Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1[CH:3]=[C:4]([CH:29]=[CH:30]C=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C([O:48]C)C(OC)=C(OC)C=2)=NC=1)C.O1C=CC(C(O)=O)=C1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][O:48][CH:3]=3)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccoc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccoc3)nn2)cc(OC)c1OC
Yield: 86 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 3-furoic acid (95 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-3-furamide (226 mg, 86%) as a yellow solid. MS m/z 399 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[Sn](CCCC)(CCCC)CCCC)[CH3:31].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:31]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Temperature: 100 °C
Yield: 67.5 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 10, 2.04 g), N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 11, 3.4 g), tri-tert-butylphosphonium tetrafluoroborate (0.246 g), tris-(dibenzylideneacetone)dipalladium (0.0.388 g) in dioxane (35 mL) was degassed and purged with argon then heated at 100° C. for 3.5 hours. After cooling, the mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ammonia in methanol (2M) and DCM with a gradient of 0-10%. The product was triturated with ether and the solid was collected by filtration to give methyl 7-[2-((Z)-3-diethylaminoprop-1-en-1-yl)-4-fluorobenzenesulfonyl-amino]-4H-furo[2,3-c]chromene-6-carboxylate (1.47 g) as a pale orange solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[N:12]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
A mixture of 4-fluorobenzenesulfonamide (6.95 g) and piperazine (17.1 g) in 30 mL of water is heated at 100° C. overnight. The solid is then collected, washed with water and toluene, and dried under reduced pressure to give 9.2 g of 4-(piperazin-1-yl)benzenesulfonamide; mp 219-221° C.; ms m/z 241; IR (mineral oil) 1160, 822, 1332, 608, 1593, 1137 cm-1. 1H NMR (DMSOd6) δ2.81. 3.17 2.3 7.01. 7.07.7.61.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.N([O-])=O.[Na+].[C:14]1(=[O:20])[NH:18][C:17](=[O:19])[CH:16]=[CH:15]1.C([O-])(=O)C.[Na+]>O.CC(C)=O.[Cu](Cl)Cl>[Br:2][C:3]1[CH:9]=[CH:8][C:6]([C:16]2[C:17](=[O:19])[NH:18][C:14](=[O:20])[CH:15]=2)=[CH:5][CH:4]=1
Reactant: O=C1C=CC(=O)N1
Reactant: Nc1ccc(Br)cc1
Agent: Cl[Cu]Cl
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1C=C(c2ccc(Br)cc2)C(=O)N1
Yield: 64.2 %

Procedure:
A solution of hydrochloric acid (37%, 27 mL) in water (11 mL) was added to 4-bromo aniline (15 g) at room temperature with vigorous stirring and the formed precipitate was allowed to stir for further 30 minutes. Temperature was reduced to 0° C. and a solution of sodium nitrite (6.60 g) in water (17 mL) was added dropwise to the stirred suspension. At the end of diazotisation, a clear yellow solution was obtained. Maleimide (16.90 g) in acetone (70 mL) was added dropwise at 0° C. and then the pH of the solution was adjusted to 3-3.5 by adding sodium acetate. Copper (II) chloride (1.76 g) was added to the vigorously stirred mixture. The reaction mixture was allowed to stir at 0° C. for 1 h and overnight at room temperature. Acetone was removed in vacuo, the residue was filtered and dried overnight in vacuo to give the crude title compound (14.12 g) which was used without further purification.
