Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][C:18]3=[S:21])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32].N1C=CC=CC=1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:31]([NH:30][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=2[Cl:22])=[O:32])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][C:18]3=[S:21])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=S)NCC3)n1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(=S)NCC3)n1
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A suspension of 7-(3-t-butyl-5-amino-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-1(2H)-thione (0.150 g, 0.499 mmol) in THF (3 mL) was added to a solution of 2,3-dichlorophenyl isocyanate (0.141 g, 0.749 mmol), pyridine (0.061 mL, 0.059 g, 0.749 mmol) and THF (3 mL). The flask which contained the starting material was again rinsed with THF (4 mL) and the solution was added to the reaction flask. The resulting yellow suspension was briefly heated with a heat gun, causing the reaction mixture to become clear. After 18 h, the solution was concentrated and the residue was purified by column chromatography to yield 1-[3-t-butyl-1-(1-thioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea as a yellow solid (203 mg, 83% yield). 1H NMR (400 MHz, acetone-d6): δ 9.60 (brs, 1H), 8.66 (d, J=2.0 Hz, 1H), 8.61 (brs, 1H), 8.26 (dd, J=8.4, and 2.0 Hz, 1H), 8.17 (brs, 1H), 7.68 (dd, J=8.0, and 2.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.30 (t, J=8.2 Hz, 1H), 7.23 (dd, J=7.6, and 1.2 Hz, 1H), 6.48 (s, 1H), 3.62-3.58 (m, 2H), 3.07 (t, J=6.6 Hz, 2H), 1.33 (s, 9H); MS (ESI) m/z: 488.0 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31]C(C)(C)C)=[O:30])[CH:24]=2)[CH2:19]1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.O>C(OC(C)C)(=O)C>[CH2:1]([N:3]([C@H:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:27][C:28]([CH3:36])([CH3:37])[C:29]([OH:31])=[O:30])[CH:24]=2)[CH2:19]1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)[C@@H]1Cc2ccc(SC(C)(C)C(=O)O)cc2C1
Temperature: 17.5 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionate (288 g, 0.534 mol) was added a solution of sulfuric acid (535 g, 5.34 mol) in isopropyl acetate (0.7 L) while maintaining the reaction temperature at about 15-20° C. The clear solution was stirred at 15° C. for 1 hour after the addition. To the reaction mixture was added cold water (0.94 L). After removal of the acidic aqueous layer, the isopropyl acetate layer was washed until the pH of the aqueous layer reached 3. The solution was used in the next step without isolation.
Reaction SMILES: [C:1]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O)#[N:2].[NH:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([NH2:25])=[C:19]2[C:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][C:27]=2[F:39])=[N:17]1.C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([CH2:15][CH:12]3[CH2:13][CH2:14][N:11]3[C:4]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:1]#[N:2])=[O:6])[N:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:28][C:27]=3[F:39])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CCN1
Reactant: CC(C)C=C(C#N)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a solution of 2-cyano-4-methyl-pent-2-enoic acid (30.7 mg, 0.220 mmol), 1-(azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (57.5 mg, 0.150 mmol in DCM (2 mL) was added PyAOP (86.2 mg, 0.160 mmol) and TEA (0.06 mL. 0.440 mmol) and the resulting yellow solution stirred at rt for 1 h. LCMS showed that the reaction was complete and the crude mixture was directly loaded onto a silica gel cartridge for purification (3 to 5% MeOH: CH2Cl2). Removal of solvent from cleanest fractions afforded 30 mg of the desired compound 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrile (30 mg, 0.0586 mmol, 39.8% yield) as judged by LCMS. (M+1=512).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH:33]1C=CC2N(O)N=NC=2C=1.CO[C@H](C)C(O)=O.C(N(C(C)C)CC)(C)C.C(Cl)CCl>C(Cl)Cl>[CH3:1][O:2][C@H:3]([CH3:33])[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: COCC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CO[C@H](C)C(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)C(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-methyl-N-(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine (3.58 mL, 0.394 mmol) (See step 3, Example 282), HOBT (0.015 g, 0.099 mmol), (R)-2-methoxypropanoic acid (0.049 g, 0.473 mmol), diisopropylethylamine (0.364 mL, 2.090 mmol), and EDC (0.091 g, 0.473 mmol) in DCM (5 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo, then taken up in H2O. The solid was collected by filtration, air-dried and purified by ISCO column (75% EtOAc/Hexanes) to give the title compound. MS (ESI, pos. ion) m/z: 448.2 (M+1). IC50 (uM) 0.000452.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)C>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:5]2[N:6]=[C:7]([N:14]3[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]3)[CH:2]=[C:3]([Cl:9])[N:4]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(c2cc(Cl)nc(N3CCN(C)CC3)n2)CC1
Temperature: 0 °C

