Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:14]=1.CCN(CC)CC>C1COCC1.Cl>[O:19]=[C:18]1[CH:17]=[CH:16][N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:14]=[C:13]1[CH:12]=[O:11]
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of oxalyl chloride (0.175 mL, 2.07 mmol) in THF (7.5 mL) was added DMSO (0.294 mL, 4.14 mmol) at −78° C. To the suspension was added a solution of 3-(hydroxymethyl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (509 mg, 1.88 mmol) in THF (7.5 mL) at −78° C. The suspension was stirred at −78° C. for 1 h. To the mixture was added Et3N (1.05 mL, 7.52 mmol) at −78° C. The mixture was gradually warmed to room temperature, stirred at room temperature for 18 h, diluted with 1 M HCl aqueous solution, extracted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 70/30). To a solution of oxalyl chloride (0.477 mL, 5.64 mmol) in THF (19 mL) was added DMSO (0.801 mL, 11.3 mmol) at −78° C. To the suspension was added a mixture of the above residue in THF (9.5 mL) at −78° C. The suspension was stirred at −78° C. for 2 h. To the mixture was added Et3N (3.14 mL, 22.6 mmol) at −78° C. The mixture was gradually warmed to room temperature, stirred at room temperature for 17 h, diluted with 1 M HCl aqueous solution, extracted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (257 mg, 51% yield) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.87 (1H, d, J=8.2 Hz), 7.81-7.91 (2H, m), 8.08-8.15 (1H, m), 8.16 (1H, s), 8.98 (1H, d, J=8.0 Hz), 10.07 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[CH2:17]([O:19][CH:20]([O:24][CH2:25][CH3:26])[CH2:21][CH2:22]Cl)[CH3:18]>>[CH2:17]([O:19][CH:20]([O:24][CH2:25][CH3:26])[CH2:21][CH2:22][N:9]1[C:8](=[O:12])[CH2:7][C:6]2[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:11]=[CH:10]1)[CH3:18]
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: CCOC(CCCl)OCC
Product: CCOC(CCN1C=Cc2cc(OC)c(OC)cc2CC1=O)OCC

Procedure:
This compound is prepared analogously to Example I(a) by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 3-chloro-propionaldehyde diethylacetal.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[C:36]3[C:32]([C:33]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])=[N:34][N:35]3COCC[Si](C)(C)C)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)([CH3:22])[CH3:21].C(OCC)(=O)C>O1CCCC1>[CH3:22][C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[C:36]3[C:32]([C:33]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])=[N:34][NH:35]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)([CH3:19])[CH3:21]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(C(C)(C)C)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(C(C)(C)C)cc3)ccc12
Temperature: 66 °C

Procedure:
14.6 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.13 g of N-[6-[4-(1,1-dimethylethyl)phenyl]-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 22 hours, the heating is then stopped and 75 cm3 of ethyl acetate are added, and the organic phase is washed with 75 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 10 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed successively with 10 cm3 of diisopropyl ether and then with 2×5 cm3 of ethyl acetate. After drying (90 Pa; 50° C.), 320 mg of N-[6-[4-(1,1-dimethylethyl)phenyl]-1H-indazol-3-yl]butanamide are thus obtained in the form of a white product melting at 246° C.
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:21].C(Cl)(Cl)Cl>ClCCl>[CH:3]12[O:21][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 46 °C

Procedure:
Benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (11.0 g, 54.1 mmol, commercially available from Aldrich) and 3-chlorobenzoperoxoic acid (17.3 g, 70.4 mmol) were added to 150 mL of chloroform and heated to 46° C. for 20 hours. The mixture was cooled, dichloromethane was added, and the reaction was washed with a saturated solution of NaHCO3 and Na2S2CO3. The combined organic layers were dried over MgSO4, filtered and concentrated to give 10.5 g (88% isolated yield) of the desired compound as an oil, which was used directly in the next step.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[Na].[O:12]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(C)C>[O:12]([CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])[CH2:24][CH2:25]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCN1CCC(COc2ccccc2)CC1
Reactant: Nc1ncnc2nc[nH]c12
Agent: [Na]
Solvent: CC(C)O
Product: Nc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Yield: 63.9 %

