged with argon for 20 minutes. To this solution was added bis(triphenylphosphine)-palladium(II) chloride (425.0 mg, 0.60 mmol) and copper(I) iodide (115.0 mg, 0.60 mmol). After sparging for an additional 10 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (20 mL) and filtered through a pad of Celite using an Et2O wash. Concentration of the filtrate under reduced pressure, followed by column chromatography (10 to 20% EtOAc/hexanes) of the residual solid afforded 675 mg (78%) of the title compound as an orange solid. 1H NMR (300 MHz, CDCl3) δ: 9.20 (1H, d, J=1.0 Hz), 8.34 (1H, d, J=1.8 Hz), 8.29 (1H, dd, J=2.2, 8.2 Hz), 7.60 (2H, m), 7.25 (1H, d, J=8.4 Hz), 4.43 (2H, q, J=7.1 Hz), 2.90 (2H, s), 1.49 (6H, s), 1.43 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl.[CH:2]([N:4]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]([CH2:7][C@@H:8]([C:10]([O:12][CH3:13])=[O:11])[NH2:9])=[CH:5]1)=[O:3].C(N(CC)CC)C.[F:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32](O)=[O:33].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32]([NH:9][C@H:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([CH:2]=[O:3])[CH:5]=1)=[O:33]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)Cc1cn(C=O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C=O)c2ccccc12)NC(=O)C=Cc1ccccc1F
Yield: 86 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 29 (4.0 g), triethylamine (2.2 mL), 2-fluorocinnamic acid (2.6 g), WSC.HCl (3.0 g), and methylene chloride (100 mL), to give the captioned compound (4.8 g, 86%) as an oily product.
Reaction SMILES: [N:1]12[CH2:15][CH2:14][CH:4]([C:5]3[NH:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]=31)[CH2:3][CH2:2]2.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][N:18]=1>>[CH3:16][C:17]1[N:18]=[CH:19][C:20]([CH2:23][CH2:24][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[N:1]4[CH2:2][CH2:3][CH:4]([C:5]2=3)[CH2:14][CH2:15]4)=[CH:21][CH:22]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN3CC1
Product: Cc1ccc(CCn2c3c(c4ccccc42)N2CCC3CC2)cn1

Procedure:
The coupling of 2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (110 mg, 0.56 mmol; Example 205A) and 2-methyl-5-vinylpyridine (99 mg, 0.83 mmol; prepared as described in International Publication No. WO 2001017968) was performed according to the procedure described in Example 106A to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 0.91-1.05 (m, 2H), 1.75-1.85 (m, 2H), 2.38 (s, 3H), 2.42-2.51 (m, 2H), 3.09-3.21 (m, 5H), 4.44-4.50 (m, 2H), 7.02-7.12 (m, 3H), 7.27 (dd, J=7.9, 2.1 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H); MS (ESI) m/z 476 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:20]=[CH:19][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:10]=2[C:9]=1[F:21].[Si]([O:29][CH2:30][C@H:31]([CH3:49])[O:32][C:33]1[CH:34]=[C:35]([CH:45]=[C:46]([OH:48])[CH:47]=1)[C:36]([NH:38][C:39]1[CH:43]=[CH:42][N:41]([CH3:44])[N:40]=1)=[O:37])(C(C)(C)C)(C)C>CN1CCCC1=O>[F:21][C:9]1[C:10]2[O:16][CH:15]([CH3:14])[N:13]([CH3:17])[C:12](=[O:18])[C:11]=2[CH:19]=[CH:20][C:8]=1[O:48][C:46]1[CH:45]=[C:35]([CH:34]=[C:33]([O:32][C@@H:31]([CH3:49])[CH2:30][OH:29])[CH:47]=1)[C:36]([NH:38][C:39]1[CH:43]=[CH:42][N:41]([CH3:44])[N:40]=1)=[O:37]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN1CCOc2c(ccc(F)c2F)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC1Oc2c(ccc(Oc3cc(O[C@@H](C)CO)cc(C(=O)Nc4ccn(C)n4)c3)c2F)C(=O)N1C
Temperature: 140 °C
Yield: 40.9 %

