Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Reactant: CCOC(=O)[C@@H]1CCCN1
Product: CCOC(=O)[C@@H]1CCCN1CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and ethyl (S )-pyrrolidine-2-carboxylate
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH2:14][CH3:15])([CH3:13])[CH3:12].CS(C)=O>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([C:11]([CH2:14][CH3:15])([CH3:12])[CH3:13])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCC(C)(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Following procedure A, 4-fluoronitrobenzene (318 mg, 2.25 mmol, 1.00 eq) and 4-tert-pentylphenol (460 mg, 2.28 mmol, 1.24 eq) were dissolved in DMSO (6 mL) Anhydrous K2CO3 (465 mg, 3.37 mmol, 1.49 eq) was added and the reaction mixture was stirred at room temperature for 2 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as colourless solid (533 mg, 1.87 mmol, 83% yield). Rf=0.70 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C17H20NO3+ [M+H]+ 285.1365. found: 285.1359. 1H NMR (400 MHz, CDCl3) δ 8.25-8.14 (m, 2H, aromatic H), 7.44-7.32 (m, 2H, aromatic H), 7.06-6.96 (m, 4H, aromatic H), 1.66 (q, J=7.4 Hz, 2H, Ar—C(CH3)2CH2CH3), 1.31 (s, 6H, Ar—C(CH3)2CH2CH3), 0.71 (t, J=7.4 Hz, 3H, Ar—C(CH3)2CH2CH3). 13C NMR (101 MHz, CDCl3) δ 163.81, 152.24, 146.94, 142.56, 127.91, 126.01, 120.06, 116.99, 37.89, 37.06, 28.63, 9.27.
Reaction SMILES: [CH:1]1[C:7](=[O:8])[CH:6]=[C:5]([OH:9])[C:4]([OH:10])=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].BrBr.[OH-:16].[K+]>>[CH:1]1[C:7](=[O:8])[C:6]([OH:16])=[C:5]([OH:9])[C:4]([OH:10])=[CH:3][C:2]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1cc(O)c(O)cc(=O)c1
Reactant: [OH-]
Agent: BrBr
Agent: [K+]
Product: O=C(O)c1cc(O)c(O)c(O)c(=O)c1

Procedure:
Puberulic acid is also obtainable by direct chemical synthesis, as disclosed by Johns et al., Jour. Chem. Soc. 1954, 198. According to this method, a solution of 3,4,6-trimethoxycycloheptatriene-caboxylic acid (an intermediate obtained by reacting diazoacetic ester and 1,2,4-trimethoxybenzene) in chloroform is reacted with a solution of bromine in carbon tetrachloride; the obtained precipitate is then heated in ethyl acetate, cooled in ice and then hydrolyzed with hydrobromic acid, obtaining stipitatic acid. Said stipitatic acid is then reacted with bromine, in order to obtain monobromostipitatic acid which is in turn reacted with potassium hydroxide to obtain the desired puberulic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[C:5]=1C=O)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[K+].CO>C(Cl)(Cl)Cl>[OH:26][C:5]1[C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc([N+](=O)[O-])c(C=O)c(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc([N+](=O)[O-])c(O)c(OC)c1OC
Yield: 71.4 %