Procedure:
9.45 g (0.07 mole) of adenine are added to a solution of 1.6 g (0.07 mole) of sodium in 250 ml of isopropanol and the reaction mixture heated under reflux for 10 minutes. It is then cooled and 21.4 g (0.08 mole) of 3-(4-phenoxymethylpiperidino)-propyl chloride in 50 ml of isopropanol added thereto. After stirring the reaction mixture under reflux for 6 hours, it is evaporated in a vacuum, the residue is taken up in methylene chloride, the methylene chloride solution is washed with 2 N aqueous sodium hydroxide solution and subsequently with water, dried over anhydrous sodium sulfate, evaporated and the residue recrystallized from isopropanol. There are obtained 16.4 g (64% of theory) of 9-[3-(4-phenoxymethylpiperidino)-propyl]-adenine; m.p. 142°-144° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[C:12]2[N:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([C:21]2[C:26]([F:27])=[C:25]([O:28][CH3:29])[CH:24]=[C:23]([O:30][CH3:31])[C:22]=2F)=[CH:19][CH:20]=1)=[O:10])[CH3:7]>CC#N>[CH2:6]([O:8][C:9]([C:11]1[C:12]2[N:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([C:21]2[C:26]([F:27])=[C:25]([O:28][CH3:29])[CH:24]=[C:23]([O:30][CH3:31])[C:22]=2[Cl:4])=[CH:19][CH:20]=1)=[O:10])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Temperature: 25 °C
Yield: 82.7 %

Procedure:
Sulfuryl chloride (0.35 mL, 4.33 mmol, 1.1 equiv) in CH3CN (10 mL) was added dropwise to a cold (−30° C.) solution of 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 143.1) (1.4 g, 3.93 mmol) in CH3CN (40 mL). The reaction mixture was quenched by addition of a saturated solution of NaHCO3, allowed to warm to rt and concentrated. The residue was diluted in EtOAc and a saturated solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) to provide 1.27 g of the title compound as a white solid. Title compound: ESI-MS: 391.1 [M+H]+; tR=4.71 min (System 1); TLC: Rf=0.12 (Hex/EtOAc, 3:2).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][N:69]([CH3:81])[CH2:70][CH2:71][O:72][C:73]1[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:77]([C:76]3[CH:79]=[CH:80][C:73]([O:72][CH2:71][CH2:70][N:69]([CH3:68])[CH3:81])=[CH:74][CH:75]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CN(C)CCOc1ccc(C=O)cc1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(OCCN(C)C)cc4)nc23)CC1
Reaction time: 6 h
Yield: 22.1 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.074 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.22 mmol, 0.22 mL) and 4-(2-(dimethylamino)ethoxy)benzaldehyde (1.1 eq, 0.088 mmol, 17 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (9 mg, 21%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.35 (d, J=6.7 Hz, 3H, CHCH3), 2.25 (s, 6H, N(CH3)2), 2.51-2.55 (m, 2H, piperazine NCH2), 2.63-2.65 (m, 2H, piperazine NCH2), 2.67 (t, J=5.6 Hz, 2H, Me2NCH2), 3.57 (q, J=6.7 Hz, 1H, CHCH3), 3.63-3.66 (m, 4H, piperazine N(CH2)2), 4.14 (q, J=5.8 Hz, 2H, OCH2), 7.10 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (d, J=6.0 Hz, 2H, pyridine H-3 & H-5), 8.11 (d, J=8.8 Hz, 2H, phenyl H-2 & H-6), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.54 (d, J=5.9 Hz, 2H, pyridine H-2 & H-6), 13.33 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]2)=[CH:14][N:13]=1.[NH2:55][C:56]1[CH:57]=[CH:58][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[N:60][CH:61]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([C:17]3[C:12]([NH:55][C:56]4[CH:57]=[CH:58][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[N:60][CH:61]=4)=[N:13][CH:14]=[C:15]([CH2:44][N:45]4[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]4)[CH:16]=3)[N:19]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
LiHMDS (Aldrich) (2.44 mL, 2.44 mmol) was added dropwise at 0° C. to a stirred solution of 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.507 g, 0.815 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (0.204 g, 0.976 mmol) in THF (2 mL). The dark red mixture was stirred at 0° C. for 2 h. More LiHMDS (1.6 mL, 1.6 mmol) was added dropwise at 0° C. and stirring was continued for another 30 min. The reaction was quenched by adding 0.3 mL of sat'd NH4Cl. The reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (100 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.306 g, 46% yield). 1H NMR (400 MHz, CDCl3) δ 11.76 (s, 1H); 8.71 (d, J=2.54 Hz, 1H); 8.42 (d, J=2.35 Hz, 1H); 8.23 (d, J=2.35 Hz, 1H); 7.94 (dd, J=9.00, 2.54 Hz, 1H); 7.83 (d, J=9.00 Hz, 1H); 7.15-7.25 (m, 5H); 6.86 (dd, J=11.15, 8.61 Hz, 4H); 4.83 (d, J=10.17 Hz, 4H); 3.76-3.85 (m, 6H); 3.50 (s, 2H); 3.18 (br. s., 4H); 2.71 (s, 3H); 2.59 (s, 3H); 2.55 (t, J=4.50 Hz, 4H); 1.53 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1)=[O:21]
Reactant: NC1CCCNC(=O)C1
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC(NC(=O)c2ccccc2F)CCCN1

