Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][NH2:15])=[O:13])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:15]/[NH:14][C:12](=[O:13])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[S:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:9])=[O:8])/[CH3:28])[CH:26]=1
Reactant: NNC(=O)c1ccccc1S(=O)(=O)N1CCOCC1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1ccccc1S(=O)(=O)N1CCOCC1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 21 %

Procedure:
2-(morpholinosulfonyl)benzohydrazide (30 mg, 0.105 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (17.94 mg, 0.105 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-2-(morpholinosulfonyl)benzohydrazide (10 mg, 0.022 mmol, 21.28% yield) as a solid. 1H NMR (CD3OD, 400 MHz): δ 7.95 (d, 1H, J=8.0 Hz), 7.95-7.70 (m, 2H), 7.66 (d, 1H, J=7.6 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.25 (dd, 1H, J=2.8 & 8.8 Hz), 6.91 (d, 1H, J=8.4 Hz), 3.66 (m, 4H), 3.2 (m, 4H), 2.36 (s, 3H). Mass [M+H]+:438.1
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([S:20][CH2:21][C:22]([OH:24])=[O:23])(=O)N.[CH3:25][N:26](C=O)C>>[C:10]1([C:8]2[N:26]=[C:25]([CH:21]([SH:20])[C:22]([OH:24])=[O:23])[O:16][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C=O
Reactant: NC(=O)SCC(=O)O
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Product: O=C(O)C(S)c1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
23 g. of 1,2-diphenyl-2-chloroethanone is heated together with 18 g. of the ethyl ester of carbamoylmercaptoacetic acid in 150 ml. of absolute DMF for 3 hours to 70°. Then, the DMF is removed, and the residue, containing the ethyl ester of N-(1,2-diphenyl-2-oxoethyl)-carbamoylmercaptoacetic acid, is refluxed for 5 hours with a mixture of 100 g. of POCl3 and 200 ml. of benzene. The mixture is then evaporated under reduced pressure and the residue is purified by chromatography on silica gel, thus obtaining the ethyl ester of 4,5-diphenyl-2-oxazolyl-mercaptoacetic acid, m.p. 54°-56°.
Reaction SMILES: CO[C:3]([C:5]1[CH:12]=[CH:11][CH:10]=[C:8](C)[C:6]=1O)=[O:4].C1C(=NNC2C=CC(/C=C/C3C=CC(NN=C4C=CC(=O)C=C4)=CC=3S([O-])(=O)=O)=C(S([O-])(=O)=O)C=2)C=C[C:15](=[O:16])C=1.[Na+].[Na+]>O>[OH:16][CH2:15][CH:10]1[CH2:8][CH2:6][CH:5]([CH2:3][OH:4])[CH2:12][CH2:11]1
Reactant: COC(=O)c1cccc(C)c1O
Reactant: O=C1C=CC(=NNc2ccc(/C=C/c3ccc(NN=C4C=CC(=O)C=C4)cc3S(=O)(=O)[O-])c(S(=O)(=O)[O-])c2)C=C1
Agent: *CC*
Agent: O=C(O)c1ccc(C(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: OCC1CCC(CO)CC1