Procedure:
A mixture of 2-nitro-4,5,6-trimethoxybenzaldehyde (19.3 g, 0.08 mol) and m-chloroperbenzoic acid (20.7 g, 0.12 mol) in chloroform (350 ml) was heated under reflux for 5 hours. After cooling, the reaction mixture was washed with 10% sodium bicarbonate solution and water. The solvent was removed by evaporation in vacuo and the residue was then treated with a mixture of 10% potassium hydroxide solution (potassium hydroxide 5.0 g, 0.088 mol in 50 ml of water) and methanol (150 ml) at room temperature under nitrogen. The solvent was removed in vacuo and the solid residue was dissolved in water (300 ml) and then acidified with 6N hydrochloric acid. The precipitated product was collected by filtration, washed well with water and dried to give (after recrystallization from 2-propanol) 13.1 g of 2-hydroxy-1-nitro-3,4,5-trimethoxybenzene, mp 72-73° C. 1H-NMR (CDCl3): δ3.87, 3.94, and 4.08 (each 3H, s, 3 ×OMe), 7.32 (1H, s, H-6), 10.78 (1H, exchangeable, OH). Analyses: Calculated for C9H11NO6 : C, 47.16; H, 4.84; N, 6.11. Found: C, 47.11; H, 5.00; N, 6.17.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:13]1[CH2:14][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: O=C1CC(=O)CC(c2cccc(Cl)c2Cl)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2cccc(Cl)c2Cl)C1
Yield: 89.2 %

Procedure:
A mixture of 5-(2,3-dichlorophenyl)cyclohexane-1,3-dione (1.8 g) and ammonium acetate (1.7 g) in ethanol (20 ml) was refluxed for 14 hours, and the reaction solution was concentrated under reduced pressure. To the residue was added water (20 ml), and the resulting crystals were filtered. The crystals were washed with water and toluene, and dried to give 1-amino-5-(2,3-dichlorophenyl)cyclohexen-3-one (1.6 g) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][CH:33]=O)([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[CH3:35][NH2:36].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][CH2:33][NH:36][CH3:35])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: CN
Reactant: COC(=O)[C@]1(CC=O)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCC[C@@]1(C(=O)OC)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C

Procedure:
The reaction was performed on the two separated batches of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(2-oxoethyl)-1,2-pyrrolidinedicarboxylate obtained from the previous step (D37, Procedure 1). The first batch (109 g) was dissolved in MeOH (440 mL) and MeNH2 in MeOH 2M solution (347 mL) was added. AcOH (11 mL) was added. NaBH(OAc)3 (49 g) was added portion wise after 10 minutes. More NaBH(OAc)3 (14.7 g) was added portion wise at 25° C. The reaction mixture was quenched with 28% aqueous malic acid (200 mL) followed by AcOEt (1000 mL). K2CO3 was added up to pH˜9. Organic phase was concentrated to dryness, re-dissolved in EtOAc (500 mL) and extracted with 20% citric acid (4×300 mL). The combined aqueous phases were treated with EtOAc (500 mL) and solid K2CO3 was added until pH˜9. The phases were separated and the organic phase was dried under Na2SO4 and evaporated to dryness to afford the title compound (80 g). The second batch (180 g) was dissolved in MeOH (628 mL) and MeNH2 in MeOH 2M solution (300 mL) was added. AcOH (31 mL) was added. NaBH(OAc)3 (78.8 g) was added portionwise at 0° C. after 10 minutes. The reaction mixture was quenched with saturated NH4Cl (890 mL) and EtOAc (890 mL). The phases were separated and the aqueous was extracted with EtOAc (4×300 mL). The organic phase was dried over Na2SO4, concentrated to dryness, re-dissolved in EtOAc (500 mL) and extracted with 20% citric acid (6×150 mL). The combined aqueous phases were treated with EtOAc (600 mL) and solid K2CO3 was added until pH 8/9. The Phases were separated and the organic phase dried over Na2SO4 and evaporated to dryness to afford the title compound (78 g). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.55 (m, 1H); 7.42 (m, 3H); 7.25 (m, 2H); 6.98 (m, 2H); 5.14 (m, 2H); 4.85-4.69 (2m, 1H); 3.75-3.73 (2s, 3H); 2.36 (bs, 3H) 2.80-2.25 (m, 2H); 2.20-2.00 (m, 3H); 1.70 (m, 1H); 1.32-1.00 (2s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].O>CN(C)C(=O)C>[F:28][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([CH:29]=[C:3]([NH:2][C:30](=[O:33])[CH2:31][CH3:32])[N:4]=3)[N:7]=2)=[CH:17][C:16]=1[NH:18][C:19]([C:21]1[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=1)=[O:20]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(=O)Nc1cn2nc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (200 mg, 0.48 mmol) in N,N-dimethylacetamide (2.0 mL) was added propionyl chloride (49.9 μL, 0.57 mmol), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) and washed with ethyl acetate to give the title compound (78 mg, 37%) as a white powder.
Reaction SMILES: [NH2:1][CH:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])=[CH:3]1.Cl[CH2:19][C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])=O>CN(C=O)C>[CH3:25][O:24][C:23](=[O:26])[NH:22][C:20]1[N:1]=[C:2]2[CH:3]=[C:4]([C:8]3[CH:17]=[CH:16][CH:15]=[C:10]([C:11](=[O:12])[NH:13][CH3:14])[CH:9]=3)[CH:5]=[N:6][N:7]2[CH:19]=1
Reactant: COC(=O)NC(=O)CCl
Reactant: CNC(=O)c1cccc(C2=CC(N)NN=C2)c1
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2cnn3cc(NC(=O)OC)nc3c2)c1
Temperature: 110 °C
Reaction time: 7.5 h