Procedure:
3-Amino-ε-caprolactam (11.0 g) and triethylamine (15.7 ml) were added to 200 ml of methylenechloride. Then a solution of 2-fluorobenzoyl chloride (15.0 g) in methylenechloride (30 ml) was added dropwise to the mixture under ice-cooling and stirring. Thereafter, the mixture was stirred for 1.5 hrs. at room temperature, and the resultant precipitate was collected by filtration to give 3-(2-fluorobenzoyl)amino-ε-caprolactam as crude crystals. This crystals and phosphorus pentasulfide (16.5 g) were added to 200 ml of pyridine, and the whole was refluxed for 12 hrs. After cooling, the pyridine was removed by distillation, and to the residue was added a saturated sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography on silica gel, and then recrystallized from ethyl ether to give the title compound (4.55 g, 24.7 %).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[Al](Br)(Br)Br.[Cl:25][C:26]([Cl:30])([Cl:29])[C:27]#[N:28].[ClH:31]>>[Cl:25][C:26]([Cl:30])([Cl:29])[C:27]1[N:28]=[C:27]([C:26]([Cl:29])([Cl:25])[Cl:31])[N:28]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: Cl
Reactant: N#Cc1ccc(SCC(=O)OCc2ccccc2)cc1
Agent: Br[Al](Br)Br
Product: O=C(CSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1)OCc1ccccc1

