Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([OH:14])=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][NH2:33])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([NH:33][CH2:32][CH2:31][NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)=[O:14]
Reactant: O=C(O)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1
Reactant: COc1ccc(NCCN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NCCNC(=O)[C@H](CC2CCCCC2)Nc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A slurry of L-cyclohexylalanine (2.44 g, 14.3 mmol) and powdered NaOH (1.14 g, 28.6 mmol) in DMSO (20 mL) was heated to 100° C. for 20 min until the mixture viscosity decreased and stirring was enabled. 2-Chlorobenzoxazole (1.99 g, 13.0 mmol) was added, and the solution was stirred at 100° C. for 4 h. Upon cooling to room temperature, the solution was poured into 1 M HCl. The precipitate was filtered and dried to afford 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid was isolated as a white powder (1.69 g, 41%). Step B. To a stirring solution of 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid (288 mg, 1.0 mmol), N1-(4-methoxy-phenyl)-ethane-1,2-diamine.2HCl (239 mg, 1.0 mmol), and iPr2NEt (0.87 mL, 5.0 mmol) in dichloromethane (4 mL) was added HATU (418 mg, 1.1 mmol). The solution was stirred at room temperature for 4 hours and then evaporated to dryness. The crude material was chromatographed over silica gel (Hexanes/EtOAc) to afford the title compound as a white powder (243 mg, 56%). HPLC-MS calcd. for C25H32N4O3 (M+H+) 437.25. found 437.5.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc(Cl)cc4)CC3)cccc2n1
Yield: 67 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-Chlorobenzyl Chloride (59.6 mg; 0.37 mmol) to obtain 49.5 mg. (67% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 9.94 (s, 1H), 8.88 (s, 1H), 7.69 (m, 2H), 7.38 (m, 4H), 7.25 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 3.57 (s, 2H), 3.03 (br d, J=10.8 Hz, 3H), 2.91 (m, 3H), 2.29 (m, 2H). ESIMS+369.2 m/z
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:10]=1[CH3:11].[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:21][C:19]2[CH:18]=[CH:17][C:3]([O:4][CH2:5][C:6]3[N:7]=[C:8]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)[O:9][C:10]=3[CH3:11])=[C:2]([Br:1])[CH:20]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Br)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A mixture of 4-{[2-bromo-4-(chloromethyl)phenoxy]methyl}-2-(2-furyl)-5-methyl-1,3-oxazole (3.52 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (2.27 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl 1-benzyl-3-[(3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (5.17 g, yield 95%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)C(=O)OCC(C)C
Product: CC(C)COC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure A above and using 3,5-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure O above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:25]1([CH2:24][CH:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([O:10][CH3:9])[CH:12]=2)[C:20]([OH:22])=[O:21])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C(CC2CCCC2)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (58.5 mL of a 0.91M stock solution, 53.2 mmol) cooled to −78° C. was treated with (3,4-dimethoxy-phenyl)-acetic acid (4.97 g, 25.3 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min and at 25° C. for 15 min. At this time, the reaction was cooled to 0° C. and was treated with a solution of iodomethylcyclopentane (5.87 g, 27.8 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at 0° C. for 30 min. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-propionic acid (4.5 g, 63.8%) as a yellow solid: mp 111-112° C.; EI-HRMS m/e calcd for C16H22O4(M+) 278.1518 found 278.1517.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([N:8]2[CH2:31][CH2:30][C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9]2)[CH:7]=1.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36]>N1C=CC=CC=1>[CH3:32][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH2:33][CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:7][C:6]=1[N:8]1[CH2:31][CH2:30][C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1
Reactant: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1
Reactant: CCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc(C)c(N2CCc3nc(Nc4ccc(N5CCN(C)CC5)cc4)ncc3C2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (50.0 mg, 0.116 mmol) in Pyridine (1 ml) at 0° C. was added Butane-1-sulfonyl chloride (21.3 mg, 0.139 mmol) dropwise The reaction mixture was stirred for 15 minutes at 0° C. and then allowed to attain room temperature. It was then further stirred for 3 hours at room temperature. The reaction mixture was concentrated under vacuum. The reaction mass was then, diluted with water and extracted with dichloromethane. The dichloromethane layer was washed with water, then with brine solution. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform) to give 50.4 mg (78.9%) Butane-1-sulfonic acid (4-methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-amide [49] as off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[CH3:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:44]3[CH2:45][CH2:46][N:41]([C:33]4[N:32]([CH3:31])[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=4)[CH2:42][CH2:43]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4nc5ccccc5n4C)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1e from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:31][C:29]1[CH:28]=[C:27]([S:32]([NH:23][C:22]2[C:16]3[CH2:15][O:14][C:13]([NH:12][CH:9]4[C:8]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[O:11][CH2:10]4)=[N:18][C:17]=3[CH:19]=[CH:20][CH:21]=2)(=[O:33])=[O:34])[CH:26]=[C:25]([F:24])[CH:30]=1
Reactant: COc1cccc2c1C(NC1=Nc3cccc(N)c3CO1)CO2
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: COc1cccc2c1C(NC1=Nc3cccc(NS(=O)(=O)c4cc(F)cc(F)c4)c3CO1)CO2

