Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.S1C=CC(C=O)=C1C=O.Br[C:13]1[C:14]([CH:21]=[O:22])=[C:15]([CH:19]=[O:20])[S:16][C:17]=1[Br:18].C(Cl)Cl>C(O)(=O)C>[Br:18][C:17]1[S:16][C:15]([CH:19]=[O:20])=[C:14]([CH:21]=[O:22])[CH:13]=1
Reactant: O=Cc1sc(Br)c(Br)c1C=O
Agent: BrBr
Agent: O=Cc1ccsc1C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=Cc1cc(Br)sc1C=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Bromine (1.2 mL, 7.5 mmol) was added drop wise to a solution of 2,3-thiophenedicarboxaldehyde (1.0 g, 7.1 mmol) in 20 mL of glacial acetic acid. The reaction mixture was stirred overnight at 70° C. and then excess bromine was quenched with a saturated solution of Na2S2O3. The organic layer was extracted with CH2Cl2, dried over Na2SO4 and volatiles were removed in vacuo to obtain a mixture of 1 and 4,5-dibromo-2,3-thiophenedicarboxaldehyde 2 as a brown solid (30:65 by 1H NMR spectroscopy). Spectroscopically pure compound was isolated by column chromatography using silica gel as stationary phase and a 4:1 mixture of CH2Cl2:hexanes. 1H NMR (500 MHz, CDCl3): δ 10.37 (s, 1H), 10.26 (s, 1H), 7.59 (s, 1H). 1H NMR data for 4,5-dibromo-2,3-thiophenedicarboxaldehyde (500 MHz, CDCl3): δ 9.81 (s, 1H), 7.36 (s, 1H).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[CH2:9]Br.C(=O)(O)[O-].[Na+].[CH2:21]([C:28]1[NH:29][C:30]2[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:34]=[CH:33][C:31]=2[N:32]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(OCC)(=O)C>[CH2:21]([C:28]1[N:32]([CH2:9][C:8]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:7]=2[Cl:6])[C:31]2[CH:33]=[CH:34][C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][C:30]=2[N:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: CCOC(=O)c1ccc2nc(Cc3ccccc3)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 14 %

Procedure:
N,N-dimethylformamide (15 ml), 2,4-dichlorobenzyl bromide (4.45 g) and sodium bicarbonate (1.23 g) are added to 2-benzyl-5-ethoxycarbonyl-benzimidazole (2.37 g) (example 11) and the solution is heated for one hour at 60° C. After adding ethyl acetate (70 ml) and water (70 ml) and separating the solution, the organic layer is washed with water three times and extraction is performed on the aqueous layer using ethyl acetate three times. By concentrating the obtained organic layer under reduced pressure, a mixture of 2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonylbenzimidazole (0.49 g) and 2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonylbenzimidazole (0.52 g) is obtained. Separation and purification is performed using medium pressure silica gel column chromatography (eluate: hexane/ethyl acetate=1/4˜0/100).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].I[CH2:29][CH:30]([OH:33])[CH2:31][OH:32].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([O:25][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC(O)CI
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OCC(O)CO)c1

Procedure:
A solution of 7.34 g. of 4-(hexadecylamino)-2-thiophenecarboxylic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(hexadecylamino)-2-thiophenecarboxylate as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7](/[C:10](=[N:18]/[NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])/[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O1CCCC1.[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]2[N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[N:18]=[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)[C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)N1CCC(/C(Cc2ccncn2)=N/NS(=O)(=O)c2ccc(C)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nn(S(=O)(=O)c3ccc(C)cc3)c(-c3ccc(Cl)cc3)c2-c2ccncn2)CC1

