Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:13])([O:11][CH3:12])[CH3:10])[CH2:3][CH2:4][OH:5].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:14])[CH:20]=[CH:19][C:18]([S:21]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C:9]([CH3:13])([O:11][CH3:12])[CH3:10])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(C)(C)CCCC(C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(C)(C)CCCC(C)CCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
3.76 g. of 3,7-dimethyl-7-methoxy-1-octanol are dissolved in 20 ml. of anhydrous pyridine and mixed, while stirring and with ice cooling, with 4.2 g. of p-toluenesulfochloride. Subsequently, the solution is left overnight at 5° C., then poured onto ice-water and extracted three times with diethyl ether. The extracts are washed successively with cold 2-N aqueous hydrochloric acid solution, water and twice with saturated aqueous sodium chloride solution, dried over sodium sulfate/potassium carbonate and evaporated under reduced pressure, finally at 0.05 mmHg. There is obtained 3,7-dimethyl-7-methoxy-octyl p-toluenesulfonate; nD20 = 1.4927.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:8]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[H-].[Na+].CN(C=O)C.Cl[CH2:37][O:38][CH:39]=[O:40]>O>[CH3:37][O:38][C:39]([NH:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:12]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)=[O:40]
Reactant: Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: O=COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Yield: 45.4 %

Procedure:
0.19 g (0.50 mmol) of 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine synthesized in (1) of the Example 6 and 60% sodium hydride (24 mg, 0.60 mmol) added to DMF (2 ml) were reacted at room temperature for 1 hour. The reaction mixture was added and reacted with 0.040 ml (0.55 mmol) of chloromethylformate at room temperature for 16 hours. The reaction solution was poured into water and extracted with methyl acetate. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 100 mg (yield: 46%) of the titled compound as colorless crystals.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:40]2[CH2:41][CH2:42][CH:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([F:27])[CH:29]=4)[NH:33][CH:32]=3)[CH2:38][CH2:39]2)=[O:7])[CH2:12][CH2:13]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCC(c3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 22.9 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (387.7 mg, 1.1 mmole) was added to a solution of 5-fluoro-3-piperidine-4-yl-1H-indole (240.1 mg, 1.1 mmole) in dioxane (11 ml). The solution was boiled under reflux for 16 hours. The solution was worked up by distilling off the solvent in vacuo. The residue contained, apart from phenol, also the two diastereoisomers of 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (25 g). Methanol/EE (1:1, 900 ml) was used as eluent. The non-polar diastereoisomer (150 mg, m.p. 95°-98° C., 29%) and the polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (120 mg, m.p. 206°-208° C., 23%) were thereby obtained in pure form.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:20]([O:27]C1C(Br)=C2C(=CC=1)NC=C2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[C:10]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Reactant: Brc1c(OCc2ccccc2)ccc2[nH]ccc12
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)c(OCc3ccccc3)ccc21

