Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[S:3][C:4]=3[N:5]=2)[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc4nc(N)sc4n3)c2)c1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc4nc(NC(=O)C5CC5)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (139 mg, 324 μmol) in pyridine (4 mL) was added cyclopropanecarbonyl chloride (59 μL, 648 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→30/70), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (96 mg, 59%) as colorless crystals.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:10]([C:11]([NH:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1)=[O:12])[CH:9]=[C:8]2[Cl:23])CCC.C(C1C=C2C(=CC=1)N=C(C(Cl)=O)C=C2Cl)CCC.NC1NN=NN=1>>[Cl:23][C:8]1[C:7]2[C:20](=[CH:21][CH:22]=[CH:5][CH:6]=2)[N:19]=[C:10]([C:11]([NH:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:12])[CH:9]=1
Reactant: CCCCc1ccc2nc(C(=O)Nc3nnn[nH]3)cc(Cl)c2c1
Agent: CCCCc1ccc2nc(C(=O)Cl)cc(Cl)c2c1
Agent: Nc1nnn[nH]1
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1

Procedure:
In a similar manner 6-butyl-4-chloro-N-(1H-tetrazol-5-yl)quinaldamide, m.p. 275° was prepared from 6-butyl-4-chloroquinaldoyl chloride and 5 -aminotetrazole.
Reaction SMILES: C([O:3][C:4](=[O:33])/[C:5](/[CH3:32])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:29]3[CH2:31][CH2:30]3)[C:18]3[O:25][C:22]4([CH2:24][CH2:23]4)[C:21]([CH3:26])=[C:20]([CH3:27])[C:19]=3[CH:28]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH:29]1([C:17]2[C:18]3[O:25][C:22]4([CH2:24][CH2:23]4)[C:21]([CH3:26])=[C:20]([CH3:27])[C:19]=3[CH:28]=[C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7](/[CH:6]=[C:5](\[CH3:32])/[C:4]([OH:33])=[O:3])=[CH:12][CH:11]=3)[CH:16]=2)[CH2:30][CH2:31]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(C#Cc2cc3c(c(C4CC4)c2)OC2(CC2)C(C)=C3C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(C)C2(CC2)Oc2c1cc(C#Cc1ccc(/C=C(\C)C(=O)O)cc1)cc2C1CC1
Temperature: 55 °C

Procedure:
A solution of (E)-3-{4-[8-cyclopropyl-3,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl]ethynyl-phenyl}-2-methyl-acrylic acid ethyl ester (Intermediate 3, 0.06 g, 0.13 mmol) in ethanol (2 mL) was treated with a 1M solution of sodium hydroxide (0.5 mL, 0.5 mmol) and the resulting reaction mixture was heated at 55° C. for 4 h. The reaction mixture was cooled to ambient temperature and the volatiles were evaporated in vacuo to a residue that was neutralized with 5% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid after flash column chromatography over silica gel (230-400 mesh) (0.044 g, 82%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[N:6]1([C:17](=[O:18])[C:16]2[NH:15][CH:14]=[N:13][C:12]=2[N:10]([CH3:11])[C:8]1=[O:9])[CH3:7].[Na]>CN(C)C=O>[CH3:7][N:6]1[C:17](=[O:18])[C:16]2[N:15]([CH2:2][CH2:3][CH:4]=[CH2:5])[CH:14]=[N:13][C:12]=2[N:10]([CH3:11])[C:8]1=[O:9]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: C=CCCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: C=CCCn1cnc2c1c(=O)n(C)c(=O)n2C
Reaction time: 7 h

