Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5](I)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(Cl)c2c1S(=O)(=O)NC(C1CCCCC1)=N2
Yield: 72.6 %

Procedure:
A mixture of 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (290 mg, 0.68 mmol), 2-methoxyphenylboronic acid (122 mg, 0.80 mmol), Pd(PPh3)2Cl2 (10 mg, 2 mol %) in 1,2-dimethoxyethane (50 ml) and Na2CO3 (2M, 2 ml, 4 mmol) were refluxed under N2 for 2 h. The solvents were removed under reduced pressure and the residue was extracted with EtOAc (2×40 ml) and the organic layer was washed with saturated NaHCO3 (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:2, v/v) as eluent, yielding 200 mg (73%) of 5-chloro-3-cyclohexyl-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1cccc(OCc2ccccc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-[3-(benzyloxy)phenyl]ethanol (700 mg) in DCM (10 mL) was added Dess-Martin periodinane (1.43 g) at 0° C. The reaction mixture was stirred for 5 hours at ambient temperature. The mixture was diluted with diethylether (25 mL), and the resulting suspension was added to saturated NaHCO3 aqueous solution (15 mL) and saturated sodium thiosulfate aqueous solution (15 mL). After the mixture was stirred for 10 minutes, the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=90:10-70:30) to give a [3-(benzyloxy)phenyl]acetaldehyde.
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([CH2:19][C:20]3[O:21][CH:22]=[C:23]([Br:25])[CH:24]=3)[C:17](=[O:26])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+].O>CN(C)C=O>[N:27]([CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([CH2:19][C:20]3[O:21][CH:22]=[C:23]([Br:25])[CH:24]=3)[C:17](=[O:26])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)=[N+:28]=[N-:29]
Reactant: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
2-[(4-{4-[(4-Bromo-2-furyl)methyl]-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]ethyl methanesulfonate (9.1 g, 20 mmol, containing also some of the corresponding bromo-compound) was dissolved in dimethylformamide (90 mL). Sodium azide (1.97 g, 30.3 mmol) was added in one portion and after 5 minutes, the temperature was brought to 65° C. The reaction stirred for 2 hours and was allowed to cool back to room temperature. Water (200 mL) was added to quench the reaction. The product was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with brine (2×150 mL) and water (150 mL). After drying over sodium sulfate, the solvent was removed in vacuo to give the desired product (7.7 g, 96%). LCMS calculated for C11H9BrN8NaO4 (M+Na)+: m/z=418.7, 421.0. 1H NMR (400 MHz, DMSO-d6): δ 7.88 (s, 1H), 6.71 (t, J=5.7 Hz, 1H), 6.68 (s, 1H), 5.08 (s, 2H), 3.54 (t, J=5.7 Hz, 2H), 3.47 (q, J=5.7 Hz, 2H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]3[CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+].Cl>C(O)C>[CH:31]1([CH2:30][O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=2)[CH2:33][CH2:32]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (205 mg; 0.41 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 160 mg; 83%. HPLC-MS: m/z: 468.1 (M+H)+; Rt: 1.78 min.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][C:9]=1[C:10]#[N:11])(=O)C.S(=O)(=O)(O)[OH:21]>C(O)C>[NH2:4][C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][C:9]=1[C:10]([NH2:11])=[O:21]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Nc1sc(-c2ccc(C#N)cc2)cc1C#N
Solvent: CCO
Product: N#Cc1ccc(-c2cc(C(N)=O)c(N)s2)cc1

Procedure:
2-Acetylamino-3-cyano-5-(4-cyanophenyl)thiophene (470 mg) was heated at reflux in ethanol (15 ml) and concentrated sulphuric acid (1.5 ml) for 2.5 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was basified with 2N sodium hydroxide, with cooling, and the product was filtered off and dried (360 mg).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.OO.[C:8]([OH:11])(=[O:10])[CH3:9]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(=O)C=CC(=O)C=C1>[C:8]([O:11][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1)(=[O:10])[CH3:9]
Reactant: C1=CCCC1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)C=C1
Product: CC(=O)OC1C=CCC1
Reaction time: 2 h
Yield: 60 %

