Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:15][C:16]([C:18]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[C:20]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:28])[CH:19]=1)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Pd].C(OCC)(=O)C.C1COCC1>[CH2:30]([O:29][C:27]([C:20]1[CH:21]=[C:22]([NH2:24])[CH:23]=[C:18]([C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:17])[CH:19]=1)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOC(=O)c1cc(N)cc(C(=O)OCCCCCCCCCCCCCC)c1
Reaction time: 17 h
Yield: 98.7 %

Procedure:
A mixture of 2.09 g of 5-nitro-1,3-benzenedicarboxylic acid ditetradecyl ester and 0.5 g of 10% palladium on carbon in 80 ml of ethyl acetate and 25 ml of THF was shaken under an initial hydrogen pressure of 53 psi for 17 hours. The catalyst was removed by filtration and the filtrate was concentrated to give 1.96 g of pure 5-amino-1,3-benzenedicarboxylic acid ditetradecyl ester, mp 74°-75°.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](OC)(OC)(OC)C>>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: COC(C)(OC)OC
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Yield: 99 %

Procedure:
A solution of 4-iodo-3-nitrobenzoic acid (3 g, 10 mmol) in trimethyl orthoacetate (30 ml) is refluxed (˜110° C.) for 15 hours and then solvent is evaporated under reduced pressure. The 4-iodo-3-nitrobenzoic acid methyl ester is obtained as a yellow solid (3.11 g, 99% yield, 97.5% HPLC).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[Na].[CH:10]([OH:13])([CH3:12])[CH3:11]>>[Br:8][CH:7]([O:13][CH:10]([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: BrCCCCCCBr
Reactant: CC(C)O
Agent: [Na]
Product: CCCCCC(Br)OC(C)C