Procedure:
13.9 g of 4-bromo-but-1-ene are reacted with 20.2 g of sodium theophylline in 200 ml of dimethyl-formamide at 120° C. with stirring for approximately 6 to 8 hours until the reaction is complete as indicated by thin-layer chromatography. The solvent is then removed under reduced pressure. The residue is dissolved at 20° C. in 100 ml of methylene chloride, separated from insoluble sodium bromide and purified through a column packed with neutral aluminum oxide to remove small quantities of dark-coloured accompanying substances. Melting point: 110° C. (acetone); yield: 21.6 g (91% of theory relative to the starting material used). After thin-layer chromatography on Merck DC finished plates of silica gel 60 F254 with benzene/acetone (6:4) as eluent, the product has an Rf value of 0.54; and with nitromethane/benzene/pyridine (20:10:3) as eluent, an Rf value of 0.65. Utra-violet light was used as indicator, the pyridine of the eluent having, however, to be removed at 50° C. under reduced pressure because of its property to extinguish fluorescence.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
A solution of bis-(4-bromophenyl)methanone (406 mg, 1.19 mmol) in THF (12 mL) is cooled to 0° C., treated portion-wise with sodium borohydride (37.8 mg, 0.893 mmol), and stirred at RT overnight. The reaction mixture is again cooled to 0° C., then quenched with 1 N HCl. Water is added, and the mixture is extracted with ethyl acetate (3×). The combined organic layers are dried and concentrated to give bis-(4-bromophenyl)methanol (410 mg, in excess of theoretical yield) as a crude residue to be used as is.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[N:10]=[C:9]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:8](S(C(F)(F)F)(=O)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH2:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]([C:3]1[C:11]2[NH:10][C:9]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2S(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylbenzimidazole (1.42 g, 3.29 mmol) and anhydrous methanol (20 ml). This solution was cooled to 0° C. and potassium carbonate (911 mg, 6.59 mmol) was added. The resulting mixture was stirred for two hours at 0° C., permitted to warm to room temperature, and stirred at this temperature for about three days. The progress of the reaction was monitored by thin layer chromatography. The desired title product was further purified by radial chromatography.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.O>CN(C)C=O>[N:3]1([C:8]2[N:9]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1ccc2[nH]c(N3CCCC3)nc2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (402 mg, 11 mmol) was added to a suspension of 2-pyrrolidino-1H-benzimidazole (1.9 g, 10.1 mmol) in dry N,N-dimethylformamide (30 mL). All solids dissolved. The solution was allowed to stir at ambient temperature for 15 minutes following the cessation of foaming. The solution was cooled to 5° C. and a solid formed. Methyl 4-(bromomethyl)benzoate (2.1 g, 01 mol) was added to the suspension and all the solids dissolved. The solution was allowed to stir at ambient temperature and a solid formed. The mixture was stirred at ambient temperature overnight and then it was poured into cold water. A solid was isolated by filtration, washed with water and dried to provide 3.0 g of crude product as an off-white solid. This material was recrystallized from methanol to provide methyl 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoate. Analysis: Calculated for C20H21N3O2: % C, 71.62; % H, 6.31; % N, 12.53. Found: % C, 71.44; % H, 6.41; % N, 12.50.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:24])[CH:18]=1.I[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:26]([CH3:28])[CH3:27])=[C:19]([OH:24])[CH:18]=1
Reactant: CC(C)I
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 70 °C
Yield: 70.8 %