Procedure:
Potassium carbonate (152 mg, 1.1 mmol) was added to a solution of 8,9-difluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (117 mg, 0.55 mmol) and 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (223 mg, 0.55 mmol) in 1-methyl-2-pyrrolidinone (10 mL) and the mixture heated at 140° C. for 3 days. The mixture was concentrated in vacuo and the residue suspended in ethyl acetate (20 mL). The suspension was filtered through Celite® and evaporated. The residue was purified by column chromatography (eluting with 0-20% methanol in DCM) to afford a colourless gum which solidified on evaporation from 30% methanol in DCM to afford the title compound as a colourless solid (109 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH2:11]([N:14]1[C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:23]Cl)[CH2:12][CH3:13]>C(#N)C>[CH2:11]([N:14]1[C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:23][NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:12][CH3:13]
Reactant: CCCn1c(CCl)nc2cccnc21
Reactant: COc1ccc(CN)cc1
Solvent: CC#N
Product: CCCn1c(CNCc2ccc(OC)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.9 %

Procedure:
4-Methoxybenzylamine (3.8 g, 27 mmol) is dissolved in 20 mL dry acetonitrile. 1-propyl-2-chloromethyl-7-azabenzimidazole (173)(940 mg, 4.5 mmol) dissolved in 4.5 mL acetonitrile is added dropwise. The mixture is stirred 10 hours at room temperature. The solvent is removed in vacuo and the residue dissolved in 20 mL ethyl acetate. This solution is washed once with 20 mL 1 N NaOH, once with 20 mL water, once with 20 mL 5% HOAc in water, then once with 5 N NaOH. The organic phase was dried over MgSO4, filtered, then concentrated in vacuo. The product mixture is purified by flash chromatography eluting with ethyl acetate followed by 95/5/1 ethyl acetate/methanol/triethylamine to afford 850 mg of the 1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole (184).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[N:6]=[C:5]2[OH:20].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[O:31])=[CH:10][CH:9]=2)[C:5]([OH:20])=[N:6]1
Reactant: Nc1ccc2c(c1)c(O)nn2Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Nc2ccc3c(c2)c(O)nn3Cc2ccc(Cl)c(Cl)c2)cc1

Procedure:
1.54.g 5-amino-1-(3,4-dichlorobenzyl)-1H-indazole-3-ol and 1.12 g 4-methoxyphenyl isocyanate are stirred in 75 ml tetrahydrofuran for 5 hours at room temperature. the solution is concentrated to one third of its volume under vacuum and the precipitate crystallized out after cooling is filtered off under suction. It is recrystallized from n-butanol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([Cl:11])[N:5]=1.[C:12]([O:16][C@@H:17]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[CH3:18])([CH3:15])([CH3:14])[CH3:13].CCOC(C)=O.CCCCCCC>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C@@H:17]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:8]1[CH:7]=[C:6]([Cl:11])[N:5]=[C:4]([Cl:3])[N:9]=1)[CH3:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
To a round bottom flask was added NaH (0.54 g, 13.5 mmol, 57% dispersion in mineral oil) to a solution of 2,4,6-trichloropyrimidine (1.22 ml, 10.6 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (1.8 g, 9.61 mmol) in DMF (32 mL) at 0° C. (ice bath) under a bubbler. The yellow suspension was then stirred at 0° C. for 15 min and then the ice bath was removed and reaction mixture allowed to stir 1 hr at room temperature. Reaction mixture was diluted with EtOAc and then carefully quenched with brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (2.1 g, 6.28 mmol, 65% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.04 (d, J=6.55 Hz, 3H) 1.26 (s, 9H) 4.38-4.48 (m, 2H) 4.64-4.75 (m, 2H) 8.22 (s, 1H). LCMS m/z 334.1 (M+H)+, Rt 1.10 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[NH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:14]=3)[N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:30](O)(=[O:34])[C@H:31]([CH3:33])[OH:32].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[OH:32][C@@H:31]([CH3:33])[C:30]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]5[NH:29][N:28]=[CH:27][CH:26]=5)=[CH:23][CH:24]=4)[CH:14]=3)[N:9]=2)[CH2:2][CH2:3]1)=[O:34]
Reactant: C[C@H](O)C(=O)O
Reactant: c1cc(-c2ccc(Oc3ccc4nc(CN5CCNCC5)ccc4c3)cc2)[nH]n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](O)C(=O)N1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cc4)ccc3n2)CC1
Reaction time: 72 h