Procedure:
100 g of polyethylene terephthalate fibres in 4 l of water are dyed with 1 g of the dyestuff prepared according to the above example, which has first been brought to a finely divided state in the presence of dispersing agents, the dyeing being carried out in the presence of 15 g of o-cresotic acid methyl ester as the carrier for 2 hours at 100°C and pH 4.5. A brilliant yellow-tinged pink dyeing is obtained, which is distinguished by good built-up and high fastness to washing, thermofixing, rubbing and light. A similar colouration is obtained if polyester fibres from 1,4-bis-(hydroxymethyl)-cyclohexane and therephthalic acid are used.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:21])[C@H:9]([CH:10]=[C:11](Br)Br)[C@H:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCOCC.P(O)(O)([O-])=O.[Na+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1([CH3:21])[C@H:9]([C:10]#[CH:11])[C@H:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@@H](C=C(Br)Br)C1(C)C
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#C[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: -80 °C
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
47 ml of a solution of 2.34M of butyllithium in hexane were slowly added at -100° C. to a solution of 38.7 g of tert.-butyl (1R,trans) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate, 200 ml of ether and 200 ml of tetrahydrofuran and the mixture was stirred for 90 minutes at -80° C. and was poured into iced aqueous monosodium phosphate solution. The mixture was extracted with benzene and the organic phase was evaporated to dryness under reduced pressure. The residue was rectified under reduced pressure to obtain 9.3 g of tert.-butyl (1R,trans) 2,2-dimethyl-3-ethynyl-cyclopropane-carboxylate with a boiling point of 30° C. at 0.1 mm Hg.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A solution of (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.38 g, 0.76 mmol) in methanol (7.66 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (22 mg, 0.11 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction diluted with ethyl acetate (75 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane gradient) afforded (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.30 g, 86%) as a white solid: HR-ES-MS m/z calculated for C23H30N4O6 [M+H]+ 459.2238, observed 459.2237. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.36-1.64 (m, 2H), 1.66-1.81 (m, 1H), 3.20-3.32 (m, 2H), 3.77 (s, 4H), 3.86 (dd, J=13.3, 7.5 Hz, 1H), 4.04-4.11 (m, 1H), 4.14 (d, J=18.1 Hz, 1H), 4.53 (d, J=18.1 Hz, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.75 (s, 1H), 4.87 (dd, J=10.6, 4.8 Hz, 1H), 4.93 (d, J=5.1 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.00 (d, J=9.1 Hz, 2H), 7.23 (d, J=9.1 Hz, 2H), 7.53 (d, J=2.1 Hz, 1H), 10.74 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH:9](O)[CH2:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C1C[O:29]CC1>>[CH3:21][S:22]([O:24][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:29])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: C1CCOC1
Reactant: CCCC(O)OCc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCOCc1ccccc1

Procedure:
The 1-benzyloxy-1-butanol (Aldrich, 0.22 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:23]3[CH2:28][CH2:27][C@@H:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:23]3[CH2:28][CH2:27][C@@H:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12
Reactant: CC(C)c1noc([C@H]2CC[C@@H](n3ncc4c(Cl)ncnc43)CC2)n1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc([C@H]2CC[C@@H](n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Temperature: 180 °C
Yield: 55.8 %

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 101 mg, 0.53 mmol), 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 25; 185 mg, 0.53 mmol) and potassium carbonate (48 mg, 0.53 mmol) in anhydrous DMF (5 mL) was heated in a microwave at 180° C. for 10 min. The mixture was filtered. The filtrate was concentrated and purified using a Supelco 23 g column, eluting with 0-3% methanol/dichloromethane to give 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (148 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:7]1[CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[CH:4]=[C:3]([CH3:11])[C:2]=1[F:1])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: Cc1cc([N+](=O)[O-])cc(S(=O)(=O)Cl)c1F
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A dry reaction flask equipped with a stirring bar, a reflux condenser and nitrogen inlet was charged with 4-fluoro-3-methylnitrobenzene (25) (3.10 g, 20 mmol). To this at 0° C., was added dropwise chlorosulfonic acid (5.29 mL, 80 mmol) over a period of 15 minutes. After bringing the homogeneous solution to room temperature, it was stirred at 110° C. for 24 hours. The resulting slurry was then poured over ice water (100 gm), extracted with diethyl ether (3×75 mL), and the organic phase washed with water (75 mL), then dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to afford the corresponding sulfonyl chloride derivative (26), which was used further without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[CH2:11]([Li])[CH2:12]CC.ICC.Cl>C(OCC)(=O)C.C1COCC1>[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7](=[O:8])[CH2:9][CH2:11][CH3:12]
Reactant: COC(=O)CC(C)=O
Reactant: [Li]CCCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
44.4 g of sodium hydride suspension (60% in paraffin oil) is introduced into 1500 ml of THF, and 107.5 ml of acetoacetic acid methyl ester 3 is added under nitrogen at 0° C. After 10 minutes, 440 ml of n-butyllithium solution (2.5 M in hexane) is then added in drops, and it is stirred for another 30 minutes at 0C. Now, 88.9 ml of iodoethane is added, and it is stirred overnight at room temperature. For working-up, it is again cooled to 0° C. and neutralized with 4N hydrochloric acid. The organic phase is diluted with ethyl acetate, washed with thiosulfate solution and sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is then chromatographed on silica gel with ethyl acetate/hexane, whereby 95.13 g of title compound 13 is obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.C(O)C.[ClH:14].[C:15]([CH2:18][O:19][NH2:20])([OH:17])=[O:16].C(CON)(O)=O.C([O-])(=O)C.[Na+]>O>[Cl:14][CH:18]([O:19][N:20]=[CH:4][C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][CH:2]=1)[C:15]([OH:17])=[O:16]
Reactant: Cl
Reactant: NOCC(=O)O
Reactant: O=Cc1c(F)cccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cl)ON=Cc1ccccc1F