Procedure:
The above compound is produced in analogy to Example 10, using isopropanol and 1,6-dibromohexane and sodium instead of sodium hydride. B.P.: 96°-98°/15 mm Hg.
Reaction SMILES: ClC1C=CC=C([C:8](OO)=[O:9])C=1.[CH3:12][O:13][CH:14]1[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:15]1>CO>[CH3:12][O:13][C:14]1([O:9][CH3:8])[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:15]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC1SC(c2ccncc2)=C(C)NC1=O
Solvent: CO
Product: COC1(OC)SC(c2ccncc2)=C(C)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
m-Chloroperbenzoic acid (2.8 g) was added to a stirred solution of 2 -methoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (2.7 g) in methanol (100 ml) under ice/water-cooling. The reaction mixture was further stirred at ambient temperature for 2 hours. Methanol was removed under reduced pressure and the residue was dissolved in ethyl acetate, was washed with saturated sodium bicarbonate aqueous solution and successively with water, and was dried over magnesium sulfate. Ethyl acetate was removed under reduced pressure and the residue was crystallized from ether to give the titled compound (2 g, yield 66.7%) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:29]1[N:33]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[N:32]=[N:31][C:30]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][C:29]3[N:33]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)[N:32]=[N:31][C:30]=3[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: Oc1cccc(OCCCN2CCN(Cc3ccc(Cl)cc3)CC2)c1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Oc1cccc(OCCCN2CCN(Cc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A solution of 1-[4-(4-chlorobenzyl)piperazin-1-yl]-3-(3-hydroxyphenoxy)propane (7.00 g, 0.019 mole), in dry dimethyl formamide, (200 ml) was treated portionwise with 60% sodium hydride in oil, (0.776 g, 0.019 mole), under a slow stream of nitrogen. The mixture was stirred at room temperature for 0.5 h, then Ethyl 5-chloro-1-(4-methoxybenzyl)-1,2,3-triazole 4-carboxylate (5.74 g, 0.019 mole) was added. The reaction was stirred at 100° C. for 24 hours, then cooled and the solvent removed in vacuo. The brown residue was partitioned between ethyl acetate and water and the organic phase separated, washed with water (twice), and dried, (MgSO4). Evaporation in vacuo gave the crude product as a pale brown oil which was purified by column chromatography to yield 8.52 g (72%) of the title compound as a pale yellow oil. νmax (film) 1510, 1560, 1590, 1615, 1730, 2810, 2940 cm-1 δ(CDCl3 ) 1.11 (3H, t, J 7 Hz, ester CH3), 1.91 (2H, m, CH2), 2.51 (10H, piperazinyl+CH2), 3.46 (2H, s, --NCH2), 3.73 (3H, s, OCH3), 3.87 (2H, t, J 6 Hz, OCH2), 4.18 (2H, q, J 7 Hz, ester CH2), 5.33 (2H, s, --NCH2), 6.33 (2H, m, aromatics), 6.80 (1H, m, aromatics), 7.00 (4H, ABq, Δν=39 Hz, J 9 Hz, --C6H4OCH3), 7.16 (1H, m, aromatics), 7.28 (4H, s, C6H4 --Cl). Mass Spec. Observed mass 619.2572, theoretical mass 619.2561 (C33H38ClN5O5).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:14][C@H:15]1[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@H:18]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][OH:45])=[CH:39][CH:38]=3)[CH:30]=2)[O:17][C@@H:16]1[CH2:46][O:47][C:48](=[O:50])[CH3:49])(=[O:13])[CH3:12].CCN(CC)CC>C(Cl)Cl.CCOCC>[C:11]([O:14][C@H:15]1[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@H:18]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([CH2:43][CH:44]=[O:45])=[CH:41][CH:42]=3)[CH:30]=2)[O:17][C@@H:16]1[CH2:46][O:47][C:48](=[O:50])[CH3:49])(=[O:13])[CH3:12]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(CCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(CC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (0.086 mL, 1.01 mmol) was added to a solution of DMSO (0.14 mL, 2.0 mmol) in dry DCM (1 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred for 5 min. at the same temperature and then a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-hydroxyethyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.35 g, 0.6 mmol, prepared by following the procedure as described in WO2011070592), in dry DCM (3 mL) was added. The reaction mixture was stirred at the same temperature for 20 min. NEt3 (0.41 mL, 3.0 mmol) was added and the reaction mixture was allowed to come to r.t. Pet.ether (3 mL) was added to the reaction mixture and the solid was filtered. The filterate was concentrated in vacuo to afford the title compound, which was used as such in next step.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1.[OH-].[Na+]>CO>[F:1][C:2]([F:17])([F:18])/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1
Reactant: COC(=O)c1ccc(/C=C/C(F)(F)F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(/C=C/C(F)(F)F)ccc1C(=O)O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of (E)-methyl 4-(3,3,3-trifluoroprop-1-enyl)-2-methoxybenzoate (340 mg, 0.0013 mol), MeOH (20 mL), and 2 N aqueous NaOH solution (1.5 mL) was stirred at 65° C. overnight. The solvents were removed under reduced pressure and the residue was treated with water, acidified with 1N HCl to pH 2-3, and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the product as a white solid. LC-MS: 2.59 min, 244.8 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(O[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])C.C(OCC)(=O)C>C(O)C>[NH2:22][C:21]1[N:12]([C:3]2[C:2]([Cl:1])=[C:6]([C:7]([F:10])([F:8])[F:9])[N:5]([CH3:11])[N:4]=2)[N:13]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: Cn1nc(NN)c(Cl)c1C(F)(F)F
Reactant: CCOC=C(C#N)C#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(-n2ncc(C#N)c2N)c(Cl)c1C(F)(F)F

Procedure:
1.4 g (6.5 mmole) 4-Chloro-3-hydrazino-1-methyl-5-trifluoromethylpyrazole and 0.81 g (6.5 mmole) ethoxymethylenemalononitrile in 20 ml ethanol were stirred for 10 hours at room temperature and for 2 hours at 50° C. After addition of 100 ml ethyl acetate, the mixture was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (methylene chloride).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([O:14]C(C2CC2)=O)[C:10]2[C:5](=[CH:6][C:7]([F:21])=[C:8]([F:20])[CH:9]=2)[N:4]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[C:8]([F:20])[CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2cc(F)c(F)cc2c(O)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 121 %