Reaction SMILES: ClCCl.[C:4]([O:8][C:9](=[O:32])[N:10]([CH2:14][C:15]1[CH:20]=[C:19]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[OH:22])[C:18]([CH3:30])=[C:17]([Br:31])[CH:16]=1)[CH:11]1[CH2:13][CH2:12]1)([CH3:7])([CH3:6])[CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>CCOCC>[C:4]([O:8][C:9](=[O:32])[N:10]([CH2:14][C:15]1[CH:20]=[C:19]([C:21](=[O:22])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:18]([CH3:30])=[C:17]([Br:31])[CH:16]=1)[CH:11]1[CH2:13][CH2:12]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: Cc1c(Br)cc(CN(C(=O)OC(C)(C)C)C2CC2)cc1C(O)c1cccc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(Br)cc(CN(C(=O)OC(C)(C)C)C2CC2)cc1C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dichloromethane (0.1 M) solution of tert-butyl{3-bromo-5-[(3-fluorophenyl)(hydroxyl)methyl]-4-methylbenzyl}cyclopropylcarbamate (1 eq.) from the previous step was added Dess-Martin periodinane (1.0 eq.) and sodium bicarbonate (1.2 eq.). After stirring at RT for 1 h, the reaction mixture was diluted with ether and washed sequentially with sat. aq. NaHSO3, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a colorless oil.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[N:14]=[C:13]2[C:25]1[N:30]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:32]2)[CH:28]=[N:27][CH:26]=1.[F:45][C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O>>[F:45][C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[N:14]=[C:13]2[C:25]1[N:30]=[C:29]([N:31]2[CH2:32][CH2:33][CH:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[CH2:35][CH2:36]2)[CH:28]=[N:27][CH:26]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cccc(-c2ccc3c(c2)c(-c2cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)n2)nn3C2CCCCO2)c1F
Temperature: 150 °C
Yield: 54 %

Procedure:
To a 5 mL conical microwave vial was added potassium phosphate (Aldrich, 129 mg, 0.61 mmol), PdCl2AmPhos (17.1 mg, 0.02 mmol), tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e, 135 mg, 0.24 mmol), and 2-fluoro-3-methoxyphenylboronic acid (Frontier Scientific, 45.3 mg, 0.27 mmol) which was sealed, evacuated and back-filled with N2 3×. Dioxane (2.0 mL) and water (0.4 mL) were added and the resulting mixture was heated at 150° C. for 30 min with microwave irradiation. After the reaction mixtures were filtered, the crude reaction mixture was concentrated under reduced pressure. The dark brown residue was dissolved with DMSO, filtered, and purified by HPLC (5% 0.1% TFA in water to 95% 0.1% TFA in ACN over 20 min) to give tert-butyl 1-(6-(5-(2-fluoro-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (78.1 mg, 53.5%). MS (ESI, pos. ion) m/z: 603 (M+1). A mixture of 5N HCl in IPA (25.9 μL, 0.13 mmol), tert-butyl 1-(6-(5-(2-fluoro-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (78.1 mg, 0.13 mmol), DCM (1.3 mL) and MeOH (1.3 mL) was heated at 80° C. for 30 min with stirring. The resulting reaction mixture was cooled to RT and concentrated to a yellow solid. The above solid was stirred with a 1:1 mixture of DCM:MeOH and applied to a pre-washed (10 mL MeOH) column of Si-propylsulfonic acid (Silicycle, Cat# R51230B). The compound was released with 30 mL of MeOH (with 2M NH3) to yield the title compound product as a yellow oil. MS (ESI, pos. ion) m/z: 419 (M+1).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].O.[Cl-].[Na+].[NH2:15][C:16]1[CH:17]=[C:18]([C:33]([O:35][CH3:36])=[O:34])[C:19]2[CH2:20][N:21]([CH:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])[C:22](=[O:25])[C:23]=2[CH:24]=1>ClCCl>[CH3:7][S:8]([NH:15][C:16]1[CH:17]=[C:18]([C:33]([O:35][CH3:36])=[O:34])[C:19]2[CH2:20][N:21]([CH:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])[C:22](=[O:25])[C:23]=2[CH:24]=1)(=[O:10])=[O:9]
Reactant: CCCC(CCC)N1Cc2c(C(=O)OC)cc(N)cc2C1=O
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCCC(CCC)N1Cc2c(C(=O)OC)cc(NS(C)(=O)=O)cc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
In a three-necked flask, 500 mg of methyl 6-amino-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylate are dissolved in 5 cm3 of dichloromethane. 150 μl of pyridine are added and the reaction mixture is cooled to a temperature in the vicinity of 0° C. 188 mg of methanesulfonyl chloride are added over 15 min, then the mixture is left to return to a temperature in the vicinity of 25° C. and stirred for 12 h. 5 cm3 of distilled water and 20 cm3 of a saturated solution of sodium chloride are added successively and left stirring for 1 h at a temperature in the vicinity of 25° C. 10 cm3 of dichloromethane are added. The organic phase is separated, dried then concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual yellow solid is triturated with 15 cm3 of hot diisopropyl ether. The mixture is left to return to a temperature in the vicinity of 25° C. The residual solid is filtered, then rinsed with 2×5 cm3 of diisopropyl ether. 574 mg of methyl 6-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylate are obtained in the form of a beige solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([OH:6])([CH3:5])[CH3:4].[H-].[Na+].F[C:12]1[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[F:1][C:2]([F:8])([F:7])[C:3]([CH3:5])([CH3:4])[O:6][C:12]1[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=1
Reactant: N#Cc1ccc(F)cn1
Reactant: CC(C)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(Oc1ccc(C#N)nc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
Add 2-trifluoromethyl-2-propanol (1.1 g, 8.3 mmol) slowly to a slurry of sodium hydride (202 mg, 60% mineral oil, washed with hexane) in HMPA (3 mL) under nitrogen. Stir the slurry for 15 min, then add 5-fluoro-pyridine-2-carbonitrile (510 mg, 4.2 mmol). Stir the slurry for 16 h at ambient temperature. Adjust the mixture to pH 9 with sodium carbonate then extract with diethyl ether (3×50 mL). Collect the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95/5 to 80/20) to obtain the desired intermediate (768 mg, 79%). GC-MS m/z: 230 (M+).
