Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14]>CO>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[O:9][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]2=[O:14]
Reactant: O=C(O)c1cccnc1Cl
Reactant: Oc1ccc(Br)cc1
Agent: [Na]
Solvent: CO
Product: O=c1c2cc(Br)ccc2oc2ncccc12
Temperature: 130 °C
Yield: 2.3 %

Procedure:
Sodium metal (2.30 g, 100 mmol) was added to ice-cooled methanol (75 mL) with stirring under nitrogen. After the sodium had reacted completely, a slurry of 4-bromophenol (8.65 g, 50 mmol) and 2-chloronicotinic acid (7.88 g, 50 mmol) in methanol (50 mL) was added. The resulting light yellow solution was concentrated under vacuum, and the solid residue was taken up in DMF (50 mL) and heated to 130° C. for 18 h. The mixture was cooled, concentrated under vacuum, and the residue was diluted with water (50 mL) and extracted with ether (2×50 mL). The aqueous phase was acidified with 5% sulfuric acid (60 mL) to pH ˜3, and the slurry was stirred for 1 h and the precipitate was isolated by filtration and dried at 50° C. The tan solid (3.48 g), a 3:2 mixture of 2-(4-bromophenoxy)nicotinic acid and 2-chloronicotinic acid, was used directly for the cyclization. The solid (1.0 g) was added in one portion to a solution of phosphorous pentoxide (2.6 g) in methanesulfonic acid (27 g) at 80° C. The brownish solution was heated at 80° C. for 15 h, then cooled and poured onto ice (100 g). The mixture was brought to pH>9 by addition of 50% NaOH (17 mL) and extracted with dichloromethane (2×40 mL). The organic extract was dried (MgSO4) and concentrated to provide the title compound as a white solid (0.32 g, 8% from 4-bromophenol). 1H NMR (300 MHz, CD3OD) δ ppm 7.59 (dd, J=8, 5 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 8.00 (dd, J=9, 3 Hz, 1H), 8.36 (d, J=2 Hz, 1H), 8.73 (dd, J=8, 2 Hz, 1H), 8.78 ppm (dd, J=5, 2 Hz, 1H); MS (DCl/NH3) m/z 276/278 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[O:4][C:5]1[C:6]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][CH:8]=[N:9][C:10]=1[O:11][CH2:12][CH2:13][OH:14].[CH3:33][S:34][C:35]1[CH:36]=[N:37][C:38](Cl)=[N:39][CH:40]=1>>[CH3:33][S:34][C:35]1[CH:36]=[N:37][C:38]([O:14][CH2:13][CH2:12][O:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][S:16](=[O:26])(=[O:25])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[O:4][C:3]2[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:2]=2[Cl:1])=[N:39][CH:40]=1
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)NCc3ccccc3)ncnc2OCCO)c1
Reactant: CSc1cnc(Cl)nc1
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)NCc3ccccc3)ncnc2OCCOc2ncc(SC)cn2)c1
Yield: 45.7 %

Procedure:
Benzylsulfamic acid [6-[2-(5-methylsulfanyl-pyrimidin-2-yloxy)-ethoxy]-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amide (138 mg) (Example 213) was prepared from benzylsulfamic acid [5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide (240 mg) (Example 211) and 5-methylsulfanyl-2-chloropyrimidine (180 mg) according to the procedure described in Example 14. LC-MS: tR=5.22; [M+H]+=606.75.
Reaction SMILES: [C:1]([C:4]([C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)(C(=O)C)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].C(OCC)(=O)C.O>FC(F)(F)C(O)=O>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([CH:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:27])=[CH:24][CH:23]=1)#[N:26]
Reactant: CCOC(=O)CCCCCC(C(C)=O)(C(C)=O)C(=O)c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCCCC(C(C)=O)C(=O)c1ccc(C#N)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
Ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (3.5 g) was dissolved in trifluoroacetic acid (12.6 ml) and the mixture was stirred at 20° C. for 15 minutes. The mixture was partitoned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, dried over MgSO4 (magnesium sulfate), and evaporated to give ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.25 g) as an oil.
Reaction SMILES: Cl.[CH3:2][NH2:3].[CH3:4][C:5]([O:8][C:9]([NH:11][CH:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[N:18]=[CH:17][S:16][CH:15]=1)=[O:10])([CH3:7])[CH3:6]>>[C:5]([O:8][C:9]([NH:11][C@@H:12]([CH2:13][C:14]1[N:18]=[CH:17][S:16][CH:15]=1)[C:19]([NH:3][CH3:2])=[O:21])=[O:10])([CH3:4])([CH3:6])[CH3:7]
Reactant: CN
Reactant: CC(C)(C)OC(=O)NC(Cc1cscn1)C(=O)O
Agent: Cl
Product: CNC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C