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-6,7-difluoroquinoline (5.5 g) prepared as described in Example 1 was dissolved in 50 ml of methanol. A solution of 2.5 g of sodium hydroxide in 50 ml of water was added to this solution, and the mixture was stirred at 50° C. for 3 hr. The reaction solution was allowed to stand for cooling and was then poured into 50 ml of water. The mixture was neutralized with 1N hydrochloric acid, and the precipitate was then collected by filtration to give 5.1 g of 2-ethyl-3-methyl-4-hydroxy-6,7-difluoroquinoline. In 20 ml of tetrahydrofuran was suspended 96 mg of 60% sodium hydride. Separately, 446 mg of the 2-ethyl-3-methyl-4-hydroxy-6,7-difluoroquinoline (starting material 1) was suspended in 10 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The mixture was stirred for 1 hr, and 188.4 mg of acetyl chloride (starting material 2) was then added thereto. The mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 168.6 mg of 2-ethyl-3-methyl-4-acetyloxy-6,7-difluoroquinoline (compound 3). 1H-NMR data are shown in Table 3.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.S(=O)(=O)(O)[OH:22].[OH-].[Na+]>>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:17])=[O:22])[N:8]=1
Reactant: N#CCCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)CCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-[3-(2-[2,2,2-Trifluoroethyl]guanidino)pyrazol-1-yl]valeronitrile (13 g.) was added over 10 minutes to concentrated sulphuric acid (65 ml.) with stirring. The resulting solution was kept at 20° for 18 hours then diluted with ice (300 ml.) and basified to pH 9 with 10.8 N sodium hydroxide. The mixture was extracted with EtOAc (3×200 ml.) and the extract was dried (MgSO4) and evaporated in vacuo to an oil which crystallised. The crude material was recrystallised from EtOAc to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide, m.p. 130°. The maleic acid salt was prepared in acetone, m.p. 183°-184°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27])[NH:10][CH:9]2[C:30]([OH:32])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:34][C:35]1[CH:39]=[CH:38][N:37]([CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])[N:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:43][C:41]([CH3:44])([CH3:42])[CH2:40][N:37]1[CH:38]=[CH:39][C:35]([NH:34][C:30]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:33])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27])[NH:10]2)=[O:32])=[N:36]1
Reactant: CC(C)(CCO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C2NC(CC(C)(C)CCO)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Yield: 54.6 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid prepared in Example 116c (0.48 g, 0.78 mmol) was reacted with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (0.15 g, 0.9 mmol), HATU (0.6 g, 1.6 mmol) and iPr2NEt (0.41 mL, 2.4 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a white solid (0.27 g, 55%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:8]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])[CH:9]=[CH:10][CH:11]=1.[C:21](=O)([O-])[O-:22].[Na+].[Na+]>CN(C=O)C>[Br:6][C:7]1[N:8]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])[C:9]([CH:21]=[O:22])=[CH:10][CH:11]=1
Reactant: Cc1cc(C#N)ccc1-n1cccc1Br
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1-n1c(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
DMF (0.1 mL) was added to phosphorus oxychloride (0.5 mL, 5.2 mmol) at 0° C., and the mixture was stirred at room temperature for 1.5 h. At 0° C., a solution of compound 50B (100 mg. 0.36 mmol) in DMF (2 mL) was added, and the resultant mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice-water, adjusted to pH=8 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to afford 50C (60 mg, yield 58%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[O:5](C(OC(C)(C)C)=O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O>C(Cl)Cl>[C:9]([O:8][C:6]([NH:1][CH2:2][CH2:3][NH2:4])=[O:5])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN
Reaction time: 20 h

Procedure:
To a stirred solution of 1,2-diaminoethane 2-3 (50 g, 832 mmol) and CH2Cl2 (500 ml) was added a solution of BOC2O (45 g, 208 mmole) in CH2Cl2 (100 ml) dropwise over a 3 h period. After 20 h, the reaction was filtered and then the filtrate was concentrated at 60° C. to furnish amine 2-4 as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[CH3:12][N:13]1C(=O)CCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[F:11][C:3]1[C:2]([C:12]#[N:13])=[CH:10][C:6]2[NH:7][CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: CN1CCCC1=O
Reactant: Fc1cc2nc[nH]c2cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc2[nH]cnc2cc1F
Temperature: 110 °C
Yield: 93.5 %