Procedure:
Using the same procedure as for Intermediate 44 starting from 5-(benzyloxy)-4-bromo-1H-indole, 3.85 g (12.7 mmol) yielded 5.71 g (101%) a dark green crystallizing oil. MS (ESI+) for C21H16BrNO3S m/z 442/444 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[C:10](=[O:13])([O-])[O-:11].[Cs+].[Cs+].[CH3:16][O:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH2:19][CH2:18][O:17][CH3:16])[C:3]=1[C:10]([OH:11])=[O:13]
Reactant: Oc1ccc(F)c(F)c1
Reactant: COCCBr
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(F)c(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 3,4-difluorophenol (1.43 g) and cesium carbonate (4.89 g) in N,N-dimethylformamide (10 mL) was added 2-methoxyethyl bromide (0.94 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (39 mL). To the solution was added n-butyllithium (2.64 mol/L n-hexane solution, 3.25 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dryice (10 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (1.48 g). The obtained 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (0.5 g) was dissolved in 1,4-dioxane (10 mL). To the solution were added triethylamine (0.45 mL) and diphenylphosphoryl azide (0.61 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethanol (0.99 g), and the mixture was heated for reflux for 5 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To a suspension of the residue in ethanol (10 mL) was added 5 mol/L aqueous sodium hydroxide solution (4.3 mL), and the mixture was heated for reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (75 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2S[CH:8]=[CH:7][C:6]=2[CH:10]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:22]([O-:26])([O-])(=[O:24])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:22](=[O:26])(=[O:24])[CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: O=S([O-])([O-])=S
Reactant: Brc1ccc2sccc2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S1(=O)C=Cc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
5-Bromo-1-benzothiophene (1.50 g, 7.04 mmol) was dissolved in chloroform (47 mL) and allowed to stir vigorously at ambient temperature. m-CPBA (4.34 g, 17.6 mmol) was added in three portions and the resulting mixture was maintained at ambient temperature for 16 hours. The mixture was then diluted with 1M aqueous sodium thiosulfate and extracted with EtOAc. The organic layer was again washed with 1M aqueous sodium thiosulfate, saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-30% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, CDCl3): δ 7.65 (dd, J=7.9, 1.8 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.15 (d, J=6.9 Hz, 1H), 6.74 (d, J=6.9 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[C:9]1([C:15](=[N:22][NH2:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[CH:7]=[N:23]/[N:22]=[C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: O=Cc1sccc1Br
Solvent: CCO
Product: Brc1ccsc1/C=N/N=C(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
3-Bromothiophene-2-carbaldehyde (8.0 g, 41.9 mmol) and (diphenylmethylene)hydrazine (9.45 g, 48.2 mmol) were dissolved in ethanol (60 mL) and the solution was heated at 80° C. overnight. Volatiles from the reaction mixture were removed via rotary evaporation and the crude product was purified by normal phase silica gel chromatography (ISCO-Combiflash) eluting with a gradient of 0-30% hexane and EtOAc. The pure fractions were combined and evaporated to give the title compound as a mixture of cis/trans isomers (15.0 g, 97%). ESI-MS m/z [M+H]+ calc'd for C18H13BrN2S, 370. found, 370.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].B(O)(O)[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH:23]=[CH:22][N:21]=1>O1CCOCC1.CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:20]3[N:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH:29]([C:32]5[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)[CH:23]=[CH:22][N:21]=3)=[CH:9][C:10]=2[O:16][CH2:15]1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccnc(-c4ccc5c(c4)OCO5)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere 0.2 mL Na2CO3-solution (2 mol/L) and 3 mg (0.004 mmol) bis(triphenylphosphine)-palladium(II) chloride are added to a mixture of 50 mg (0.30 mmol) 3,4-(methylenedioxy)phenylboronic acid and 36 mg (0.10 mmol) (S)—N-(1-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound XIV.3) in 2 mL dioxane/1 mL MeOH. The mixture is stirred at 90° C. for 3 h. After that time, the mixture is diluted with DMF/water and is filtered. The filtrate is purified using reversed phase HPLC (water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]4[S:21][C:22]([CH:25]5[CH2:27][CH2:26]5)=[N:23][N:24]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:28]=1.C[O-].[Na+].C([NH2:34])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]4[S:21][C:22]([CH:25]5[CH2:27][CH2:26]5)=[N:23][N:24]=4)=[C:14]([C:16]([NH2:34])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: COC(=O)c1nc2n(c1-c1nnc(C3CC3)s1)C1CC(C1)c1ccc(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)c1nc2n(c1-c1nnc(C3CC3)s1)C1CC(C1)c1ccc(Br)cc1-2