Procedure:
This reaction was carried out in a 100 ml round bottom flask. N′-[(1E)-1-(1-acetylpiperidin-4-yl)-2-pyrimidin-4-ylethylidene]-4-methylbenzenesulfonohydrazide (7) (5g, 11 mmol) was charged to the reactor, followed by tetrahydrofuran (“THF”, 31 ml), which, in turn, was followed by 2.15 ml of triethylamine (“TEA”, 2.15 ml) and 4-dimethylaminopyridine (“DMAP”, 0.134 g). 4-Chlorobenzoyl chloride (8) (“4-CBC”, 2.09 ml) was then charged all at once while stirring the mixture. The reaction was brought to reflux. Liquid chromatography indicated that the reaction was complete in just over 1 hr. The solution was washed with saturated ammonium chloride (2×25 ml), and the THF was removed in vacuo to yield a yellow oil (11.18 g), which solidified upon sitting. Recrystallization from ethanol/water yielded 4.88 g of a white powder (76% yield). The product had the following characteristics: 1H NMR (CDCl3, 300 MHz) δ 9.20 (1H, s), 7.63 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.1 Hz), 7.29 (1H, s), 7.21 (2H, d, J=8.4 Hz), 6.64 (1H, d, J=5.1 Hz), 4.71–4.52 (1H, m), 4.01–3.82 (1H, m), 3.59–3.44 (1H, m), 3.28–3.08 (1H, m), 2.84–2.58 (1H, m), 2.46 (3H, s), 2.16 (3H, s), 2.02–1.62 (4H, m). 13C NMR (CDCl3, 75 MHz) δ 169.11, 158.91, 146.39, 136.80, 134.55, 132.01, 130.13, 129.19, 126.72, 34.91, 31.15, 22.01, 21.69.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[NH:4][C:5](=[NH:8])[O:6][CH3:7].[C:11]([N:15]=[C:16]=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][N:2]([CH3:10])[C:3]([N:4]=[C:5]([O:6][CH3:7])[NH:8][C:16]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:9]
Reactant: CC(C)(C)N=C=O
Reactant: COC(=N)NC(=O)N(C)C
Product: COC(=NC(=O)N(C)C)NC(=O)NC(C)(C)C

Procedure:
5 Parts of methyl 4,4-dimethylallophanimidate and 20 ml of t-butylisocyanate are refluxed overnight. The next day, the solution is evaporated to give an oil, which crystallizes when tirturated with petroleum-ether under cooling. In order to remove some unreacted starting material and byproducts, the solids are first triturated with water and filtered. After drying, the solids are then triturated with carbon tetrachloride and impurities removed by filtration. The carbon tetrachloride filtrate is then evaporated and the residue recrystallized from petroleum-ether to give pure methyl N-dimethylcarbamoyl-4-t-butylallophanimidate (a compound of Formula I), m.p. 96°-98° C.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20].O>CN(C)C=O>[CH3:5][N:4]([CH3:6])/[CH:3]=[CH:9]/[C:10]1[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1c([N+](=O)[O-])cccc1C(F)(F)F
Temperature: 110 °C

Procedure:
3.5 ml of DMF-DMA (N,N-dimethylformamide-dimethyl acetal) are added to a solution of 1 g of 2-methyl-3-nitrobenzotrifluoride in 6 ml of N,N-dimethylformamide. The reaction medium is heated at 110° C. until the starting material has disappeared, then poured into water and extracted with ethyl acetate. The organic phases are washed successively with a 10% sodium bicarbonate solution, a 10% ammonium chloride solution and a saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure so as to give 1.2 g of dimethyl[(E)-2-(2-nitro-6-trifluoromethylphenyl)vinyl]amine in the form of an oil which is used in the next step.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:7][C:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:26][CH:25]=1)([C:13]([F:23])([F:22])[C:14](=[O:21])[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([F:12])([F:11])[F:10])=[O:6])([CH3:4])[CH3:3].[H-].[Na+].[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46]Br)=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[CH2:46]([N:7]([C:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:35])[F:36])=[CH:26][CH:25]=1)([C:13]([F:22])([F:23])[C:14](=[O:21])[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([F:10])([F:11])[F:12])[S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])[C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)S(=O)NC(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N(Cc1ccccc1)C(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
A solution of Intermediate 103D (461 mg, 0.814 mmol) in anhydrous DMF (0.5 mL) was added to a suspension of NaH (65 mg, 1.627 mmol) (60% in mineral oil) at 0° C. After stirring for 5 min, BnBr (0.484 mL, 4.07 mmol) was added. The reaction mixture was warmed to rt and stirred for 1 h. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (4 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (260 mg, 44%) as a yellow gum. 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J=8.5 Hz, 2H), 7.33-7.27 (m, 3H), 7.14 (dd, J=7.3, 2.1 Hz, 2H), 6.80 (d, J=9.1 Hz, 2H), 4.46-4.38 (m, 2H), 4.00-3.95 (m, 2H), 3.72 (br. s., 1H), 3.51 (br. s., 1H), 3.35-3.10 (m, 2H), 2.37-2.25 (m, 2H), 2.09-1.99 (m, 2H), 1.70-1.39 (m, 6H), 1.34-1.29 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:20]([Mg]Br)#[C:21][CH3:22].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:20]#[C:21][CH3:22])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: CC#C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CC(O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a cold (−78° C.) suspension of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (1.50 g, 5.47 mmol) in tetrahydrofuran (10 mL) was added 1-propynyl magnesium bromide (12.0 mL, 0.5 M in tetrahydrofuran, 6.02 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then at 0° C. for 2 hours. The resultant solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) provided 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-ol (1.3 g, 72%) as a white solid. Rf 0.44 (2:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 7.99 (d, 1H), 7.78 (m, 2H), 7.14 (m, 3H), 6.95 (d, 1H), 5.70 (m, 1H), 2.21 (d, 1H), 1.85 (d, 3H); MS m/z 315 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](/[CH:14]=[N:15]/[NH:16][C:17]3[N:22]=[CH:21][C:20]([C@H:23]([N:28]4[CH2:32][CH2:31][C@@:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:33])[CH2:29]4)[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][C:5]=1[F:42])[CH3:2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:22]4[CH:21]=[C:20]([C@H:23]([N:28]5[CH2:32][CH2:31][C@@:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:33])[CH2:29]5)[C:24]([F:27])([F:25])[F:26])[CH:19]=[CH:18][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:42])[CH3:2]
Reactant: CCOc1cc2nc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CCOc1cc2nc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Yield: 85.8 %