Procedure:
3-(6-Amino-1,6-dihydro-pyridazin-4-yl)-N-methyl-benzamide (Intermediate A—Step E) (1 eq, 2.74 mmol, 735 mg) is added to a solution of methyl (chloroacetyl)carbamate (1.2 eq, 3.28 mmol, 498 mg) in DMF (30 ml) and the reaction mixture is stirred at 110° C. for 7.5 h. The solvent is then removed in vacuo and the product is purified by flash column chromatography eluting with 9:1 DCM/MeOH to afford [7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin -2-yl]-carbamic acid methyl ester as a green solid; [M+H]+=326
Reaction SMILES: [CH:1]([N:4]([C:8]1[C:13]2[CH2:14][CH2:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:8]2[C:9](=[CH:10][CH:11]=[C:12]3[O:16][CH2:15][CH2:14][C:13]3=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)N(C(N)=O)c1cccc2c1CCO2
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)NC(c2ccccc2)c2ccc3c(c21)CCO3

Procedure:
A solution of 5.0 g. of 1-isopropyl-1-(2,3-dihydro-4-benzofuranyl)urea, 3.5 ml. of benzaldehyde, 3 drops of methanesulfonic acid and 150 ml. of toluene is stirred and refluxed under a water separator for 20 hours. The resulting solution is cooled and the cooled solution is washed with 150 ml. water, dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an oil of 1-isopropyl-3,4,7,8-tetrahydro-4-phenyl-furo[2,3-h]quinazolin-2(1H)-one.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10](=[O:12])[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc2[nH]ccc12
Reaction time: 16 h

Procedure:
To a mixture of 1H-indole-4-carboxylic acid (322 mg, 2.00 mmol), tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (554 mg, 2.00 mmol), and diisopropylethylamine (700 μL, 4.00 mmol) in DMF (3 mL) was added HATU (950 mg, 2.50 mmol) and the solutions stirred for 16 h. The solvent was removed and the resulting residue was purified by silica gel chromatography, using a gradient of 70% to 100% EtOAc in hexanes as eluent and the solvent removed. This gave 557 mg (66%) of the product.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:17][CH2:16][CH2:15][C:9]2[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:32]1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3C)CC2)nn1-c1ccccc1

Procedure:
124 mg (66%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (100 mg, 0.413 mmol), 1-(2,3-dimethylphenyl)piperazine (79 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=2)[N:12]([CH3:21])[C:11]=1[CH3:22])=[O:9].B(Br)(Br)Br>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]([CH3:21])[C:11]=1[CH3:22])=[O:9]
Reactant: COc1ccc2c(C(=O)Nc3ccccn3)c(C)n(C)c2c1
Agent: BrB(Br)Br
Product: Cc1c(C(=O)Nc2ccccn2)c2ccc(O)cc2n1C