Procedure:
Acetoxylation du cyclopentene A 500 ml three-neck flask is charged with 15 g of cyclopentene (0.22 moles), 150 g of acetic acid, 0.77 g of benzoquinone (7 mmoles) and 80 mg of palladium acetate (0.35 mmoles). The temperature is taken to 50°, then 12 g (0.25 moles) of 70% by weight hydrogen peroxide are introduced in 8 h, and the reaction is allowed to proceed for a further 2 h while maintaining the temperature at 50°. The acetic acid is then distilled (35°, 20×102Pa). The residue is distilled under vacuum (56°-60°, 15×102Pa) to provide cyclopent-2-en-1-yl acetate (13 g, yield 60%). cyclopent-2-en-1-yl acetate
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][CH2:9][CH3:10])=[CH:5][N:6]=1.Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([Cl:19])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:14]1[N:13]=[C:12]([N:8]([CH2:7][C:4]2[S:3][C:2]([Cl:1])=[N:6][CH:5]=2)[CH2:9][CH3:10])[C:17]([Cl:18])=[CH:16][CH:15]=1
Reactant: Clc1ccc(Cl)c(Cl)n1
Reactant: CCNCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1Cl
Yield: 39.5 %

Procedure:
18.0 g of 2-chloro-5-ethylaminomethylthiazole, 18.6 g of 2,3,6-trichloropyridine, 30.0 g of potassium carbonate and 200 mL of N,N-dimethylformamide (DMF) were added in a 500 mL single neck flask equipped with a magnetic stirrer. After stirred at reflux temperature for 4 to 6 hours, the reaction mixture was extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 25.0 g of crude product which was purified by a silica gel column chromatography using a petroleum ether/ethyl acetate (20/1) as an eluent to obtain 13.0 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-chloropyridin-2-amine, having the content 91.0%, as a yellow viscous liquid, and rod-like crystals were generated after standing, m.p.: 95.8-96.8 □ GC-MS (M+) (EI, 70 eV, m/z) calc: 321. found: 321. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.179 (t, J=7.2 Hz, 3H, CH3), 3.413 (q, J=7.2 Hz, 2H, CH2), 4.726 (s, 2H, CH2), 6.378 (d, J=8.7 Hz, 1H, Py H), 7.447 (d, J=8.7 Hz, 1H, Py H), 7.497 (s, 1H, Thiazole-H).
Reaction SMILES: C1(N2C(=O)C3SC=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C1(N)CCCCCCC1>C(O)(=O)C>[CH:10]1([N:9]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[C:24]=3[N:23]=[CH:8]2)[CH2:16][CH2:17][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1scc(-c2ccccc2C)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC1CCCCCCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: Cc1ccccc1-c1csc2c(=O)n(C3CCCCCCC3)cnc12
Yield: 60.6 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(o -tolyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1 ml), cyclooctylamine (0.107 ml, 0.77 mmol), and acetic acid (0.1 ml) were used to give 85.4 mg (0.24 mmol, 60.6% yield) of the title compound.
Reaction SMILES: NC1C=CC(N2CCN(C(OC(C)(C)C)=O)CC2)=CC=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].CS(C1C=CC=CC=1S(Cl)(=O)=O)(=O)=O>>[C:25]1([S:22]([NH2:21])(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Agent: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: NS(=O)(=O)c1ccccc1

Procedure:
2-(Methylsulfonyl)-N-[2-[phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2-methylsulfonylbenzenesulfonylchloride (61 mg, 0.239 mmol) according to general method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 551.2. Calcd: 551.10. 1H-NMR δ 8.36-7.46 (m, 9H), 6.95 (d, 1H), 6.68 (dd, 1H), 6.46 (d, 1H), 3.47 (s, 3H), 3.28-3.17 (m, 8H).
Reaction SMILES: C(Cl)CCl.Cl.[N:6]1[C:11]2[NH:12][CH2:13][CH2:14][O:15][CH2:16][C:10]=2[CH:9]=[C:8]([CH:17]=[CH:18][C:19]([OH:21])=O)[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:32][NH:33][CH2:34][C:35]1[O:36][C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[C:39]=1[CH3:40].C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:32][N:33]([CH2:34][C:35]1[O:36][C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[C:39]=1[CH3:40])[C:19](=[O:21])[CH:18]=[CH:17][C:8]1[CH:7]=[N:6][C:11]2[NH:12][CH2:13][CH2:14][O:15][CH2:16][C:10]=2[CH:9]=1
Reactant: O=C(O)C=Cc1cnc2c(c1)COCCN2
Reactant: CNCc1oc2ccccc2c1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)C=Cc2cnc3c(c2)COCCN3)oc2ccccc12
Temperature: 35 °C
Reaction time: 8 h