Procedure:
Trichloropyrimidine is added in portions to an ice cool solution of N-methylpiperazine (40 g) in ethanol (200 ml). The mixture is then heated at 60° for 2 h. The mixture is concentrated and chromatographed on silica gel with 2-5% methanol and methylene chloride to give 2,4-bis[4-methylpiperazino]-6-chloropyrimidine. This material is heated at 130° in water (30 ml) with piperazine (32 g) in a Parr bomb for 20 h. The product is partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give the title compound, TLC (methylene chloride/methanol/ammonium hydroxide--91.5/8/0.5) Rf =0.3.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:31])[CH:26]1[O:30][CH2:29][CH2:28][CH2:27]1>CCO>[O:30]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:25][NH:31][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)cc2n(CCC)c1=O
Reactant: NCC1CCCO1
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(NCC4CCCO4)nc3)cc2n(CCC)c1=O
Temperature: 164 °C
Reaction time: 120 h
Yield: 82.1 %

Procedure:
8a (154 mg) was suspended in tetrahydrofurfurylamine (2.0 g) in EtOH (5 ml) in a pressure tube and stirred at 164° C. for 5 days. After cooling to room temperature, the solid was filtered and washed with methanol to give the product (9b) (150 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]3=[CH:10][S:11][C:6]=2[C:5](C(O)=O)=[C:4]([C:19]([OH:21])=[O:20])[CH2:3]1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:1]=[C:2]1[C:7]2[N:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]3=[CH:10][S:11][C:6]=2[CH:5]=[C:4]([C:19]([OH:21])=[O:20])[CH2:3]1
Reactant: O=C(O)C1=C(C(=O)O)C2=C(C(=O)C1)N1C=CC=CC1=CS2
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=C(O)C1=CC2=C(C(=O)C1)N1C=CC=CC1=CS2
Temperature: 230 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A mixture of 6 g of 1-oxo-pyrido[2,1-C][1,4]benzothiazine-3,4-dicarboxylic acid in 60 ml Dow-Therm-A was stirred at 230° C. for 1 hr. (until no more gas was evolved). It was then allowed to cool, filtered, and the precipitate washed with ether giving 4.1 g crude product which was crystallized from 1N NaOH and 1N HCl to give 3.5 g product, m.p. 222° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:35])[CH:10]=1.N1C=CC=CC=1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[CH:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)ccc32)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)ccc32)c1
Yield: 42 %