Procedure:
To a solution of (4Z)-6-bromo-4-{[(3,4-dihydroxybenzyl)-amino]methylene}isoquinoline-1,3(2H,4H)-dione (0.74 g, 1.9 mmol) in 5 mL of N,N′-dimethylformamide is added 2-iodopropane (0.19 mL, 1.9 mmol) and 0.52 g (3.8 mmol) of potassium carbonate. The reaction mixture is heated at 70° C. under N2. Mass spectroscopy indicated the completion of reaction after 3.5 h. The reaction mixture is filtered through a pad of celite, and water is added to give a precipitate. It is filtered and washed successively with MeOH, Et2O and hexane, dried in oven (60° C.) overnight to afford 0.58 g (70.7% yield) of tan solid: mp 212-213° C.; MS (ESI) m/z 431.2 and 433.2 (M+H)+1
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10]Br)=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22](=[N:30][OH:31])[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>CN(C)C=O>[F:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][O:31][N:30]=[C:22]([C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])[CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:6][CH:5]=1
Reactant: ON=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reactant: Fc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OCCON=C(Cc2cccnc2)c2ccc(Cl)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
0.55 g of sodium hydride dispersion (50% in oil) and then 2.20 g of 2-(4-fluorophenoxy)ethyl bromide are added with stirring to a solution of 2.81 g of 2',4'-dichloro-2-(3-pyridyl)acetophenone oxime in 20 ml of dimethylformamide. The reaction mixture is heated to 100° C. and stirred at this temperature for 1 hour. It is then cooled to room temperature and poured onto ice. The aqueous mixture is extracted with methylene chloride, and the organic phase is washed twice with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After chromatography on silica gel using n-hexane/ethyl acetate (7:3) as the eluent, 2',4'-dichloro-2-(3-pyridyl)acetophenone O-[2-(4-fluorophenoxy)ethyl]oxime is obtained as an E/Z isomer mixture in the form of a slightly yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[CH:14]2[CH2:16][CH2:15]2)=[N:12]/[OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:20][C:21]1[C:22]([CH3:33])=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1.CN(C)C=O>C1(C)C=CC=CC=1>[CH3:33][C:22]1[C:21]([CH2:20][O:13]/[N:12]=[C:11](/[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=2)\[CH:14]2[CH2:16][CH2:15]2)=[CH:26][CH:25]=[CH:24][C:23]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1c(CCl)cccc1-c1ccccc1
Reactant: CC(C)(C)c1ccc(/C(=N/O)C2CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(CO/N=C(/c2ccc(C(C)(C)C)cc2)C2CC2)cccc1-c1ccccc1

Procedure:
In a manner similar to Example 2, the reaction of 0.75 g (0.0034 mole) of (E)-(4-t-butylphenyl)(cyclopropyl)methanone oxime with 0.2 g (0.008 mole) of sodium hydride and 0.74 g (0.0034 mole) of 3-chloromethyl-2-methyl[1,1'-biphenyl] in 25 ml of a 20% solution of N,N-dimethylformamide in toluene produced (E)-(4-t-butylphenyl)(cyclopropyl)methanone O-[(2-methyl[1,1'-biphenyl]-3-yl)methyl]oxime as an oil.
Reaction SMILES: [F-].[K+].[OH:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.F[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[N:27]4[N:28]=[C:29]([N:32]5[CH2:36][CH2:35][CH2:34][C@@H:33]5[C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=5)[CH:30]=[CH:31][C:26]4=[N:25][CH:24]=3)[N:18]=2)[CH:14]=[CH:13][N:12]=1>CS(C)=O>[F:43][C:39]1[CH:38]=[C:37]([C@H:33]2[CH2:34][CH2:35][CH2:36][N:32]2[C:29]2[CH:30]=[CH:31][C:26]3[N:27]([C:23]([C:19]4[N:18]=[C:17]([C:15]5[CH:14]=[CH:13][N:12]=[C:11]([N:7]6[CH2:8][CH2:9][CH:4]([OH:3])[CH2:5][CH2:6]6)[CH:16]=5)[CH:22]=[CH:21][CH:20]=4)=[CH:24][N:25]=3)[N:28]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(-c5ccnc(F)c5)n4)n3n2)c1
Reactant: OC1CCNCC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: OC1CCN(c2cc(-c3cccc(-c4cnc5ccc(N6CCC[C@@H]6c6cccc(F)c6)nn45)n3)ccn2)CC1