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid pyridin-2-ylamide 69a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (300 MHz, CD3OD) δ 8.29 (1H, m), 8.24 (1H, d, J=8.3 Hz), 7.82 (1H, m), 7.64 (1H, d, J=8.7 Hz), 7.12 (1H, m), 6.82 (1H, d, J=2.2 Hz), 6.76 (1H, dd, J=2.2, 8.7 Hz), 3.66 (3H, s), 2.69 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 282. found 282.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[N:5]1[CH:9]=[CH:8][N:7]2[CH2:10][CH2:11][C:12](=[O:13])[C:6]=12>C1COCC1>[C:1]([C:12]1([OH:13])[C:6]2=[N:5][CH:9]=[CH:8][N:7]2[CH2:10][CH2:11]1)#[CH:2]
Reactant: C#C[Mg]Br
Reactant: O=C1CCn2ccnc21
Solvent: C1CCOC1
Product: C#CC1(O)CCn2ccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethynylmagnesium bromide (0.5M in THF, 14.6 mL, 7.3 mmol) at 0° C. was added 5H,6H-pyrrolo[1,2-a]imidazol-7-one (900 mg, 4.86 mmol) in THF (10 mL) slowly. The reaction mixture was allowed to warm to RT and stirred for 1 hr. The reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and the organics were removed in vacuo. The product was extracted into EtOAc (10 mL×2) and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (Biotage), eluting with 3-10% methanol in DCM afforded the title product; 1H NMR (500 MHz, CDCl3) delta 2.55 (1H, s), 2.96 (1H, ddd, J=13.24, 7.57, 4.26 Hz), 3.03-3.12 (1H, m), 3.16-3.22 (1H, m), 4.01 (1H, ddd, J=10.56, 8.12, 4.33 Hz), 4.15 (1H, ddd, J=10.52, 7.29, 6.62 Hz), 6.84 (1H, d, J=1.10 Hz), 7.11 (1H, d, J=0.79 Hz); LC-MS: m/z=+136.9 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:12][C:13](=[NH:17])[NH:14][CH2:15][CH3:16])=[O:11].[CH3:18]OC(OC)N(C)C>CC#N>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:18]=[N:17][C:13]([NH:14][CH2:15][CH3:16])=[N:12][C:10]1=[O:11]
Reactant: CCNC(=N)NC(=O)Nc1ccccc1C
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC#N
Product: CCNc1ncn(-c2ccccc2C)c(=O)n1

Procedure:
To a magnetically stirred suspension of 9.02 g (35.2 mmol) of 1-(2-methylphenyl)-3-ethylamidinourea hydrochloride in 30 ml of CH3CN, was added 8.40 g (70.5 mmol) of N,N-dimethylformamide dimethylacetal and 20 ml of CH3CN. All of the solid dissolved. The reaction mixture was refluxed for two hours, allowed to come to ambient temperature, and partitioned between CHCl3 and H2O.
Reaction SMILES: Br[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=O.Br[C:10]1[CH:14]=[CH:13][NH:12][C:11]=1Br>>[NH:12]1[CH:13]=[CH:14][CH:10]=[C:11]1[CH:4]1[CH2:3][NH:2][C:6](=[O:7])[CH2:5]1
Reactant: Brc1cc[nH]c1Br
Reactant: O=C1CCC(=O)N1Br
Product: O=C1CC(c2ccc[nH]2)CN1

Procedure:
Alternatively, using the same experimental procedure and 2 equiv. of N-Bromo-succinimide, dibromopyrrole 237 can be obtained.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[CH:8]=[C:7]([NH2:23])[C:6]=1[NH2:24].[NH:30]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[N:31]1>>[F:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[C:6]2[N:24]=[C:35]([C:32]3[CH:33]=[CH:34][NH:30][N:31]=3)[NH:23][C:7]=2[CH:8]=[C:9]([O:11][C:12]2[CH:13]=[N:14][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[CH:10]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(N)c(N)c(Oc3c(F)cccc3F)c2)cn1
Reactant: O=Cc1cc[nH]n1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Oc3c(F)cccc3F)c3nc(-c4cc[nH]n4)[nH]c3c2)cn1