Procedure:
The mixed solution of 10 g of benzyl 2-(4-cyanophenylthio)acetate (35.3 mmol), 0.8 g of AlBr3, and 50 g of trichloroacetonitrile was bubbled by dry HCl at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H-].[Na+].Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
A solution of 1 g (4.73 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate is added dropwise to a suspension of 0.38 g (9.45 mmol) of 60% sodium hydride in 10 ml of dimethylformamide, stirred at 0° C. under argon. The mixture is stirred for 30 minutes at 0° C. and then for 30 min at 20° C. The reaction mixture is cooled and 1.24 g (4.2 mmol) of 4-bromomethylpyridine hydrobromide are added portionwise. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled again to 0° C. and a further 0.38 g (9.45 mmol) of 60% sodium hydride in 10 ml of dimethylformamide is added. After 30 minutes at 0° C., 1.24 g (4.2 mmol) of 4-bromomethylpyridine hydrobromide are added portionwise. The reaction mixture is then stirred for 20 hours at 20° C. After this time, the mixture is poured into a solution of 100 ml of ice-water and 100 ml of ethyl ether. The organic phase is separated out and the aqueous phase is re-extracted with 100 ml of ethyl ether. The organic phases are combined, washed with 50 ml of water and then dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane/acetone). 0.65 g of expected product is obtained in the form of an oil, which is used without further purification in the subsequent synthesis.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH2:34][CH2:35][CH3:36])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH2:34][CH2:35][CH3:36])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: CCCc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)ccc1OC
Temperature: 25 °C
Yield: 53.4 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-methoxy-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (77 mg, 154 μmol) in dichloromethane (2.4 mL) was added trifluoroacetic acid (350 mg, 237 μL, 3.07 mmol) and the mixture stirred at room temperature. After 16 h the mixture was concentrated in vacuo then diluted with 25% aqueous NH4OH and dichloromethane. The mixture was washed with water, then the organic phase was concentrated in vacuo and purified by chromatography (silica, 3 to 10% methanol in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (33 mg, 82.2 μmol, 54%) as a an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (s, 1H), 8.33 (s, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.41 (d, J=8.7 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 3.98 (br. s, 1H), 3.84 (m, 1H), 3.79 (s, 3H), 3.70 (d, J=11.3 Hz, 1H), 3.51 (d, J=11.5 Hz, 1H), 3.40 (t, J=11.2 Hz, 1H), 2.99 (s, 1H), 2.72 (t, J=7.4 Hz, 2H), 1.81 (m, 1H), 1.72 (m, 2H), 1.72 (m, 3H), 0.94 (t, J=7.3 Hz, 3H); MS (EI/CI) m/z: 402.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][Si](C(C)C)(C(C)C)C(C)C)[CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:41][C:42](=[O:44])[CH3:43].CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH2:41][C:42](=[O:44])[CH3:43])[CH:5]=1
Reactant: COC(=O)c1ccnc(S[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(SCC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Triisopropylsilanylsulfanyl-isonicotinic acid methyl ester (1.5 g, 4.6 mmol) was dissolved in THF (50 mL) and tetrabutylammonium fluoride (1 M in THF, 6.9 mL, 6.9 mmol) was added. After 15 minutes TLC indicated complete cleavage of the protecting group and chloroacetone (0.440 mL, 5.52 mmol) and Hünig's base (2.8 mL, 16.1 mmol) were added. After 1 hour additional portions of chloroacetone (1.2 eq.) and Hünig's base (3.5 eq.) were added. After stirring at room temperature for 2 hours the reaction was diluted with EtOAc and washed with H2O/brine with back-extraction. The combined organic portions were dried over MgSO4 and concentrated then purified on silica gel (0-100% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[Br:20][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Solvent: ClCCl
Product: O=c1cc(O)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2.45 g (10.0 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2.b) in 25 mL DCM is added 470 μL (5.00 mmol) phosphorus tribromide at 0° C. The mixture is stirred overnight at RT and then poured into ice water. The precipitate is collected, washed with DCM and dried.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:30][CH:31]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 54.9 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (280 mg, 0.89 mmol) was reacted with (S)-tert-butyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate (320 mg, 1.1 mmol) to afford the desired product (220 mg, 55%) as a white solid: ESI MS m/z 351 [C25H26N2O4S-Boc]+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]=[C:11]=[O:12])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[CH:15]=[C:16]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>C1(C)C=CC=CC=1>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][O:29][C:11](=[O:12])[NH:10][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)[CH2:24][CH2:25]2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: OCCCN1CCN(c2cccc(Cl)c2)CC1
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(Nc1ccc2c(c1)OCO2)OCCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 187.1 %

Procedure:
A mixture of 3,4-methylenedioxyphenylisocyanate (330 mg; 2.0 mmol) (produced as in Example 13) and 3-[4-(3-chlorophenyl) -1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (30 ml) was refluxed for 16 h. The reaction mixture was then concentrated and submitted to flash chromatography on silica gel 60 eluting with toluene graduated to toluene/ethyl acetate (1:3). The product was taken up in ethanol which was treated with hydrogen chloride in ether. Recrystallization from methanol/ether afforded 850 mg of the title compound M.p. 182°-184° C. MS (70 eV): m/z 417 (42%, M+), 254 (24), 209 (100), 194 (7), 163 (70), 136 (37), 70 (51).