Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C(Cl)=O.[Si:21]([O:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[O:14]=[C:1]([N:32]1[CH2:33][CH2:34][CH:29]([O:28][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH2:30][CH2:31]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Reactant: CCCCCCCCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve lauric acid (0.77 g) in methylene chloride (50 mL) and cool to 0° C. Add oxalyl chloride (0.37 mL) and dimethylformamide (3 drops). Allow to warm to room temperature and stir for 1 hour. Add this solution to a mixture off 4-(O-tert-butyldimethylsilyloxy)piperidine and triethylamine (1 mL) in methylene chloride (25 mL). Heat at reflux overnight. Dilute with methylene chloride (50 mL) and separate the organic phase. Wash twice with 10% sodium hydroxide, once with water, and once with brine. Dry (Na2SO4) and evaporate the solvent in vacuo. Dissolve the residue in hexane (100 mL) and wash twice with 10% hydrochloric acid (50 mL), once with saturated sodium hydrogen carbonate and once with brine. Dry (Na2SO4) and evaporate the solvent in vacuo to give 1-oxododecyl-4-(O-tert-butyldimethylsilyloxy)piperidine.
Reaction SMILES: C([Li])CCC.CCCCCC.C([O:16][C:17](C)(C)C)(C)(C)C.[K].[Cl:22][C:23]1[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C1C[O:34]CC1>>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([F:30])[C:24]=1[C:17]([OH:16])=[O:34]
Reactant: CC(C)(C)OC(C)(C)C
Reactant: Fc1cc(Cl)cc(Cl)c1
Reactant: C1CCOC1
Agent: [K]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(O)c1c(F)cc(Cl)cc1Cl
Yield: 35 %

Procedure:
A solution of 2.5 M n-butyllithium in hexane (8.72 mL, 21.8 mmol) was added to anhydrous THF (100 mL) at −78° C. under nitrogen with stirring, followed by the addition of 1.0 M potassium t-butyloxide in THF (21.81 mL, 21.8 mmol). The reaction mixture was stirred at −78° C. for 30 min, then 3,5-dichlorofluorobenzene (3.0 g, 18.2 mmol) was added over 10 min and the mixture was stirred at −78° C. for 40 minutes. Carbon dioxide gas was then bubbled into the reaction mixture for 10 min The reaction mixture was allowed to come to RT, diluted with ether (100 mL), extracted with a solution of aqueous 1.0 M sodium hydroxide (2×50 mL). The combined sodium hydroxide extract was washed with ether (100 mL). The sodium hydroxide layer was then acidified to pH 3 with a solution of aqueous concentrated HCl, extracted with ethyl acetate (2×50 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated. The crude product was purified by ISCO flash chromatography (silica gel/hexane-ethyl acetate 100:0 to 0:100 gradient) to afford the title compound as a brown solid (1.34 g, 35% yield).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13]Cl)[CH:7]=1)[C:3]([OH:5])=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>CO>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][N:15]=[N+:16]=[N-:17])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCc1cc(C(N)C(=O)O)ccc1O
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid (252 mg, 1 mmole) in 4 ml of methyl alcohol is added sodium azide (156 mg, 2.4 mmole). The mixture is stirred at about 40° C. for 15 minutes. After about 10 minutes the title compound begins to precipitate. The mixture is cooled, filtered and the product is washed with a small amount of methyl alcohol and acetone. The title compound is collected (210 mg, 95% yield). M.P.>300°; [α]D18 =-73.03° (c 1.7, water), NMR (DMSO-D6) ppm (δ) 4.22 (s,1), 4.35 (s,2), 6.7-7.5 (superimposed q and s,3).
Reaction SMILES: [N+:1]([C:4]([CH3:9])([CH2:7][OH:8])[CH2:5][OH:6])([O-:3])=[O:2].O1CC[CH2:13]OO1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:9][C:4]1([N+:1]([O-:3])=[O:2])[CH2:7][O:8][CH2:13][O:6][CH2:5]1
Reactant: C1COOOC1
Reactant: CC(CO)(CO)[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1([N+](=O)[O-])COCOC1