Procedure:
10-bromo-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-6,7-dihydro-5H-5,7-methanobenzo [c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L Methyl 10-bromo-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford the crude title compound which was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][CH:58]=1)[CH:53]([OH:55])[CH3:54]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:55][CH:53]([C:52]2[CH:56]=[CH:57][CH:58]=[C:50]([F:49])[CH:51]=2)[CH3:54])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cccc(F)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4cccc(F)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 38.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (99 mg) was added to toluene/triethylamine=10/1 (10 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (150 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-fluoro-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].O>ClCCl>[Cl:8][C:4]1[N:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Cl)n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-6-chloropyridine (3.0 g, 23.3 mmol) in dichloromethane (45 mL) under argon was added triethylamine (4.10 mL, 29.2 mmol) and the reaction cooled to 0° C. (ice bath). A solution of trimethylacetyl chloride (3.16 mL, 25.7 mmol) in dichloromethane (10 mL) was added dropwise over 20 min before stirring for 30 min at 0° C. The reaction was brought up to rt and stirred for a further 5 h, then water (30 mL) was added. The organics were separated and washed with Na2CO3 solution (2×50 mL), dried (MgSO4) and solvent removed in vacuo. Purification by column chromatography (SiO2, CH2Cl2) gave the title compound. m/z (ES+)=213.04 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:31](=O)[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][OH:36]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)[CH:12]=[CH:11][C:10]=1/[C:31](=[N:35]/[OH:36])/[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)=O)c(OCc4ccccc4)c3)c2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(/C(C)=N/O)c(OCc4ccccc4)c3)c2)CCOCC1
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 7, 2'-benzyloxy-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-2'-benzyloxy-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]acetophenone oxime in 47% yield, m.p. 130°-131° C.;
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1.C([O-])([O-])=O.[K+].[K+].C1COCC1>CCOCC.O>[N:12]1([C:1]([O:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:10])[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Benzyl carbonochloridate (4.5 mL, 31.7 mmol) at 0° C. was added to ethyl piperidine-3-carboxylate (5.0 g, 30.2 mmol) and K2CO3 (4.2 g, 30.2 mmol) in 1:1 THF:water (100 mL). The reaction mixture was stirred at room temperature for 2 hours, and then ether (50 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (hexane:ethyl acetate, 5:1) to give 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (7.60 g 86% yield) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([O:26][CH:27]([CH3:29])[CH3:28])[CH:10]=1.[CH3:30][I:31]>CC(C)=O>[I-:31].[CH2:18]([O:17][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[CH:7]=[CH:6][N+:5]([CH3:30])=[CH:4][C:3]=2[O:2][CH3:1])=[CH:10][C:11]=1[O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CI
Reactant: COc1cnccc1-c1ccc(NC(=O)OCc2ccccc2)c(OC(C)C)c1
Solvent: CC(C)=O
Product: COc1c[n+](C)ccc1-c1ccc(NC(=O)OCc2ccccc2)c(OC(C)C)c1
Product: [I-]
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.58 g of benzyl [4-(3-methoxypyridin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate and 1.14 ml of methyl iodide in 107 ml of acetone is heated at 50° C. (bath) for 1 h. 568 μl of methyl iodide are added and the heating is continued at 50° C. for 30 minutes. The mixture is then concentrated under vacuum, so as to give 4.57 g of 4-[4-{[(benzyloxy)carbonyl]amino}-3-(propan-2-yloxy)phenyl]-3-methoxy-1-methylpyridinium iodide in the form of a yellow solid.
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[O:14][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:12][CH:11]=1>CC(C)=O>[Br-:8].[CH2:1]([N+:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:14][C:10]([CH3:9])=[CH:11][N:12]=2)=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cnc(-c2ccncc2)o1
Solvent: CC(C)=O
Product: Cc1cnc(-c2cc[n+](Cc3ccccc3)cc2)o1
Product: [Br-]
Yield: 92.3 %

Procedure:
141 g benzylbromide was added to 66 g 4-(5-methyl-oxazol-2-yl)-pyridine in 1.5 L acetone. The mixture was refluxed over night. The precipitate was filtered to give 126 g of the desired product. Rf: 0.00 (petrolether/ethyl acetate=1/1), (M+H)+: 252
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1.CCOC(C)=O.CCOCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Reactant: [OH-]
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)-ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0 M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extractd 2× with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatograohed on silica gel eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08, H, 7.81; N, 5.86.
Reaction SMILES: [C:1]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.P(Cl)(Cl)([Cl:17])=O.[C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>C1C=CC=CC=1>[ClH:17].[C:20]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:1]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: O=C1CCCCCCCCCCCN1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cl
Product: c1ccc(-c2ccccc2N=C2CCCCCCCCCCCN2)cc1
Reaction time: 1 h

Procedure:
To 43.5 g (0.22 mole) of 2-azacyclotridecanone in 200 ml of dry benzene is added dropwise 30.7 g (0.2 mole) of phosphorousoxychloride. The reaction mixture is stirred at room temperature for 4 hours after which 33.8 g (0.2 mole) of o-biphenylamine is added and stirring is continued at room temperature for 1 hour then at reflux temperature for 4 hours. The reaction mixture is alowed to stand overnight then is washed with 2N hydrochloric acid, dried and evaporated leaving a residue which is recrystallized from acetone/methanol to give 2-(o-biphenylylimino)azacyclotridecane hydrochloride, M.P. 249°-251° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:31])=[CH:4][N:3]=1.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([O:43][CH3:44])[CH:35]=1)#[N:33]>>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[C:5]([F:31])=[CH:4][N:3]=2)=[C:36]([O:43][CH3:44])[CH:35]=1)#[N:33]
Reactant: COc1cc(C#N)ccc1B(O)O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)cc1
Product: COc1cc(C#N)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ccncn3)ccc12

Procedure:
Example 218 was synthesized in a similar manner to Example 212, except that 1-chloro-4-fluoro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate QQQ) and (4-cyano-2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 25 to 100% EtOAc:Heptane) to afford 1-(4-cyano-2-methoxyphenyl)-4-fluoro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.74 (s, 1H), 8.59 (d, J=15.7 Hz, 2H), 8.37-8.14 (m, 1H), 8.05 (d, J=7.4 Hz, 1H), 7.75 (d, J=1.3 Hz, 2H), 7.66-7.60 (m, 1H), 7.57-7.50 (m, 1H), 3.72 (s, 3H). m/z (ESI) 436.2 (M+H)+.