Procedure:
EDC (0.10 g, 0.52 mmol) was added to a solution of 3-(5,7,8,9-Tetrahydro-6-oxa-1,9-diaza-benzocyclohepten-3-yl)-acrylic acid hydrochloride (0.11 g, 0.43 mmol), HOBt (64 mg, 0.47 mmol), Methyl-(3-methyl-benzofuran-2-ylmethyl)-amine (91 mg, 0.52 mmol) and (i-Pr)2EtN (0.44 mL, 2.58 mmol) in DMF (6 mL). The mixture was allowed to stir overnight at 35° C. The mixture was cooled to 0° C. and diluted with H2O (15 mL) with rapid stirring. The resulting precipitate was filtered, washed with H2O (30 mL) then dried under high vacuum. The solid was triturated with Et2O (30 mL), stirred for 20 min then filtered to give a beige solid as a mixture of amide rotamers. Yield: 0.10 g (62%); 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.94 (s, 1H), 7.59-7.03 (m, 6H), 6.79 (br s, 1H), 4.98 and 4.79 (2×s, 2H), 4.53 (s, 2H), 3.77-3.73 (m, 2H), 3.25-3.19 (m, 2H), 3.17 and 2.93 (2×s, 3H), 2.28 (s, 3H); ESI MS m/z 378 [C22H23N3O3+H]+
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].C(C1NC2C(C=1)=CC=CC=2)(C)(C)C.[N+:27]([O-])([O-:29])=[O:28].[K+].C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:27]([O-:29])=[O:28])=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1Cc2ccccc2N1
Reactant: O=[N+]([O-])[O-]
Agent: CC(C)(C)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Product: CC(C)(C)C1Cc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of the mixture of 2-tert-butyl-2,3-dihydro-1H-indole and 2-tert-butyl-1H-indole (9.7 g) in H2SO4 (98%, 80 mL) was slowly added KNO3 (5.6 g, 55.7 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h, carefully poured into cracked ice, basified with Na2CO3 to pH˜8 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (4.0 g, 32% over 2 steps).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[O:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)=[CH:6][CH:5]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][N:29]=1.C(OCC)(=O)C>O1CCCC1>[N:38]1([CH2:37][CH2:36][CH2:35][CH2:34][C:31]2[CH:32]=[N:33][C:28]([O:18][CH2:17][C:15]3[N:16]=[C:12]([CH:11]=[CH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=4)[O:13][CH:14]=3)=[N:29][CH:30]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: Clc1ncc(CCCCn2ccnn2)cn1
Reactant: OCc1coc(C=Cc2ccc(OC(F)(F)F)cc2)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ncc(CCCCn4ccnn4)cn3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.097 g, 0.34 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (4 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.040 g, 0.41 mmol). After stirring for 15 min at r.t. 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.090 g, 0.38 mmol) is added slowly and stirred for further 1.5 h at r.t. Ethyl acetate (20 ml) is added; the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate) 5-(4-[1,2,3]triazol-1-yl-butyl)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyrimidine is obtained as a colorless solid. Yield 0.104 g (63%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19](Br)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:27]4[CH:26]=[C:25]([F:24])[CH:30]=[CH:29][C:28]=4[O:34][CH3:35])=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CC(C)OC(=O)N(C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)cc1-c1cnc2ccc(N3CC[C@H](N(C)C(=O)OC(C)C)C3)nn12
Yield: 40.5 %