Procedure:
The title compound, MS (ISP) m/e=488.0 [(M+H)+], was prepared from N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,5-diamine (example 3) and 3,5-difluoro-benzenesulfonyl chloride according to the procedure described for example 5.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.C1C(=O)N([I:50])C(=O)C1>C(#N)C>[CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:50])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)nc2ccnn12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)nc2c(I)cnn12
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
To a solution of benzyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (2.27 g, 3.7 mmol) in acetonitrile (15 mL) was added NIS (833 mg, 1 eq). After stirring 1.5 hour, solvent was removed and the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-50%) gave the title compound (2.38 g, 86%) as gum.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[P:6](=[O:14])([N:11]=[C:12]=[O:13])([S:9][CH3:10])[O:7][CH3:8]>CCOCC>[S:1]1[CH2:5][CH2:4][N:3]([C:12]([NH:11][P:6](=[O:14])([S:9][CH3:10])[O:7][CH3:8])=[O:13])[CH2:2]1
Reactant: COP(=O)(N=C=O)SC
Reactant: C1CSCN1
Solvent: CCOCC
Product: COP(=O)(NC(=O)N1CCSC1)SC
Temperature: 25 °C

Procedure:
A solution of 4.45 g of thiazolidine in 100 ml of ether was cooled to about 0° C. and 8.35 g of O,S-dimethyl phosphoroisocyanatidothioate was added dropwise with stirring. The mixture was allowed to warm to ambient temperature and react for about 1 hour at which time the precipitate that formed was collected by filtration. This precipitate was then recrystallized from a small amount of 2-propanol to obtain 3.6 g (28 percent of theory) of the title compound as white crystals melting at 84°-86° C.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1)[S:3]([CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:5])=[O:4].Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=2)=[C:28]([F:39])[CH:27]=1>>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:29]2[CH:30]=[CH:31][C:26]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:2]([CH3:1])[S:3]([CH2:6][CH:7]([CH3:8])[CH3:9])(=[O:4])=[O:5])=[CH:27][C:28]=2[F:39])=[N:33][CH:34]=1
Reactant: CC(C)CS(=O)(=O)N(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: CC(C)CS(=O)(=O)N(C)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Step B of Example 369 using N-methyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropanesulfonamide and 5-(4-bromo-2-fluoro-phenyl)pyrazin-2-amine yielding the title compound after purification by HPLC (32 mg, 41%). MS (ESI): mass calcd. C21H23FN4O2S, 414.15; m/z found, 415.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.11 (d, J=1.3, 1H), 8.04-7.94 (m, 1H), 7.47-7.37 (m, 4H), 7.36-7.31 (m, 1H), 7.30-7.24 (m, 1H), 4.69 (s, 2H), 3.13 (s, 3H), 2.70 (d, J=6.6, 2H), 2.26-2.11 (m, 1H), 1.00 (d, J=6.7, 6H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][NH:28][CH3:29]>O1CCOCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:28]([CH2:27][C:21]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])[CH3:29])=[CH:6][CH:7]=1
Reactant: CNCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CC(=O)c1ccc(Br)cc1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(4-bromophenyl)ethanone (9.3 g, 33.45 mmol, 1.00 equiv) in dioxane (100 mL), triethylamine (5.0 g, 1.50 equiv), and (2,4-dichlorophenyl)-N-methylmethanamine (6.4 g, 33.68 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 25° C. The solids were filtered out. The filtrate was used for next step directly.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17](Br)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:31]3[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=3[F:36])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: OB(O)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)CCCCCNc1ncnc2oc(-c3c(F)cccc3F)c(-c3ccc(OC)cc3)c12
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Dissolve 150 mg (0.34 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 106 mg (0.70 mmol) (2,6-difluorophenyl)boronic acid in 3.5 ml toluene and 1.0 ml ethanol, and add 0.34 ml of 2 M aqueous sodium carbonate solution and 25 mg (0.03 mmol) 1,1′-bis(diphenylphosphano)ferrocene palladium(II) chloride. Next, stir for 15 h at 70° C. Purify the reaction mixture directly by preparative RP-HPLC (gradient: water/acetonitrile). 13 mg (8% of theor.) of the desired product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:17][C:18]1[C:19]([OH:31])=[C:20]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:21]=[CH:22][C:23]=1[OH:24]>ClCCCl.ClCCl>[Cl:1][C:2]1[C:3]([C:8]([OH:7])=[O:9])=[C:4]([C:5]([C:22]2[CH:21]=[C:20]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:19]([OH:31])=[C:18]([Cl:17])[C:23]=2[OH:24])=[O:6])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: COC(=O)CCc1ccc(O)c(Cl)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCc1cc(C(=O)c2cccc(Cl)c2C(=O)O)c(O)c(Cl)c1O
Yield: 48.5 %