Procedure:
A stirred suspension of intermediate F (35.0 mg, 0.076 mmol) in DCM (2.00 mL) is treated with L-(+)-lactic acid (17.2 mg, 0.191 mmol), triethylamine (53 mL, 0.382 mmol) and TBTU (30.7 mg, 0.095 mmol). After 72 h, the mixture is concentrated and purified using silica gel flash chromatography (0-10% MeOH in DCM) to afford the title compound (13).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[I:11]I>C(#N)C>[I:11][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[O:9][CH3:10]
Reactant: II
Reactant: COc1ccc(OC)cc1
Solvent: CC#N
Product: COc1ccc(OC)c(I)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following the procedure from a previous publication (0. V. Branytska et al., J. Org. Chem., 68, 9510-12 (2003)), a 350 ml heavy wall pressure vessel fitted with a stir bar was charged with p-dimethoxybenzene (20.00 g, 144.7 mmol), iodine (18.37 g, 72.37 mmol), oxidation catalyst H5PV2Mo10O40.34H2O (T. Onoda et al., U.S. Pat. No. 4,146,574 (Mar. 27, 1979)) (3.40 g, 1.45 mmol), and acetonitrile (1.8 M). The vessel was degassed via the freeze-pump-thaw method (2 times) and warmed to room temperature prior to being backfilled with oxygen (2 atm), heated to 80° C., and stirred for 12 hr. The crude reaction mixture was filtered to remove spent catalyst, then water (100 ml) was added and the product extracted into ethyl acetate (100 ml). The organic layer was washed with sodium thiosulfate (aq) and excess water. The organic layer was dried over MgSO4, filtered, and then concentrated by rotary evaporation. Ethanol (100 ml) was added to this crude material in which a white precipitate formed and was filtered via suction filtration yielding 1 as a byproduct. The supernate was concentrated via rotary evaporation and the resulting red oil distilled yielding starting material ˜60° C. at 50 mtorr and product 8 (29.2 g, 76%) at ˜115° C. at 50 mtorr as a clear oil. 1H NMR (300 MHz, CDCl3): δ 7.32 (d, 1H, J=2.94 Hz), 6.84 (dd, 1H, J=5.99 Hz), 6.73 (d, 1H, J=8.95 Hz), 3.81 (s, 3H), 3.73 (s, 3H). 13C NMR (60 MHz, acetone-d6): δ 154.78, 153.10, 125.09, 115.01, 112.21, 85.95, 56.76, 55.75.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[OH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[OH:20][CH2:21][C:22]1[CH:27]=[C:26]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Product: O=C(O)c1csc(COc2ccc(-c3cccc(CO)c3)cc2)n1

Procedure:
2-(3′-Hydroxymethyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 22 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 3-(hydroxymethyl)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=342.
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[C:12]([I:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7](S(C)=O)[N:6]=1.O>CC(O)C>[I:13][C:12]1[CH:11]=[C:8]2[C:9]([NH2:10])=[N:3][NH:2][C:7]2=[N:6][C:5]=1[NH2:4]
Reactant: CS(=O)c1nc(N)c(I)cc1C#N
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: Nc1nc2[nH]nc(N)c2cc1I
Temperature: 80 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
275 μl (2 eq) of hydrazine monohydrate is added to a solution of 872 mg (2.84 mmol) of 6-amino-5-iodo-2-(methylsulfinyl)nicotinonitrile in 11 ml of 2-propanol. The reaction medium is stirred at 80° C. for 3 hours. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on magnesium sulfate, filtered and evaporated. The residue is triturated in a minimum of diisopropyl ether. The solid is filtered to yield 523 mg (67%) of 5-iodo-1H-pyrazolo[3,4-b]pyridin-3,6-diamine in the form of a brown powder.