Procedure:
2-Nitro-2-methyl-1,3-propanediol 405.00 grams (3.00 moles), 98% trioxane 92.80 grams (1.00 mole), p-toluenesulfonic acid 3.00 grams (0.016 mole), and benzene 600 ml were placed in a two liter three-necked RB flask. The flask was fitted with a thermometer, a mechanical stirrer and a Dean-Stark trap connected to a condenser. The mixture was stirred and refluxed. The slurry gradually became a homogeneous solution (usually about 30 minutes after heating started) and the benzene-water azeotrope started to distill over. Refluxing was continued until 45 ml of water was collected (i.e., approximately four hours). During this period the solution temperature was between 78° C. and 82° C. After 45 ml of water had been collected, the reaction mixture was cooled and neutralized with 3 ml triethylamine. Benzene was distilled from the clear solution first at atmospheric pressure (approximately 415 ml benzene was recovered at a solution temperature of 82° C.-100° C.) and then at about 125 mm of pressure (approximately 120 ml benzene was recovered at a solution temperature of about 48° C.-110° C.). A clear, pale-yellow, viscous liquid, 450.67 grams, containing a mixture of the reaction products polynitroformal and 5-methyl-5-nitro-1,3-dioxane was obtained as the resulting product.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)CCCC.C(=O)([O-])[O-].[K+].[K+].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>[Cu]=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:24][C:25]2[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: COc1ccc(N)cn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: COc1ccc(Nc2ccc(Cl)cc2C(=O)O)cn1
Temperature: 100 °C

Procedure:
To a solution of 19.1 g. of 2,5-dichlorobenzoic acid [Besley & Goldberg, J. Chem. Soc., 2448 (1954)] in 100 ml. of amyl alcohol is added 6.9 g. of anhydrous potassium carbonate and 0.1 g. of copper oxide. The mixture is stirred and heated at 100° C. for 30 minutes, then 13.0 g. of 5-amino-2-methoxypyridine is added and the mixture is heated at reflux and stirred for 3 hours. A small amount of water forms and is collected in a Dean-Stark apparatus. The reaction mixture is cooled, poured into water and made basic with potassium carbonate. The mixture is steam-distilled to remove the amyl alcohol, then filtered and the filtrate is acidified to pH 6. The mixture is again filtered and this pink filtrate is acidified with 6 N hydrochloric acid to pH 4. The solid is collected, giving 5-chloro-2-(6-methoxy-3-pyridylamino)benzoic acid as a pink crystalline solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[H][H].Br[CH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.Cl>O1CCOCC1.O>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[CH:30][C:21]([CH2:20][CH2:19][CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[CH:22][CH:23]=1)=[O:26]
Reactant: [H][H]
Reactant: C=CCOC(=O)CC(=O)OCC=C
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.125 g (28.14 mmol) of sodium hydride are added in portions to a solution of 6.91 g (37.52 mmol) of diallyl malonate in 50 ml of dioxane at 0° C. (caution: evolution of hydrogen). After warming to room temperature, the mixture is stirred at 40° C. for 1 h. Then 4.56 g (18.76 mmol) of methyl 4-(2-bromoethyl)benzoate [CAS Reg. No. 136333-97-6], dissolved in 20 ml of dioxane, are slowly added dropwise at 40° C., and the reaction solution is stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture is added to 1200 ml of water. Care must be taken during this that the pH remains <7 (if necessary, a few ml of 1 M hydrochloric acid are metered in until the pH is about 2). The mixture is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. After filtration, the solvent is evaporated to dryness in vacuo. Subsequently, excess diallyl malonate is removed by high vacuum distillation (boiling point: 57° C., 0.074 mbar). The distillation residue is purified by flash chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 10:1). 6.01 g (17.35 mmol, 92% of theory) of a colourless solid are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#N.[OH-:13].[K+].[OH2:15].Cl>C(O)CO>[F:10][C:9]([F:12])([F:11])[C:8]1[C:3]([C:1]([OH:15])=[O:13])=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#Cc1cnccc1C(F)(F)F
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: O=C(O)c1cnccc1C(F)(F)F
Temperature: 20 °C
Yield: 84 %