Procedure:
Methylamine hydrochloride (1.2 mmol) and Boc-L-3-(4-thiazolyl)alanine (1.0 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, acid wash omitted) and the product used without further purification. Yield, 250 mg, 88%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C1C=[CH:25][C:26]2N(O)N=[N:29][C:27]=2C=1.CCN=C=NCCCN(C)C.C(N)C=C>C(Cl)Cl>[CH2:27]([NH:29][C:12]([C:11]1[S:10][C:9]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[N:8][C:7]=1[CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:13])[CH:26]=[CH2:25]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: C=CCN
Solvent: ClCCl
Product: C=CCNC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred solution of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylic acid (220 mg, 0.665 mmol) in DCM (4.05 mL) was added HOBT (98.8 mg, 0.732 mmol) and EDCI (204 mg, 1.06 mmol) at room temperature and the mixture was stirred for 30 min. To the solution was added 2-propen-1-amine (0.200 mL, 2.66 mmol) then the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (10 mL) and washed with water (3 mL) and brine (2 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→75/25) to give 150 mg of the title compound as a yellow solid (61% yield). LC/MS (FA) ES+ 370. 1H NMR (400 MHz, CDCl3) δ: 8.74-8.72 (m, 2H), 7.79-7.77 (m, 2H), 7.35-7.32 (m, 2H), 7.27-7.25 (m, 2H), 5.94-5.80 (m+bs, 2H), 5.25-5.20 (m, 2H), 4.48 (s, 2H), 4.06-4.02 (m, 2H).
Reaction SMILES: C(O[CH:5]1[CH2:12][CH2:11][O:10][C:8](=[O:9])[CH2:7][CH2:6]1)(=O)C.[NH3:13]>>[OH:10][CH2:11][CH2:12][CH:5]1[NH:13][C:8](=[O:9])[CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCOC(=O)CC1
Reactant: N
Product: O=C1CCC(CCO)N1

Procedure:
22.4 g of 4-acetoxycaprolactone were stirred for 1 hour at 330° C. in an autoclave together with 100 g of 25% strength aqueous ammonia. After cooling and depressurizing the autoclave, the reaction product was concentrated on a rotary evaporator (40° C./30 mbar) and purified by short path distillation. In this case, 10.1 g of 5-hydroxyethylpyrrolidone were obtained (61%, based on the 4-acetoxycaprolactone employed) and identified by NMR spectroscopy.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>C1CCCCC1>[C:1]1([C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][Br:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: C=C(c1ccccc1)c1ccccc1
Solvent: C1CCCCC1
Product: BrC=C(c1ccccc1)c1ccccc1
Reaction time: 20 h
Yield: 83.4 %