Procedure:
A mixture of 6-bromo-5-fluoro-1H-benzo[d]imidazole (10.0 g, 46.5 mmol), Pd(PPh3)4 (7.97 g, 6.9 mmol), and Zn(CN)2 (8.46 g, 93 mmol) in NMP (150 mL) under nitrogen was heated at 110° C. for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (100 mL×5). The combined extracts were washed with brine (300 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 6-fluoro-3H-benzo[d]imidazole-5-carbonitrile as white solid (7.0 g, 93.5%).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>>[ClH:2].[ClH:1].[ClH:2].[CH2:24]([NH:28][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][NH:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH:15]=1)[CH:10]=2)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Agent: Cl
Product: CCCCNCCOc1ccc2cc3ccc(OCCNCCCC)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and n-butylamine as described in Example 15, giving 1.45 g. of the desired product as yellow crystals, m.p. 254°-256° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH2:30]([N:32]([CH2:37][CH3:38])[S:33](Cl)(=[O:35])=[O:34])[CH3:31]>C(N(CC)CC)C>[CH2:30]([N:32]([CH2:37][CH3:38])[S:33]([N:23]1[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]2[CH:26]=[CH:27][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)(=[O:35])=[O:34])[CH3:31]
Reactant: CCN(CC)S(=O)(=O)Cl
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Product: CCN(CC)S(=O)(=O)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1

Procedure:
In the manner given in Example 14, 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine is reacted with diethylsulfamoyl chloride, in the presence of triethylamine to give 1-[(diethylamino)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: C=C1OC(=O)C1.ClCl.[Cl:9][CH2:10][C:11](=[O:16])[CH2:12][C:13](Cl)=[O:14].[CH2:17]([OH:19])[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:13](=[O:14])[CH2:12][C:11]([CH2:10][Cl:9])=[O:16])[CH3:18]
Reactant: CCO
Reactant: O=C(Cl)CC(=O)CCl
Agent: C=C1CC(=O)O1
Agent: ClCl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCl
Temperature: -20 °C
Reaction time: 6 h

Procedure:
A reactor having interior enameling, a total capacity of 630 liters, an effective capacity of 500 liters and a cooling surface of 2.73 m3, was charged with 500 liters of a 15 weight-percent solution of diketene in methylene chloride, and cooled to -20° C. During a period of about 6 hours, a total of 82 kg of chlorine gas was fed into the reactor. The addition of the chlorine gas was in such a way that the temperature at no time rised above -10° C. The reaction mixture was stirred by means of an impeller during the entire time. To the γ-chloroacetoacetic acid chloride a equimolar quantity of ethyl alcohol was added to form the corresponding γ-chloroacetoacetic ethyl ester. The total reaction time was about two hours. The unreacted excess of chlorine and the methylene chloride were removed by distilling them off. A gas chromatographic analysis showed a yield of:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][NH:13][C:14](=[O:17])[CH2:15][CH3:16])[CH2:7][CH2:6][CH2:5]2.[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>N1C=CC=CC=1>[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]([CH2:12][NH:13][C:14](=[O:17])[CH2:15][CH3:16])[CH2:7][CH2:6][CH2:5]3)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)NCC1CCCc2cc(N)ccc21
Solvent: c1ccncc1
Product: CCC(=O)NCC1CCCc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
To a solution of N-(6-amino-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-propionamide (290 mg, 1.26 mmol) in pyridine (10 ml) at 0° C. 4-isopropyl-benzenesulfonyl chloride (280 mg, 1.26 mmol) was added. The mixture was stirred at 0° C. for 1 h and 16 h at room temperature. After evaporation under reduced pressure the obtained residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed twice with saturated aqueous NaHCO3, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a brown resin (530 mg, 100%).
Reaction SMILES: O[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:6][C:3]=1[C:4]#[N:5].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2cc(C#N)c(O)nc2-c2ccccc2)cc1
Product: Cc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccccc2)cc1

Procedure:
A solution of 2-hydroxy-6-phenyl-5-p-tolylnicotinonitrile (Compound 114, 528 mg, 1.9 mmol) in POCl3 (5 ml) was heated to 110° C. overnight. POCl3 was removed and the residue was purified by MPLC column chromatography (silica gel, 10% ethyl acetate in hexane) to obtain the title compound as an oil-foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc3nc(NC(=O)c4cccnc4)nn3c2)c1
Yield: 51.9 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-methoxybenzeneboronic acid (71 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/DCM, gradient from 0:100 to 10:90) gave the title compound as a beige powder (43 mg, 53%). HPLC, Rt: 2.41 min. (purity 99.2%). LC/MS, M+(ESI): 346.4, M−(ESI): 344.4.