Procedure:
The entitled compound was obtained in the same method as in Example 202 or in accordance with the method or by combining it with an ordinary method but using 3-(2,6-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 268 and 1H-pyrazole-3-carboxaldehyde.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[CH2:2]1.Cl[C:18]1[N:19]([CH3:31])[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:23]=1.C(N(CC)CC)C>O1CCCC1>[CH3:31][N:19]1[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:23]=[C:18]1[N:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[CH2:2]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1
Yield: 58 %

Procedure:
A solution of N-(4-((2S)-morpholin-2-yl)phenyl)acetamide (2.63 g, 11.9 mmol), 2-chloro-1-methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidine (2.60 g, 11.9 mmol), and triethylamine (3.60 g, 35.7 mmol) in tetrahydrofuran (100 ml) was stirred at 95° C. for one hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to afford N-(4-((2S)-4-(1-Methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidin-2-yl)morpholin-2-yl)phenyl)acetamide (2.8 g, 58%) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.52 g, 2.59 mmol) in anhydrous CH2Cl2 (5 mL) under argon were added acetic anhydride (0.37 mL, 3.89 mmol) and Pyridine (0.31 mL, 3.89 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with saturated 1N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.62 g, 100%) as a white solid. 1H NMR (CDCl3) δ: 1.46 (d, J=7.0 Hz, 3H), 1.99 (s, 3H), 5.03-5.12 (m, 1H), 5.68 (brs, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H). ESIMS (MNa+): 264.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13]>>[CH3:9][C:10]1[CH:11]=[C:12]([NH:13][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:8])[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1ccc(N)cc1C
Reactant: N#Cc1ccccc1
Product: Cc1ccc(NC(=N)c2ccccc2)cc1C
Yield: 77.8 %

Procedure:
The title compound was prepared from benzonitrile (4.25 g, 41 mmol) and 3,4-dimethylaniline (5 g, 41 mmol) by following the procedure described in preparation 10 (7.2 g, yield 77.8%, purity 99.8% by HPLC). 1H-NMR (CDCl3):δ 2.24-2.25 (d, 6H), 4.84 (bs, 2H, D2O exchangeable), 6.73-6.75 (d, 1H), 6.79 (s, 1H), 7.1-7.11 (d, 1H), 7.41-7.49 (m, 3H), 7.86-7.88 (d, 2H). MS m/z:225.2 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:6]([CH3:12])=[N:7]2.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:23][CH2:12][C:6]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Cc1nc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2nc1CBr
Temperature: 25 °C
Reaction time: 21.5 h

Procedure:
5-Chloro-2-methyl-3-(2-(trifluoromethyl)phenyl)quinoxaline (1.4455 g, 4.479 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.6404 g, 2.240 mmol) were suspended in carbon tetrachloride (44.79 mL, 4.479 mmol). To the mixture was added benzoyl peroxide (0.1447 g, 0.4479 mmol) and the mixture was heated at reflux. After 21.5 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 9% gradient of EtOAc in hexane over 2 min, then 9% isocratic of EtOAc for 13 min, then 9 to 100% gradient of EtOAc in hexane over 23 min, then 100% isocratic of EtOAc for 4 min as eluent to give 2-(bromomethyl)-5-chloro-3-(2-(trifluoromethyl)-phenyl)quinoxaline as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (1 H, dd, J=8.4, 1.4 Hz), 8.13 (1 H, dd, J=7.8, 1.2 Hz), 7.81-8.03 (5 H, m), 4.69 (2 H, dd, J=88.4, 10.2 Hz); LC-MS (ESI) m/z 400.9 and 403.0 [M+H]+.