Procedure:
20 g (111 mmoles) of 1,1-diphenylethylene was dissolved in 70 ml of cyclohexane, to which was then added dropwise 35 g (222 mmoles) of bromine at room temperature. The mixture was stirred at the same temperature for 20 hours and further heated under reflux for one hour. After cooling, the reaction mixture was washed with a sodium thiosulfate aqueous solution and saturated salt water, and an organic phase was separated by liquid separation. The organic phase was concentrated and subjected to Kugel distillation (at 145 to 148° C./0.6 Torr) to obtain 24 g (yield: 86%) of desired 1,1-diphenyl-2-bromoethylene. 4.8 g (18 mmoles) of 1,1-diphenyl-2-bromoethylene, 0.486 g (20 mmoles) of Mg, a small piece of iodine, and 100 mL of THF were added to a 300 ml eggplant type flask to prepare a Grignard reagent. The reaction mixture was cooled to −78° C., to which trimethoxyborane was then added dropwise while maintaining the same temperature. The mixture was stirred at room temperature for 2 hours, to which 2N hydrochloric acid was then added. An organic phase was treated to isolate desired 1,1-diphenylvinylboronic acid as a white powder in a yield of 35%. The same procedures as in Synthesis Example 4 were followed, except for using 3.28 g of 1,1-diphenylvinylboronic acid in place of the 4-biphenylylboronic acid, to obtain 3.77 g (yield: 72%) of the desired compound.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C1CCN2C(=NCCC2)CC1.[Cl:17][C:18]1[CH:19]=[C:20]([O:25][C:26]2[C:41]([F:42])=[CH:40][C:29]([C:30](OC3C=CC(C)=CC=3)=[O:31])=[C:28]([F:43])[CH:27]=2)[CH:21]=[N:22][C:23]=1[F:24]>CC#N.CCOC(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([O:25][C:26]2[C:41]([F:42])=[CH:40][C:29]([C:30]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:31])=[C:28]([F:43])[CH:27]=2)[CH:21]=[N:22][C:23]=1[F:24]
Reactant: Cc1ccc(OC(=O)c2cc(F)c(Oc3cnc(F)c(Cl)c3)cc2F)cc1
Reactant: CS(N)(=O)=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1cc(F)c(Oc2cnc(F)c(Cl)c2)cc1F
Temperature: 45 °C
Yield: 36.1 %

Procedure:
Methanesulfonamide (52.0 mg, 0.547 mmol) was suspended in MeCN (3 mL) in a sealed vial. 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine (0.085 mL, 0.57 mmol) was added followed by 4-methylphenyl 4-[(5-chloro-6-fluoropyridin-3-yl)oxy]-2,5-difluorobenzoate (Preparation 67, 215.0 mg, 0.546 mmol). The mixture was heated at 45° C. for 2 hours. The reaction mixture was diluted in EtOAc (15 mL), then washed with 10% aqueous citric acid solution (2×15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was partitioned between DCM (10 mL) and water (10 mL). The organic layer was further washed water (2×10 mL) and concentrated in vacuo to yield the title compound as a white solid (75 mg). EtOAc (15 mL) was added to the combined aqueous. The organic layer was then washed with water (3×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield a second batch of the title compound as a white solid (75.0 mg, 35%):
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([O:17][C:18]2[C:23]([F:24])=[C:22]([CH3:25])[CH:21]=[CH:20][C:19]=2[N+:26]([O-])=O)[CH:13]=[C:14]([Cl:16])[CH:15]=1>O.C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]([O:17][C:18]2[C:23]([F:24])=[C:22]([CH3:25])[CH:21]=[CH:20][C:19]=2[NH2:26])[CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 40 °C
Reaction time: 16 h
Yield: 41.9 %