Procedure:
A solution of tert-butyl (S)-1-((S)-1-(6-((E)-2-((7-ethoxy-6-fluoroquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ylcarbamate (6.320 g, 10.70 mmol) and iodobenzene diacetate (3.447 g, 10.70 mmol) in DCM (50 mL) was stirred overnight at ambient temperature. The reaction was concentrated under reduced pressure and the residue subjected to chromatography (10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes over 4 column volumes) to give tert-butyl (S)-1-((S)-1-(3-(7-ethoxy-6-fluoro quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ylcarbamate (5.406 g, 9.18 mmol, 85.83% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=1[OH:44]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=1[OH:44]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CN1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(NCC4CCN(C)CC4)c3c2)cc(Cl)c1O
Yield: 44.1 %

Procedure:
Following general procedure F, {6-bromo-4-[(1-methylpiperidin-4-yl)methylamino]quinolin-3-yl}(cyclopropyl)methanone (63 mg, 0.156 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (53 mg, 0.187 mmol) to afford the desired product (33 mg, 44%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.12 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 7.99 (dd, J=8.7, 1.9 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 3.98 (s, 3H), 3.84 (d, J=6.7 Hz, 2H), 3.20-3.13 (m, 2H), 2.87-2.80 (m, 1H), 2.51 (s, J=10.3 Hz, 3H), 2.46 (t, J=11.6 Hz, 2H), 1.97 (d, J=13.2 Hz, 2H), 1.90 (s, 1H), 1.53-1.40 (m, 2H), 1.24-1.17 (m, 2H), 1.14-1.07 (m, 2H); ESI MS m/z [C27H30ClN3O3+H]+; HPLC>99% (AUC), tR=8.32 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:21][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1.C[Mg]Br.[F:25][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>O1CCCC1>[F:25][C:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:21][C:13]=1[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: COc1ccc2c(c1)c(-c1cc3cccnc3[nH]1)cn2C
Agent: C[Mg]Br
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(-c1[nH]c3ncccc3c1F)cn2C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
A solution of 2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine [0.1 g, Example 17(a)] in dry tetrahydrofuran (4 mL), at 0° C., was treated with methyl magnesium bromide (0.042 mL) and after stirring for a further 20 minutes at 0° C. this mixture was treated with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate) (0.13 g). The reaction mixture was stirred at room temperature for 4 hours, then stood at room temperature overnight, then heated at 40° C. for 4 hours, then heated at 80° C. for 2 hours, then cooled to room temperature and then partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate (25 mL). The combined extracts and ethyl acetate layer from the partitioning were washed with brine, then dried over magnesium sulfate and then evaporated. The residue was triturated with ethyl acetate to give the title compound (0.057 g) as a white solid, m.p. 248-250° C. 1H NMR [(CD3)2SO]: δ 12.20 (1H, s); 8.24 (1H, m); 7.81 (1H, s); 7.79 (1H, d, J=9.6 Hz); 7.46 (1H, d, J=9.6 Hz); 7.27 (1H, s); 7.18 (1H, dd, J=13.1, 6.0 Hz); 6.90 (1H, d, J=9.6 Hz); 3.88 (3H, s); 3.80 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]2[CH2:25][CH2:24]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.Br[CH2:34][C:35]#[N:36].CCN(C(C)C)C(C)C>>[CH2:26]([N:22]([CH:23]1[CH2:25][CH2:24]1)[CH2:21][CH2:20][CH2:19][CH2:18][N:10]([CH2:9][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][CH2:34][C:35]#[N:36])[CH:8]=[CH:7][N:6]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N(CCCCN(Cc1ccccc1)C1CC1)Cc1cc(CN)ccn1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCCCN(Cc1ccccc1)C1CC1)Cc1cc(CNCC#N)ccn1