Procedure:
To a solution of 3-chlorophthalic anhydride (3.7 g, 20 mmol) ((J. Org. Chem., 1987, 52, 129-134) in 60 mL of anhydrous 1,2-dichloroethane was added 6.6 g (50 mmol) of AlCl3 followed by 4.6 g (20 mmol) of methyl 3-(3-chloro-2,4-dihydroxyphenyl)propanoate (WO 03/023357). The reaction was heated at reflux for 30 min, cooled and concentrated. The resultant gelatinous material was partitioned between cold 2 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was washed with 1 N HCl, brine, dried over Na2SO4 and concentrated to afford an oily material (mixture of 6- and 2-chloroisomers). The oil was dissolved in dichloromethane (˜40 mL) and briefly sonicated (ultrasound bath) to initiate crystallization. The mixture was cooled (ice/water bath) and allowed to crystallize for 30 min (extended crystallization time will result in co-crystallization of undesired 2-chloro isomer). The crystals were collected by filtration washed with cold dichloromethane. Drying under vacuum afforded 4.01 g of desired 6-chloro isomer (32). 1H NMR (DMSO-d6) δ 12.47 (br s, 1H), 10.78 (br s, 1H), 8.06 (d, J=7.7 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 6.76 (s, 1H), 3.46 (s, 3H), 2.27 (m, 2H), 2.41 (t, J=6.6 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:19]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)C1CCCCC1
Product: O=C(NCCc1c[nH]c2ccccc12)C1CCCCC1
Yield: 81.2 %

Procedure:
10 g of tryptamine and 10 g of cyclohexylcarbonyl chloride were treated in the same manner as described in Example 4-(1). 13.7 g of N-cyclohexylcarbonyl-tryptamine (i.e., 3-(2-cyclohexylcarbonylaminoethyl)-indole) were thereby obtained. Yield: 81.2%
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: Brc1cc(OCc2ccccc2)ccn1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(COc2ccnc(Nc3ccccn3)c2)cc1
Yield: 72.7 %

Procedure:
Compound I (2.325 mg, 8.80 mmol), 2-aminopyridine (911 mg, 9.68 mmol), tBuOK (1.481 g, 13.20 mmol), (±)-BINAP (219 mg, 0.35 mmol) and Pd2(dba)3 (201 mg, 0.22 mmol) were stirred in toluene (35 mL) at 90° C. under Ar(g) for 17 h. The reaction mixture was then diluted with CH2Cl2 (20 mL) and silica was added followed by the removal of the solvent under reduced pressure. The resulting dry loaded material was purified by silica gel column chromatography eluting with hexane/EtOAc (60:40 then 50:50) to furnish II as a yellow oil (1.773 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9](=S)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:12].[Na+].OO.[OH-]>O>[NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [OH-]
Reactant: Nc1ncnc2[nH]c(=S)sc12
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1ncnc2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 29 (770 mg, 4.2 mmol) in water (30 mL) was added 1N NaOH (4.2 mL) and 30% H2O2 (1.0 mL) and the reaction was stirred for 1 h at room temperature. Additional peroxide (2.0 mL) and hydroxide (5.0 mL) were added and the mixture was stirred for 1 h at 70° C. The reaction mixture was filtered and the filtrate was neutralized with glacial acetic acid. The resulting precipitate was filtered off while still hot, washed with cold water and dried to yield 0.52 g (74%): mp>370° C. UV λmax (pH 1) 267 nm (ε), 289 (): UV λmax (pH 7, 11) 285 nm (ε): 1H NMR (DMSO-d6) δ 7.18 (b, 2H, NH2, exchanges with D2O), 8.12 (s, 1H, C 5 H), 12.30 (b, 1H, N3H, exchanges with D2O). Anal. Calcd. for C5H4N4OS: C, 35.71: H, 2.40: N, 33.31: S, 19.07. Found: C, 35.50: H, 2.36: N, 33.13: S, 18.79.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13][CH3:14].ClN1C(=O)CCC1=O.[OH-].[Na+]>C(N(CC)CC)C.ClCCl>[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([CH2:12][S:13][CH3:14])[C:3]=1[NH2:4]
Reactant: CSC
Reactant: Cc1c(F)c(N)cc(F)c1F
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1c(N)c(F)c(C)c(F)c1F
Reaction time: 0.5 h

Procedure:
To anhydrous dichloromethane (170 ml) are added 2,4,5-trifluoro-3-methylaniline (16.89 g) and dimethyl sulfide (11 ml). Thereto N-chlorosuccinimide (17.2 g) is added gradually below 5° C. After stirring for 30 minutes, triethylamine (21 ml) is added dropwise and the mixture is refluxed over night. After the mixture is cooled and made alkaline with 5% aqueous sodium hydroxide solution, the resultant is extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane : n-hexane =1 : 1) to give 2,4,5-trifluoro-3-methyl-6-methylthiomethylaniline (8.3 g).