Procedure:
Sodium hydrosulfite (37.7 g, 216 mmol) dissolved in water (200 mL) was added dropwise to a vigorously stirred solution of 2-[(3-bromo-5-chlorophenyl)oxy]-3-fluoro-4-methyl-1-nitrobenzene (13.0 g, 36.1 mmol) dissolved in THF (100 mL). The reaction was stirred for 16 h at 40° C. The layers were separated and the aqueous phase was extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The crude oil was purified by column chromatography (5% to 100% EtOAc/hexanes gradient) to afford the title compound (5.0 g, 42%) as a light tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.39-7.38 (m, 1H), 6.98-6.97 (m, 1H), 6.90-6.85 (m, 2H), 6.54-6.52 (m, 1H), 2.08 (s, 3H).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.N1C(C)=CC=CC=1C.[F:24][C:25]([CH3:29])([CH3:28])[CH2:26]O>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:26][C:25]([F:24])([CH3:29])[CH3:28])(=[O:8])=[O:9]
Reactant: CC(C)(F)CO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Trifluoromethanesulfonic anhydride (12.06 ml, 71.24 mmol), followed by 2,6-lutidine (11.42 ml, 81.42 mmol) were added to a solution of 2-fluoro-2-methylpropan-1-ol (6.25 g, 67.85 mmol) in DCM (146 ml) at −10° C. The reaction was stirred for 1 hr. then washed with 2N HCl (2×100 ml) and saturated NaHCO3 solution (2×100 ml). The organic phase was then cried over Na2SO4 and concentrated to give 2-fluoro-2-methylpropyl trifluoromethanesulfonate (12.89 g, 85%) as a red oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[N:14]1[N:13]([CH2:9][CH2:10][C:11]#[C:12][C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=12
Reactant: Nc1cccc(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: Nc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 30.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 6-bromo-pyridin-2-ylamine (960 mg, 5.55 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (950 mg, 5.55 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 1:1) to yield 0.45 g (1.71 mmol, 31%) of 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine as a brown solid
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:6](=[O:12])[N:5]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:4](=[O:17])[C:3]=1[N:18]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(O)C>[NH2:18][C:3]1[C:4](=[O:17])[N:5]([CH2:13][CH:14]2[CH2:15][CH2:16]2)[C:6](=[O:12])[N:7]([CH2:8][CH:9]2[CH2:10][CH2:11]2)[C:2]=1[NH2:1]
Reactant: Nc1c(N=O)c(=O)n(CC2CC2)c(=O)n1CC1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1c(N)n(CC2CC2)c(=O)n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
Compound c (3.0 g, 11.4 mmol) was suspended in a mixture of 25 ml of water and 40 ml of ethanol. Twenty milliliters of aqueous solution of 6.9 g (40 mmol) of sodium hydrosulfite was added, and the resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was extracted three times with 50 ml of chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: 3% methanol/chloroform) to give 2.40 g (yield: 84%) of Compound b as an amorphous substance.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)=O.C(C1(C(OC)=O)CCC1)=O>>[O:22]1[CH2:23][CH2:24][CH:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:3][CH2:2][N:1]([CH2:25][C@H:27]5[CH2:28][CH2:29][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:31][CH2:32]5)[CH2:6][CH2:5]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: c1cc(OC2CCOCC2)c2c(OCC3CCNCC3)noc2c1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)[C@H]1CC[C@H](CN2CCC(COc3noc4cccc(OC5CCOCC5)c34)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 3-(piperidin-4-ylmethoxy)-4-(tetrahydro-2H-pyran-4-yloxy)-1,2-benzisoxazole (EXAMPLE 27, Step 1) and methyl trans-4-formylcyclohexanecarboxylate (JP 49-48639) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH:17]=[N:18][OH:19])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N+:18]([O-:19])=[CH:17][C:16]3[C:11]([CH:10]=2)=[CH:12][N:13]=[CH:14][CH:15]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(C#Cc2cnccc2C=NO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc3cnccc3c[n+]2[O-])cc1
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 79.5 %

Procedure:
3-(4-Methoxyphenylethynyl)-4-pyridine aldoxime (4.724 g) was dissolved in ethanol (100 ml), followed by the addition of potassium carbonate (2.768 g)/water (30 ml) solution, and the mixture was stirred at 70° C. for 50 min. After cooling as it was, the resulting insoluble matters were collected by filtration, and then washed with water and ethanol, to give the title compound as a dark green solid (3.757 g, yield; 75%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11]I.Cl>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][CH3:11])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)s1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of (5-bromothiophen-2-yl)methanol (460 mg, 2.38 mmol) in 5 mL anhydrous tetrahydrofuran at room temperature was added carefully hexanes-washed sodium hydride (60% in oil, 143 mg, 3.57 mmol). After stirring at room temperature for 30 minutes, methyl iodide (0.3 mL, 4.76 mmol) was added in a single portion and the reaction mixture stirred for 16 h at room temperature. The reaction mixture was poured into 20 mL of 0.2 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (3×25 mL), washed with 30 mL each of 5% aqueous sodium bisulfite solution and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (2-3% ethyl acetate in hexanes) to give 2-bromo-5-(methoxymethyl)thiophene (439 mg, 89%) as an oil. Used without further characterization.
Reaction SMILES: [Na].[C:2]([C:5]1[N:6]([NH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([O-:19])=[O:18])=[CH:15][CH:14]=2)=O)[CH:7]=[CH:8][CH:9]=1)(=[O:4])[NH2:3].[CH3:22]O>>[CH3:22][O:19][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([C:11]2[NH:3][C:2](=[O:4])[C:5]3=[CH:9][CH:8]=[CH:7][N:6]3[N:10]=2)=[CH:14][CH:15]=1
Reactant: CO
Reactant: NC(=O)c1cccn1NC(=O)c1ccc(C(=O)[O-])cc1
Agent: [Na]
Product: COC(=O)c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1