Procedure:
A warm solution of 2.0 gm. (0.013 mole) of 2-chloro-6-fluorobenzaldehyde in 40 ml. of ethanol was stirred into a warm solution of 1.4 gm. (0.013 equiv.) of carboxymethoxylamine hemihydrochloride and 0.6 gm. (0.007 mole) of anhyd. sodium acetate in 40 ml. of water. The mixture was heated a half-hour on the steam bath, and was then evaporated to dryness under reduced pressure to yield an oil, which was induced to crystallize by vigorous stirring. The solid material was triturated under water, removed by filtration, washed with water and dried in air to obtain 2.7 gm. (92.5%) of crude product melting from 95°-115° C. Recrystallization from n-heptaine/isopropyl alcohol gave 2.0 gm. of product melting at 116°-118° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CC(C)([O-])C.[K+].[C@H:35]1([NH2:42])[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1>C1COCC1.CO>[NH2:41][C@H:38]1[CH2:39][CH2:40][C@H:35]([NH:42][C:2]2[CH:3]=[C:4]([NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:36][CH2:37]1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Cl)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Nc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.307 mmol) in THF (1 mL) was treated with pyridin-2-amine (57.7 mg, 0.613 mmol). A solution of potassium tert-butoxide (0.613 mL, 0.613 mmol) in THF was added and the reaction was stirred at room temperature. The solvent was removed under a stream of nitrogen and the residue was taken up in MeOH and filtered. The solid material was dried under vacuum. The material was taken up in NMP (2 mL) and transferred to a microwave vial. (trans)-Cyclohexane-1,4-diamine (0.350 g, 3.07 mmol) was added and the reaction was irradiated at 300 W power, 110° C. for 40 minutes. After cooling, the crude material was diluted with 2 mL of MeOH and purified via preparative HPLC using a YMC ODS C-18 30×250 mm column with 10-100% B (Solvent A: 10% aq MeOH with 0.1% TFA; Solvent B: 90% aq. MeOH with 0.1% TFA) and a linear gradient over 60 min at 25 mL/min, monitoring at 220 nm, and a total run time of 70 min. (RT of desired=45.100 min). The appropriate fractions were concentrated under reduced pressure and lyophilized overnight, furnishing 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-(pyridin-2-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (0.057 g, 0.083 mmol) as a white, fluffy solid. LC/MS, m/z 462.3 (M+1). HPLC Rt=3.345 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min.
Reaction SMILES: O[CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:12].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]([N:20]2[N:21]=[CH:22][CH:23]=[N:24]2)=[C:13]([CH:18]=1)[C:11]([N:4]1[CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:2][N:29]1[C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30])=[O:12]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CO)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of (1-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (1 equiv.), phthalimide (2 equiv.) and PPh3 (3 equiv.) in THF (0.5M in amine) was added with DIAD (5 equiv.) dropwise. The resulting suspension was allowed to warm to rt gradually, stirred overnight, and then concentrated in vacuo to a brown oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 456 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CO[C:22](OC)([N:24](C)C)[CH3:23].N1C=CC=CC=1.NOS(O)(=O)=O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[C:5]2[N:6]([N:24]=[C:22]([CH3:23])[N:8]=2)[CH:7]=1
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Reactant: COC(C)(OC)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Temperature: 130 °C
Reaction time: 20 h
Yield: 28.9 %