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][C@@H:38]([CH3:42])[CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:63][CH3:64])[N:32]2[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50](C(OCC2C=CC=CC=2)=O)[CH2:49][CH2:48]1>>[CH3:42][C@H:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:63][CH3:64])[N:32]2[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:48][CH2:49][NH:50][CH2:51][CH2:52]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{4-[6-amino-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-9-yl]butyl}-1-piperidinecarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(F)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(F)c1
Yield: 54.7 %

Procedure:
Tert-butyl (6aS,10aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (116 mg, 55%) was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (189 mg, 0.5 mmol) and 2-fluoro-4-methoxyphenylboronic acid (158 mg, 1.0 mmol).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]([C:14]1[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1)[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][N:12]([C:14]1[CH:19]=[C:18]([CH:20]=[O:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1)[CH3:11]
Reactant: CN(C)c1cc(Cl)cc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)c1cc(Cl)cc(C=O)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a solution of DMSO (7.58 g, 97.0 mmol) in CH2Cl2 (100 μL) at −78° C. was added oxalyl chloride (6.16 g, 48.5 mmol) over the course of 10 min. After an additional 15 min at −78° C., a solution of 3-chloro-5-N,N-dimethylaminobenzyl alcohol (8.18 g, 44.1 mmol; see step (i) above) in CH2Cl2 (100 mL) was added over the course of 15 min. The resulting solution was stirred at −78° C. for 1 h prior to the addition of DIPEA (28.5 g, 220.5 mmol). The solution was warmed to 25° C. and stirred for 18 h, before being concentrated in vacuo to give the crude product. Flash chromatography on silica gel, eluting with Hex:EtOAc (5:1), gave 7.50 g (93%) of the sub-title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 100 °C
Yield: 67.7 %

Procedure:
5-Bromo-6-chloronicotinic acid (3.00 g, 12.7 mmol), 2,4-difluorophenol (3.30 g, 25.4 mmol) and cesium carbonate (16.5 g, 50.8 mmol) were combined in DMSO (25.4 mL), heated at 100° C. for 6 hours, cooled, diluted with 150 mL of iced water and the pH was adjusted to pH 3 with 12M HCl. The resulting solid was collected by filtration, washed with cold water and dried to constant mass to afford the title compound (2.84 g, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[N:10]1[N:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=[N:11]1.[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>CC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[CH:4][C:3]=1[N:10]1[N:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=[N:11]1
Reactant: Oc1ccc(CBr)cc1-n1nc2ccccc2n1
Reactant: OCCNCCO
Solvent: CC(C)=O
Product: OCCN(CCO)Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
2-(2′-Hydroxy-5′bromomethylphenyl)benzotriazole (3.03 g. 0.01 mole), diethanol amine (3.14 g. 0.03 mole) were dissolved in 100 ml. of acetone. The reaction mixture was refluxed with constant stirring at 75° C. for 6 h. The solvent was then removed by rotary evaporation. Crude product was purified using silica gel column chromatography Product was identified by 1H-NMR.