Procedure:
Sodium (65.3 mg, 2.84 mmol) is dissolved in methanol (5.0 ml). Then 4-[(2-carbamoylpyrrol-1-yl)carbamoyl]benzoate (544 mg, 1.90 mmol) is added. The mixture is irradiated in a microwave reactor at 150° C. for 1 hour. The solvent is evaporated and the residue is triturated with water. The solid is filtered off and washed with water. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to give 4-(4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-benzoic acid methyl ester as white fluffy solid; HPLC/MS 1.72 min (C), [M+H] 270;
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11](=O)[NH:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[N:12]=[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[N:9][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc(-c2ccncc2F)c(-c2cccnc2)[nH]1
Product: Fc1cnccc1-c1ncc(Cl)nc1-c1cccnc1
Reaction time: 8 h
Yield: 33 %

Procedure:
A suspension of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2(1H)-one (0.79 g, 2.95 mmol) in phosphorus oxychloride (5 mL) was heated to reflux and stirred overnight. The mixture was evaporated and carefully neutralised with 4% aqueous sodium hydrogen carbonate solution with external cooling. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography (CH2Cl2 to CH2Cl2/MeOH 98:2) to give the title compound (0.279 g, 33%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH3:20][CH2:21][O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:28]3[CH2:27][CH2:26][N:25]([C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:30][CH2:29]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 7.88 g (0.025 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-one and 1200 ml toluene was heated under nitrogen until a solution resulted. Then there was added 39.6 g (0.250 mole) of ethyl N-piperazinocarboxylate followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was taken up in 25 ml of hot methanol from which 8.5 g (75%) of product crystallized. Recrystallization from ethyl acetate gave the analytical sample, mp 128°-131° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH:6]([O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][NH:26][C:27]([C:29]3[O:30][C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]=3[CH3:34])=[O:28])[CH:21]=2)[C:16]=1[Br:39])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CO>[Br:39][C:16]1[C:17]2[C:22](=[CH:21][C:20]([CH2:25][NH:26][C:27]([C:29]3[O:30][C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]=3[CH3:34])=[O:28])=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:40])=[O:4]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CNC(=O)c3oc4ccccc4c3C)ccc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)NCc2ccc3c(Br)c(OC(Cc4ccccc4)C(=O)O)ccc3c2)oc2ccccc12
Reaction time: 6 h

Procedure:
A mixture of 1 N NaOH (5 mL, 5 mmol) and 2-(1-bromo-6-{[(3-methyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (1.58 g, 2.76 mmol), prepared in the previous step, in 200 mL of methanol plus 5 mL of water was stirred under nitrogen at room temperature overnight and then at 60° C. for 6 h. 1 N HCl (6.2 mL, 6.2 mmol) was added and the reaction concentrated under reduced pressure to remove the methanol. The solid that precipitated was collected by filtration and dried under reduced pressure to give the title compound as an off-white solid, mp 110-113° C.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(N[C@H]1CCCC[C@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Product: O=C(N[C@H]1CCCC[C@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1S,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 4-chlorophenylboronic acid as starting materials, MS (ISP) 497.1 (M+H)+; [α]D20=−20.0°.