Procedure:
By General Procedure T from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N-{4-[benzyl(cyclopropyl)amino]butyl}carbamate (1 equiv.) and bromoacetonitrile (1.1 equiv.), using 2 equiv. DIPEA. Aqueous work up gave the title product, which was used without further purification.
Reaction SMILES: Cl(O)(=O)(=O)=O.CO[CH:8]=[C:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1.Cl.[CH2:18]([O:20][NH2:21])[CH3:19]>C(Cl)(Cl)Cl.CO.O>[CH2:18]([O:20][N:21]=[CH:8][CH:9]1[CH:14]2[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]2)[CH2:10]1)[CH3:19]
Reactant: CCON
Reactant: COC=C1CN2CCC1CC2
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCON=CC1CN2CCC1CC2
Reaction time: 1 h

Procedure:
4.8 cm3 of a 70% aqueous solution of perchloric acid is added at ambient temperature to 2 g of 3-methoxy methylidene quinuclidine in solution in 20 cm3 of chloroform. After agitating for one hour, 1.4 g of O-ethylhydroxylamine hydrochloride in 2.5 cm3 of methanol and 2.5 cm3 of water are added, and the reaction medium is maintained in this way for one night. After concentrating, alkalizing with sodium hydroxide, extracting with ethyl acetate, and distilling at 135° C. under 0.05 mbar, 2.05 g of expected product is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:49][Cl:50]>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:49][Cl:50])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)OCCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoic acid (2.0 g, 5.0 mmole) in 1,4-dioxane (20 ml) was added a 40% solution of tetrabutylammonium hydroxide (3.1 g, 4.75 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and coevaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in dichloromethane (10 ml) and iodochloromethane (13.2 g, 75 mmole) was added The solution was stirred overnight at room temperature and evaporated under reduced pressure. About 50 ml ethyl acetate were added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.5 g=23%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([OH:23])[CH:20](O)[CH3:21].CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+]>CC1C=CC=CC=1.C(O)CCC>[CH3:21][CH:20]1[CH2:19][O:23][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9]1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: CC1COC(c2ccccc2)(c2ccc(N)c([N+](=O)[O-])c2)O1

Procedure:
A solution of 31.5 parts of (4-amino-3-nitrophenyl)phenylmethanone, 15.2 parts of 1,2-propanediol and 5 parts of 4-methylbenzenesulfonic acid in 40 parts of butanol and 450 parts of methylbenzene is stirred and refluxed for 17 hours. The reaction mixture is cooled and 90 parts of ammonium hydroxide are added (to remove the 4-methylbenzenesulfonic acid). The organic phase is separated, washed with water, dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off (the filtrate is set aside), yielding a first fraction of 13.8 parts of 4-(4-methyl-2-phenyl-1,3-dioxolan-2-yl)-2-nitrobenzenamine; mp. 155.2° C. The filtrate, which was set aside, is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane, methanol and hexane (88:2:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding a second fraction of 3.6 parts of 4-(4-methyl-2-phenyl-1,3-dioxolan-2-yl)-2-nitrobenzenamine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2(O)[CH2:15][CH2:14][CH:13]([CH:16]=[CH2:17])[CH2:12][CH2:11]2)=[C:6]([F:19])[C:5]=1[F:20])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[CH2:17])[CH2:12][CH:11]=2)=[C:6]([F:19])[C:5]=1[F:20])[CH3:2]
Reactant: C=CC1CCC(O)(c2ccc(OCC)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC1CC=C(c2ccc(OCC)c(F)c2F)CC1
Yield: 14.9 %

Procedure:
Eighth Step: 18.5 g of the compound (17), 0.4 g of p-toluenesulfonic acid and 60 mL of toluene were mixed, and the mixture was refluxed under heating for 1 hour while water distilled out was removed. After cooling the resulting reaction mixture to 25° C., 100 mL of water and 100 mL of toluene were added to and mixed with the reaction mixture. Thereafter, the mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography using a mixed solvent of heptane and toluene (heptane/toluene=3/1 by volume) as eluent, and then further purified by recrystallization from ethanol to obtain 2.58 g of 1-ethoxy-2,3-difluoro-4-(4-vinylcyclohex-1-enyl)benzene (No. 12) in white color. The yield based on the compound (16) was 20.2%.