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>ClCCl>[CH2:23]([O:22][C:20]([NH:1][C:2]12[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH2:5]3)[CH2:11]1)[CH2:9]2)=[O:21])[CH:24]=[CH2:25]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: C=CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
1-Aminoadamantane (10 mmol; 1.51 g) and triethylamine (1.9 ml) in dry dichloromethane (30 ml) are stirred at 0°-5° C. and allyl chloroformate (1.1 ml) added dropwise. After 0.5 hour, the solution is washed with dilute sulfuric acid and water. After drying over anhydrous magnesium sulfate, the solution is evaporated to give 1-(allyloxycarbonylamino)adamantane, as a white solid, with a melting point of about 56°-58° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[C:7]2[OH:12]
Reactant: Oc1cccc2c(O)cccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2c(O)cccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a stirred solution of 1,5-dihydroxy naphthalene (40 g, 0.25 mol) in dry acetone (200 mL) was added, K2CO3 (34.5 g, 0.25 mol) and the mixture was stirred at RT for 3 h, and then cooled to 0° C. To this, a solution of methyl iodide (124.5 mL, 2 mol) in dry acetone (100 mL) was added drop wise and the reaction mixture was stirred for 2 h at 0° C. and then for 10 h at RT. After completion (TLC), the mixture was filtered and washed with EtOAc. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (8% EtOAc:Hexanes) to afford the desired compound (19.2 g, 44%) as a light green solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[CH:11][CH3:12])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(OCC)C>[C:13]([N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[N:10]=[CH:11][CH3:12])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC=NNc1ccc(OC)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC=NN(C(=O)c1ccccc1)c1ccc(OC)cc1
Reaction time: 24 h

Procedure:
Combine N-(4-methoxyphenyl)-N'-ethylidene hydrazine (6.0 g, 43 mmol), benzoyl chloride (5.2 mL. 44 mmol), pyridine (3.7 mL, 46 mmol), and diethyl ether (25 mL). After 24 hours, add diethyl ether (100 mL), remove the solid by filtration and dry in vacuo to give N-benzoyl-N-(4-methoxyphenyl)-N'-ethylidene hydrazine as a solid.
Reaction SMILES: [ClH:1].[CH:2]1([C:5]([NH:12][S@@](C(C)(C)C)=O)([C:7]2[N:11]=[CH:10][O:9][N:8]=2)[CH3:6])[CH2:4][CH2:3]1>CO>[ClH:1].[CH:2]1([C:5]([C:7]2[N:11]=[CH:10][O:9][N:8]=2)([NH2:12])[CH3:6])[CH2:4][CH2:3]1
Reactant: CC(N[S@](=O)C(C)(C)C)(c1ncon1)C1CC1
Agent: Cl
Solvent: CO
Product: CC(N)(c1ncon1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
HCl (1 ml, 2 mmol) (2.0 M in Et2O) was added to a stirring solution of (R)—N-(1-cyclopropyl-1-(1,2,4-oxadiazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.466 mmol) in MeOH (1 ml) at rt. The reaction was allowed to stir for 1 h at rt. The reaction was then concentrated to dryness azeotroping with toluene 3× to give the expected product 1-cyclopropyl-1-(1,2,4-oxadiazol-3-yl)ethanamine hydrochloride (87 mg, 0.46 mmol, 98% yield) consistent by NMR as a white solid. 1H NMR (500 MHz, METHANOL-d4) δ 9.38 (s, 1H), 1.67 (s, 3H), 1.44 (s, 1H), 0.74-0.66 (m, 2H), 0.62-0.56 (m, 1H), 0.51-0.45 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C[CH2:66][N:67](C(C)C)[CH:68]([CH3:70])[CH3:69].CNC(C)C>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:16]4[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:67]([CH:68]([CH3:70])[CH3:69])[CH3:66])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)N(C)C(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (120 mg, 0.29 mmol), PyBOP® (150 mg, 0.29 mmol), DIEA (152 μL, 0.87 mmol) in CH2Cl2 (5 mL) was stirred at RT for 10-15 minutes. To this solution of activated acid was added N-methylpropan-2-amine (30 μL, 0.29 mmol). The reaction mixture was stirred at RT for 3 h and concentrated in vacuo. The crude product was purified using prep HPLC (method 5-25-50_80 mins) and was further washed with ethyl ether and drops of CH2Cl2 to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropyl-N-methylacetamide. (12 mg, 0.025 mmol, 9%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-])=[CH:14][C:13]3[N:20]=[CH:21][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:31]=C=O)=O.C[O-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([NH2:31])[C:13]3[N:20]=[CH:21][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Product: CC(C)Cn1cnc2c(N)nc3ccc(OCc4ccccc4)cc3c21
Reaction time: 1 h

Procedure:
A modification of the general method described in Part C of Example 3 was followed using 8-benzyloxy-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinoline (2.0 g, 5.8 mmol) as the starting material. The reaction with trichloroacetyl isocyanate was not complete after one hour as evidenced by a TLC analysis. Additional trichloroacetyl isocyanate (0.1 equivalent) was added, and the reaction was stirred for an additional hour. Following the reaction with sodium methoxide, the solid product was isolated by filtration and recrystallized from ethanol. The crystals were dried overnight in a vacuum oven at 45° C. to provide 1.6 g of 8-benzyloxy-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 214-216° C.