Procedure:
To a stirred solution of 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 1.0 g, 3.02 mmol) in DMF (5 mL) was added dimethylacetamide dimethyl acetal (1.33 mL, 9.06 mmol) and the reaction mixture was heated at 130° C. for 3 hrs. The reaction mixture was cooled then concentrated in vacuo. The resultant residue was dissolved in MeOH (10 mL) and pyridine (486 μL, 6.04 mmol) was added before the mixture was cooled to 0° C. and hydroxylamine-O-sulfonic acid (512 mg, 4.53 mmol) was added. The reaction mixture was allowed to warm to RT and stirred at this temperature for 20 hrs. The resultant precipitate was collected by filtration, then washed with MeOH to afford the title compound as a grey solid (323 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Br:12])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)Cl>O>[C:19]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Br:12])=[CH:4][N:3]=1)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Cc1c(Br)cnc(N)c1[N+](=O)[O-]
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ncc(Br)c(C)c1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
A mixture comprising 10 g (43.1 mmol) of 2-amino-5-bromo-4-methyl-3-nitropyridine and 6.8 g of pyridine was heated to 110° C. in a nitrogen atmosphere. 5.7 g (47.4 mmol) of valeroyl chloride was dropwise added thereto and the mixture was stirred at 110° C. for 5 hours. The reaction mixture was brought to room temperature, followed by the addition of methylene chloride (50 ml) and water (50 ml). The organic phase was separated. The aqueous phase was further extracted with methylene chloride (50 ml). The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration to give a crude crystal. It was recrystallized from ethyl acetate to give 11 g of 2-valerylamino-5-bromo-4-methyl-3-nitropyridine (yield 81%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[OH-].[CH2:18]([N+:25](C)(C)C)[C:19]1C=CC=C[CH:20]=1.C(#N)C=C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:19][C:18]#[N:25])[C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: O=C1Nc2ccc(Br)cc2C12OCCCO2
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C=CC#N
Product: N#CCCN1C(=O)C2(OCCCO2)c2cc(Br)ccc21
Temperature: 52 °C
Yield: 711.1 %

Procedure:
At room temperature, to a solution of 5′-bromospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (2.50 g, 8.80 mmol) in N,N dimethylformamide (39 mL) was added benzyltrimethylammonium hydroxide (40% aq. solution, 0.347 mL, 0.88 mmol, 0.1 mole % ) followed by the dropwise addition of acrylonitrile (1.16 mL, 17.6 mmol, 2 eq). The reaction mixture was heated at 52° C. for 2 hr., cooled to room temperature, quenched with H2O (400 mL) and extracted with Et2O (3×). The combined organic extracts were dried and concentrated. The crude product was purified on Biotage KP silica gel eluting with 96/4 CH2Cl2/CH3CN to give the title compound as a yellow solid (2.11 g, 71% ). NMR (300 Mz, DMSO-d6): consistent; MS: (API-ES+) m/z 361 [M+Na].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:7]=3[C:6]=2[N:18]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>N1C=CC=CC=1>[I:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[CH2:11][C:5]3[CH:4]=[N:3][C:2]([NH:1][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:18][C:6]=3[C:7]=2[CH:16]=1
Reactant: Nc1ncc2c(n1)-c1cc(I)ccc1NC(=O)C2
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C1Cc2cnc(NC(=O)c3ccccc3)nc2-c2cc(I)ccc2N1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2-Amino-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-51) (69.7 mg, 0.20 mmol) was dissolved in pyridine (800 μL) and benzoyl chloride (23 mL, 0.20 mmol). The mixture was stirred at 110° C. for 1 h, then cooled to 22° C. Et2O was added and the product was filtered from the solution to give I-83 (37%): MS (FA) Rt═1.49 min, m/z═457 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.C(Cl)(Cl)Cl>[Br:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCC(C)=O
Product: CC(=O)Nc1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.51 %

Procedure:
A solution of N-(4-hydroxyphenyl)-acetamide (paracetamol) (1) (1.50 g, 0.01 mol) and 1,2-dibromoethane (8) (10.0 ml) in ethyl methyl ketone (25.0 ml) containing potassium carbonate (5.0 g) was stirred for 8 hr at room temperature. The reaction mixture was filtered, residue washed with ethyl methyl ketone and solvent evaporated under reduced pressure to get the residue. The residue was dissolved in chloroform (200.0 ml), washed with 5% NaOH solution (3×100 ml), water (3×50 ml), dried, filtered and crystallized from methanol to get the desired product N-[4-(2-bromo-ethoxy)-phenyl]-acetamide (10) (2.01 g, 78.51%), mp 126-127° C.