Procedure:
[(S)-1-(3-Bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid isopropyl ester (120 mg, 0.3 mmol), 5-fluoro-2-methoxy phenyl boronic acid (107 mg, 0.6 mmol), potassium carbonate (65 mg, 0.45 mmol), and Pd(dppf)Cl2 dichloromethane (26 mg, 0.03 mmol) were taken up in 2 mL acetonitrile and 1 mL water and microwaved in a sealed tube at 140° C. for 15 minutes. Reaction was then filtered through celite with acetonitrile reduced in vacuo, then purified on shimadzu neutral phase prep and product fractions lyophilized to get 52 mg (S)-isopropyl(1-(3-(5-fluoro-2-methoxyphenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)(methyl)carbamate. 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.38 (m, 1H), 7.99 (s, 1H), 7.91 (d, J=9.85 Hz, 1H), 7.13-7.18 (m, 2H), 6.92 (d, J=9.85 Hz, 1H), 4.76-4.86 (m, 2H), 3.87 (s, 3H), 3.63-3.70 (m, 2H), 3.36-3.50 (m, 2H), 2.80 (s, 3H), 2.10-2.22 (m, 2H), 1.21 (d, J=6.32 Hz, 6H). (ESI) m/z 428 [(M+H)]+, calc'd for C22H26FN5O3: 427.4.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([CH:32]2[CH2:36][C:35]3[CH:37]=[C:38](B4OC(C)(C)C(C)(C)O4)[CH:39]=[CH:40][C:34]=3[O:33]2)=[O:31])[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:38]3[CH:39]=[CH:40][C:34]4[O:33][CH:32]([C:30]([N:27]5[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]5)=[O:31])[CH2:36][C:35]=4[CH:37]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3[nH]nc(I)c3cn2)c1F
Reactant: CN1CCN(C(=O)C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CC(C(=O)N4CCN(C)CC4)O5)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-yl]carbonyl}piperazine. LCMS (M+H)+=536.2.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]2([C:19](=[O:35])[NH:20][C@@H:21]3[CH2:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[N:23]4[CH:32]=[CH:33][N:34]=[C:22]34)[CH2:18][CH2:17]2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH:32]1[N:23]2[C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[CH2:26][CH2:27][C@@H:21]([NH:20][C:19]([C:16]3([NH:15][C:13](=[O:14])[C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:37][CH:36]=4)[CH2:17][CH2:18]3)=[O:35])[C:22]2=[N:34][CH:33]=1
Reactant: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(O)cc1
Yield: 90.3 %

Procedure:
Dissolve 4-benzyloxy-N-[1-[[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamoyl]cyclopropyl]benzamide (145 mg, 294.37 μmoles) in ethanol (20 mL) and hydrogenate on a Parr shaker with 10% Pd/C (22.8 mg, 10.71 μmoles) for 18 hours (60 psi, ambient temperature). Filter off the catalyst and concentrate the filtrate under reduced pressure to give the title compound (107 mg, 90%) as a white solid: MS (m/z): 403 (M+1).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](O)(=[O:18])[C@H:15]([CH3:17])[OH:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:16][CH:15]([CH3:17])[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(O)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (0.367 g), L-(+)-lactic acid (0.213 g), and HBTU (0.822 g) was stirred at rt overnight. Diluted with DCM, the mixture was washed with water (2×), brine, and dried (Na2SO4). Filtration and concentration gave 1-tert-butyl 4-(2-hydroxypropanoyl)piperazine-1-carboxylate as viscous oil, which was treated with trifluoroacetic acid in dichloromethane. After concentration, the residue was reacted with 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine in the presence of diisopropylethylamine (10 eq) following General Procedure E of amine alkylation to give 269. LCMS: M+H+=520.3
Reaction SMILES: [CH2:1]([S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>>[CH2:1]([S:6]([CH2:9][CH2:10][CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:8])=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: C1CCNCC1
Reactant: CC(C)CCS(=O)(=O)CCCCl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCS(=O)(=O)CCCN1CCCCC1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
Heat 3-chloropropyl isopentyl sulfone (700 mg, 3.29 mmol) and piperidine (1.7 g, 20 mmol) at 125° C. for 45 minutes. Cool to room temperature, treat with 5N sodium hydroxide, extract with ethyl acetate (3×25 mL), and dry (MgSO4). Concentrate in vacuo to yield 850 mg orange oil. Purify by silica gel chromatography (50% ethyl acetate/methanol) to yield 500 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[CH3:1][C:2]1[N:6]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)c1nc(C)[nH]c1C(=O)OCC
Product: CCOC(=O)c1nc(C)n(Cc2ccc([N+](=O)[O-])cc2)c1C(=O)OCC
Yield: 80.7 %

Procedure:
Following a procedure similar to that described in Preparation 42(i), but using 6.65 g of diethyl 2-methylimidazole-4,5-dicarboxylate and 6.35 g of p-nitrobenzyl bromide as starting materials, 8.57 g of the title compound were obtained as crystals, melting at 109° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.Cl[Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12]>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Brc1cccc(Br)c1
Product: CC[Si](CC)(CC)c1cccc(Br)c1

Procedure:
1-Bromo-3-triethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chlorotriethylsilane as the ClSiR1R2 R3 compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:24]([F:27])([F:25])[F:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1

Procedure:
4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-1-nitrobenzene was dissolved in methanol in the presence of Pd/C. The solution was hydrogenated at 50 psi for 1 hour until hydrogen intake was completed. The catalyst was filtered off and the filtrate was concentrated to afford 4-[(N-(t-butoxycarbonyl)piperidin-4-yl)oxy]-3-trifluoromethylbenzenamine, >95%.