Procedure:
In step 16-4, potassium fluoride (10 g, 175 mmol) and 4-hydroxypiperidine (10.6 g, 105 mmol) were added to a solution of crude (R)-3-(2′-fluoro-2,4′-bipyridin-6-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (16-3) (16.1 g, 35 mmol) in DMSO (100 mL). The mixture was heated overnight to 120° C. (approx. 14 hours). The mixture was filtered through a celite pad and rinsed with EtOAc (1 L). The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated to give a dark oil. The mixture was purified by column chromatography (silica gel, CH2Cl2/CH3OH, gradient 5% to 15%) to yield (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,4′-bipyridin-2′-yl)piperidin-4-ol (16-4) which was crashed out from CH2Cl2, filtered and dried under high vacuum. 1H NMR (400 MHz, DMSO, ppm): δ 8.30 (s, 1H), 8.22 (d, 1H, J=5.2 Hz), 8.10-8.24 (bs, 1H), 7.90-7.98 (m, 2H), 7.76-7.86 (bs, 1H), 7.52 (s, 1H), 7.40 (q, 1H, J=7.4 Hz), 7.34 (d, 1H, J=5.2 Hz), 7.04 (t, 1H, J=8 Hz), 6.80-6.94 (bs, 1H), 5.19 (d, 1H, J=8 Hz), 4.71 (d, 1H, J=4 Hz), 4.10-4.18 (m, 2H), 3.93-4.06 (m, 1H), 3.65-3.75 (m, 2H), 3.10-3.20 (m, 2H), 1.98-2.10 (m, 2H), 1.78-1.92 (m, 3H), LC/MS: 536.2 (M+H+), 1.34-1.45 (m, 2H). 13C NMR (400 MHz, DMSO, ppm): 163.53, 161.11, 159.53, 153.95, 151.76, 148.27 (d, J=34.7 Hz), 147.69, 147.10 (d, J=25.6 Hz), 146.92, 137.61, 133.14 (d, J=23.2 Hz), 130.34 (d, J=32.4 Hz), 126.54, 126.04, 121.56, 119.26, 118.75, 113.40 (d, J=83.6 Hz), 112.41 (d, J=86.0), 110.26, 109.86, 103.75, 66.34, 61.24, 48.37, 42.72, 35.12, 33.71, 22.65.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[CH3:1][CH:2]([CH2:10][CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: CCC(C)Cc1ccccc1
Solvent: CC(=O)O
Product: CCC(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
(+)-2-Methylbutylbenzene, prepared according to the procedure of Example 2, (0.75 mol, 111.0 gm) was added to 200 ml glacial acetic acid. This solution was added dropwise to a mixture of 420 ml 90% fuming nitric acid and 180 ml glacial acetic acid, which had been cooled at -20° C. Maintaining that temperature, the mixture was stirred for one hour and then poured into 2.5 l of ice water. The reaction products were extracted with 2-500 ml portions of petroleum ether (30°-60° C.) and the combined extracts were successively washed with water (2-100 ml portions); 5% sodium hydroxide (2-100 ml portions), 10% sodium hydroxide (2-100 ml portions); and water (3-100 ml portions). The extract was dried over anhydrous calcium sulfate, the solvent was removed under reduced pressure and the resultant light yellow oil fractionated under reduced pressure. The fraction boiling at 158°-160° C. (14 mm Hg) was collected, giving a 38% yield of the product. The structure was confirmed by NMR.
Reaction SMILES: CC1C=C(C(OC)=O)C(C(OC)=O)=NC=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:36][CH:37](Br)[C:38]1[CH:39]=[C:40]([C:48]([O:50][CH3:51])=[O:49])[C:41]([C:44]([O:46][CH3:47])=[O:45])=[N:42][CH:43]=1>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:37][C:38]1[CH:39]=[C:40]([C:48]([O:50][CH3:51])=[O:49])[C:41]([C:44]([O:46][CH3:47])=[O:45])=[N:42][CH:43]=1
Reactant: COC(=O)c1cc(C(Br)Br)cnc1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: COC(=O)c1cc(C)cnc1C(=O)OC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)cnc1C(=O)OC
Temperature: 80 °C
Yield: 57 %

Procedure:
A mixture of dimethyl 5-methyl-2,3pyridinedicarboxylate (30.0 g, 0.143 mol), N-bromosuccinimide (32.0 g, 0.18 mol) and 2,2'-azobisisobutyronitrile (0.9 g, 0.0055 mol) in carbon tetrachloride (200 mL) is heated at 80° C. for 1.5 hours. Additional 2,2'-azobisisobutyronitrile (0.9 g, 0.0055 mol) is added and the reaction mixture is heated at reflux for 2 hours, cooled to room temperature and filtered. The filter cake is washed with carbon tetrachloride. The filtrate and wash are combined, washed with water and concentrated in vacuo to give an oil. The oil is shown by HPLC to contain 57% of the title product, 16% dimethyl 5-methyl-2,3-pyridinedicarboxylate and 23% dimethyl 5-dibromomethyl-2,3-pyridinedicarboxylate.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][C@H:19]([NH:23]C(OC(C)(C)C)=O)[C:20](O)=O.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:52]>C(Cl)Cl.O>[ClH:52].[ClH:52].[Br:1][C:2]1[C:3]2[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:18]([C@@H:19]([NH2:23])[CH3:20])=[N:10][C:4]=2[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(N)c(Nc2ccccc2)c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc2nc([C@H](C)N)n(-c3ccccc3)c2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 181.8 %