Procedure:
To a solution of 2′,4′-difluoro-5-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine (60 mg, 0.126 mmol) in DCM was added pyridine (19 mg, 2.52 mmol, 2.0 eq.) followed by ethanesulfonyl chloride (19 mg, 0.152 mmol, 1.2 eq). After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 42% yield (30 mg). 1H NMR (300 MHz, CD3OD): δ 8.92 (s, 1H), 8.3 (d, 1H), 8.06 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.77-7.69 (m, 5H), 7.45 (m, 1H), 6.56 (m, 1H), 3.92 (s, 3H), 3.28-3.27 (m, 4H), 1.6-1.49 (m, 6H); LC-MS (ESI): Calculated mass: 564.6; Observed mass: 565.4 [M+H]+ (rt: 1.46 min).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:30]([C:36](O)=[O:37])=[C:29]([F:39])[CH:28]=[CH:27][C:26]=4[NH:25]3)[CH:19]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:30]([C:36]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:37])=[C:29]([F:39])[CH:28]=[CH:27][C:26]=4[NH:25]3)[CH:19]=2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(F)c(C(=O)O)c4CC3(C)C)c2)cc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(F)c(C(=O)NS(C)(=O)=O)c4CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a suspension of 60% sodium hydride (75 mg, 1.86 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (181 mg, 1.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (80 mg, 0.19 mmol) and 1,1′-carbonyldiimidazole (65 mg, 0.38 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-methanesulfonamide (19 mg, 20%) as a white solid: LC/MS m/e calcd for C29H33FN2O3S (M+H)+: 509.66, observed: 509.1.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:31][CH2:32][CH:33]=[CH2:34]>CN(C=O)C.CCOC(C)=O>[CH2:34]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH2:27])[CH2:33][CH:32]=[CH2:31]
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0.3M solution of methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate in dry DMF, 60% NaH (1.5 eq) in mineral oil was added at 0° C.; after stirring for 45 min at RT, 4-bromobut-1-ene (1.5 eq) was added and the suspension was stirred for 5 h at 40° C. and then 1 day at RT (NaH and 4-bromobut-1-ene were added several times). The mixture was diluted with EtOAc, washed with 1N HCl, water and brine, dried (Na2SO4) and concentrated in vacuo to give, after chromatography (PE/EtOAc 95:5), the title compound (60%) along with recovered starting material (40%); MS (ES+) m/z 414 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17]([S:37]([C:33]5[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:42])([F:41])[F:29])[CH:32]=5)(=[O:39])=[O:38])[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)C(Oc3cnc(C4CC4)cn3)CC2C1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1C(Oc2cnc(C3CC3)cn2)CC2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CCN12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of the product from Example 207C (40 mg, 0.107 mmol) in 1,4-dioxane (0.5 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 90 minutes and then concentrated in vacuo. To the residue was added CH2Cl2 (1 mL), 3-(trifluoromethyl)-benzene-1-sulfonyl chloride (0.021 mL, 0.130 mmol) and triethylamine (0.045 mL, 0.324 mmol), and the resulting mixture was stirred at room temperature for 90 minutes. The mixture was partitioned between water and CH2Cl2, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% CH3OH in CH2Cl2 to give the title compound (47 mg, 90%). 1H NMR (300 MHz, CDCl3) δ ppm 0.84-1.04 (m, 4H) 1.55-1.65 (m, 0.6H) 1.89-2.50 (m, 4H) 2.85-2.98 (m, 0.4H) 3.00-3.20 (m, 1H) 3.69-3.84 (m, 0.4H) 3.83-3.96 (m, 1.6H) 3.95-4.07 (m, 1H) 4.20 (dd, J=13.22, 2.37 Hz, 1H) 5.43 (dd, J=8.14, 5.09 Hz, 0.6H) 5.57 (t, J=7.63 Hz, 0.4H) 7.74 (t, J=7.80 Hz, 1H) 7.86-7.99 (m, 3H) 8.00-8.04 (m, 1H) 8.07-8.13 (m, 1H); MS (ESI) m/z 483 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.CS(C)=[O:12].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>C(#N)C.O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C)cc1
Reactant: CS(C)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C=O)cc1
Reaction time: 2 h

Procedure:
In a 100 ml reactor containing argon gas, 2.44 g of 1-methoxy-4-methylbenzene (CAS Registration No. 104-93-8) [20 mmol] is dissolved in 39 ml of acetonitrile, with the addition of 1.0 ml of dimethyl sulfoxide [14.1 mmol] at 70° C. To the solution, 65 mg of Cu(OAc)2, 30 mg of FeSO4.7 H2O and 10 ml of water are added. Next, while stirring forcefully, 11.0 g of Na2S2O8, dissolved in 30 ml of water, are then added drop by drop. The reaction is ended after 120 minutes.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:14][C:15]1[CH:16]=[CH:17][CH:18]=C(C)[N+:20]=1[O-])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(O)(=O)C>[C:5]([O:4][CH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:20]=1)(=[O:7])[CH3:6]
Reactant: CCCCCCOc1cccc(C)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCCOc1cccc(COC(C)=O)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
An amount 40 ml of acetic anhydride was stirred at about 115° C. and a solution of 5.50 g of 6-hexyloxy-α-picoline N-oxide in 20 ml of glacial acetic acid was dropwise added over about one hour. After the dropwise addition, the mixture was stirred at 130° C. for 5 hours, acetic acid and acetic anhydride were removed by concentration under a reduced pressure, the reaction mixture was dissolved in ether, and the remaining acetic acid was neutralized with a sodium hydrogen carbonate solution. After extraction with ether and concentration under a reduced pressure, the residue was separated by silica gel column chromatography (ethyl acetate:hexane=1:9) to give 6.85 g of the desired product (yield 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[C:6]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:4].[Li+].[OH-]>O.O1CCOCC1>[C:17](/[CH:16]=[CH:15]/[C:7]1[C:6]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:5]([C:3]([OH:4])=[O:2])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)([OH:19])=[O:18]
Reactant: COC(=O)c1c2c(cc(/C=C/C(=O)O)c1NS(=O)(=O)c1ccccc1)CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1cc2c(c(C(=O)O)c1NS(=O)(=O)c1ccccc1)CCCC2
Temperature: 160 °C