Procedure:
To a solution of 3-bromo-4-methoxy-N2-phenylbenzene-1,2-diamine (421 mg, 1.8 mmol), Boc-ala-OH (343 mg, 1.8 mmol) and HOAT (247 mg, 1.8 mmol) in DCM (10 mL) at 0° C. was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (383 mg, 1.99 mmol) and the reaction mixture stirred at 0° C. for 1 h. The reaction mixture was diluted with water and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in HCl in dioxane (10 mL, 4 M) and the reaction mixture heated at 75° C. for 1 h. The reaction mixture was concentrated in vacuo to give the title product as a dark purple solid (758 mg, 100%). LCMS (Method C): RT=2.15 min, [M+H]+=346 & 348.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]#[C:26][C:27](O)=[O:28]>ClCCl.CO>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:27](=[O:28])[C:26]#[C:25][C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][C:15]=2[Cl:14])=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)Cc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 4-diethylaminomethylphenylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 72 mg (59% of theory); C21H20ClF3N2O (M=408.85); calc.: molecular ion peak (M+H)+: 409/411; found: molecular ion peak (M+H)+: 409/411; Rf value: 0.35 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([NH:17][CH:18](O)[CH3:19])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOCC.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(O)NC(=O)OC(C)(C)C
Reactant: Cc1cc(O)ccc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1cc(OCCNC(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-3-methylphenol (0.187 g; 1.00 mmol), N-Boc aminoethanol (0.39 mL; 2.5 mmol) and PPh3 (0.655 g; 2.5 mmol) in anhyd PhH (5 mL) at 0° C. was added DIAD (0.49 mL; 2.5 mmol), dropwise over 15 min. The mixture was stirred 16 h at room temperature, diluted with Et2O, washed (2×satd Na2CO3, 2×H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum, which solidified on standing. LC/MS (method A) tR 2.95 min, m/z 330, 332 (M+H, Br isotopes, 2%), 352, 354 (M+Na, Br isotopes, 40-43%), 230, 232 ([M−Boc]+H, Br isotopes, 100%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.Cl[CH:18]1[C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=2[F:28])[O:21][CH2:20][CH2:19]1>>[F:28][C:26]1[CH:25]=[C:24]([F:29])[CH:23]=[C:22]2[C:27]=1[CH:18]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=3[CH:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=1)[CH2:19][CH2:20][O:21]2
Reactant: COC(=O)c1cc(O)c2nc(C)n(C)c2c1
Reactant: Fc1cc(F)c2c(c1)OCCC2Cl
Product: COC(=O)c1cc(OC2CCOc3cc(F)cc(F)c32)c2nc(C)n(C)c2c1
Yield: 59 %

Procedure:
The title compound was prepared as a white solid in 59% yield (3.2 g) from methyl 4-hydroxy-1,2-dimethyl-1H-benzimidazole-6-carboxylate (3.0 g, 14 mmol, WO 2004054984) and 4-chloro-5,7-difluorochromane (4.7 g, 21 mmol, STEP 2 of Example 5) by the same manner in STEP 1 of Example 11.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>Cl.O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)=[CH:8][N:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(C2=CCNCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
A mixture of tert-butyl 4-(6-nitropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate 200a (2.0 g, 6.6 mmol) in HCl/dioxane (20 mL, 4M) was stirred at room temperature for 2 hours. It was then evaporated under reduced pressure. The residue was washed with ethyl acetate (3×7 mL) to afford 232a as a yellow solid (1.0 g, 74%). MS-ESI: [M+H]+ 206.