Procedure:
A solution of Example 476D (20 mg, 0.05 mmol) in 0.5 mL of 2:1 dioxane water was treated with LiOH (13 mg, 0.3 mmol) and heated to 160° C. for 27.5 minutes in a microwave reactor. The reaction mixture was concentrated and the residue was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 419 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 12.92 (br s, 1H), 12.11 (br s, 1H), 9.69 (br s, 1H), 7.60 (m, 2H), 7.54 (m, 1H), 7.49-7.42 (m, 4H), 6.13 (d, 1H), 2.75 (m, 2H), 2.67 (m, 2H), 1.70 (m, 4H).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[N:7]=[C:8]([O:33]C)[NH:9][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[C:25]([Cl:31])[CH:24]=2)[C:16]=1[F:32])=[O:12]>C(Cl)Cl>[Cl:5][C:6]1[NH:7][C:8](=[O:33])[NH:9][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[C:25]([Cl:31])[CH:24]=2)[C:16]=1[F:32])=[O:12]
Reactant: COc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(=O)[nH]c3Cl)c2F)c1
Reaction time: 2 h
Yield: 14.2 %

Procedure:
BBr3 (0.28 mL of a 1M solution in CH2Cl2, 0.28 mmol) was added to a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(methyloxy)-1H-imidazole-5-carboxamide (0.044 g, 0.093 mmol) in CH2Cl2 (1 mL). After 2 h, additional BBr3 (0.30 mL of a 1M solution in CH2Cl2, 0.30 mmol) was added and the reaction mixture was stirred for 3 days. The solution was evaporated, additional BBr3 (1 mL of a 1M solution in CH2Cl2, 1 mmol) was added and the reaction mixture was stirred for 5 days. Sat'd NaHCO3 was added and the mixture was extracted with EtOAc and then CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) to provide the title compound (0.006 g, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (s, 1H) 10.41 (s, 1H) 8.06 (t, J=5.68 Hz, 1H) 7.82 (s, 1H) 7.48-7.54 (m, 2H) 7.46 (t, J=1.97 Hz, 1
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 4-trifluoromethylbenzyl chloride (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 341 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21].Cl[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([CH2:24][CH2:23][N:2]([CH3:1])[CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21])([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CCCl
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 60 °C

Procedure:
A mixture of 4a (500 mg, 1.69 mmol), ethyl 3-chloropropionate (270 mg, 1.97 mmol), DIEA (109 mg, 0.14 mL, 0.84 mmol), and DMF (5 mL) was heated at 60° C. for 2 days. Starting material remained but since the solution was getting darker, heating was stopped. The reaction mixture was concentrated to dryness. The product was purified by column chromatography (7:1:0.1 chloroform:methanol:NH4OH) to give a sticky solid: yield 210 mg (31%); MS m/z 395 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.74 (d, 1H, H-1′, J1′,2′=5.6 Hz), 5.33 (bd, 1H, OH-2′), 5.16 (bd, 111, OH-3′), 5.12 (bdd, 1H, H-2′, J1′,2′=5.6 Hz, J2′,3′=5.5 Hz), 4.21 (bdd, 1H, H-3′, J2′,3′=5.5 Hz, J3′,4′=4.3 Hz), 4.01 (q, 2H, OCH2CH3), 3.91-4.00 (m, 1H, H-4′), 2.70-2.77 (m, 1H, 5′-CH2), 2.54-2.66 (m, 3H, 5′-CH2, CO—CH2), 2.53 (s, 3H, 8-CH3), 2.38 (t, 2H, N(CH3)—CH2), 2.16 (bs, 3H, N—CH3), 1.15 (t, 3H, OCH2CH3).