Procedure:
3-Cyano-4-trifluoromethylpyridine (11.47 g, 66.64 mmol) was suspended in ethylene glycol (76 ml) and 85% potassium hydroxide (13.20 g, 200 mol) was added. The mixture was stirred under heating at 20° C. for 4 hours. The reaction solution was cooled to room temperature and then water (50 ml) and 4N hydrochloric acid (60 ml) were added. The resulting reaction mixture was extracted with ethyl acetate four times. The organic layers were combined, washed with saturated salt water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 10.70 g (yield 84.0%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1([CH2:37]O)[CH2:36][O:35][CH2:34][O:33][CH2:32]1.[K+].[Br-].Cl>>[CH3:30][C:31]1([CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:37][C:31]3([CH3:30])[CH2:32][O:33][CH2:34][O:35][CH2:36]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:36][O:35][CH2:34][O:33][CH2:32]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC1(CO)COCOC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1(C)COCOC1)(C(=O)OCC1(C)COCOC1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 5-methyl-[1,3]dioxan-5-ylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) 6 0.7 (s, 3H, CH3), 0.74 (s, 3H, CH3), 1.1 (d, J=6.59 Hz, 3H, CH3), 2.6 (m, 1H, CH), 3-3.3 (m, 8H, CH, CH2), 3.6-3.7 (m, 4H, CH2), 4.6-4.8 (m, 4H, CH2), 5.04 (m, 1H, CH), 6.34 (brs, 1H, OH), 6.84 (dd, J=8.13, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.36-7.44 (m, 3H, Ar--H), 7.48 (s, 1H, Ar--H), 8.77 (brs, 1H, NH), 9.2 (brs, 1H, NH); IR (KBr, cm-) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 650 (M+H)+; Analysis for: C32H40ClNO11 ×HCl: Calc'd: C, 55.98; H, 6.02; N, 2.04; Found: C, 54.67; H, 6.58; N, 2.05.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.[C:21]([O-:24])([O-:23])=O.[K+].[K+].[CH3:27][O:28][C:29]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:30]=1[CH2:31][CH2:32]Cl>C(OCCCC)(=O)C>[C:7]([OH:28])(=[O:8])/[CH:13]=[CH:14]/[C:21]([OH:24])=[O:23].[CH3:27][O:28][C:29]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:30]=1[CH2:31][CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1
Reactant: COc1cccc(CCCl)c1OC
Reactant: O=C([O-])[O-]
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: [K+]
Solvent: CCCCOC(C)=O
Product: COc1cccc(CCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)c1OC
Product: O=C(O)/C=C/C(=O)O
Yield: 182.3 %

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (2.93 g, 0.011 mole), K2CO3 (10 g), KI (0.1 g) and 2,3-dimethoxyphenethyl chloride (2.45 g, 0.012 mole) in 100 ml of n-butyl acetate was heated at reflux for 50 hours. The mixture was then filtered and concentrated to give 5.5 g of an oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:39][C:40]1([CH3:48])[O:45][C:44](=[O:46])[CH2:43][C:42](=[O:47])[O:41]1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:39][C:40]1([CH3:48])[O:45][C:44](=[O:46])[C:43](=[C:21]([OH:22])[CH:9]2[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[C:42](=[O:47])[O:41]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(O)=C2C(=O)OC(C)(C)OC2=O)C1
Reaction time: 0.25 h
Yield: 5.8 %

Procedure:
To a solution of 1,4-bis{[(1,1-dimethylethyl)oxy]carbonyl}-2-piperazinecarboxylic acid (may be prepared as described in Intermediate 1; 14.58 g) in dichloromethane (500 mL) was added DMAP (8.09 g) and then DCC (13.66 g). The reaction was stirred for 15 minutes and then 2,2-dimethyl-1,3-dioxane-4,6-dione (9.54 g) (Meldrum's acid) was added. The reaction was stirred at room temperature for 20 h. A solid was present, which was filtered off and the product was found to be in the filtrate. The filtrate was washed with water (2×200 mL) and brine (200 mL) before it was dried (Na2SC4), filtered and the solvent removed under vacuum. The crude material was then redissolved in DCM (500 mL) and 50 mL removed and this was washed with 1M HCl (2×20 mL) before the organic phase was dried (Na2SC4), filtered and the solvent removed under vacuum to give the title compound (1.16 g). This process removed the DMAP impurity. The process was repeated with the remaining DCM solution, washing with 1M HCl (2×300 mL) before the solution was dried (Na2SC4), filtered and the solvent removed under vacuum to give the title compound as yellow viscous oil (16.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:26]=O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]([CH:19]3[CH2:20][CH2:21][N:22]([CH3:26])[CH2:23][CH2:24]3)[C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]n(C2CCNCC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(n2[nH]c(=O)c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reaction time: 1 h

Procedure:
A solution of 4-(4-chlorophenyl)-1-piperidin-4-yl-5-pyridin-4-yl-1,2-dihydro-pyrazol-3-one (0.12 g, 0.34 mmol) in anhydrous methanol (3 mL) was cooled to 0° C. in an ice-water bath and added formaldehyde (3 mL; 37 wt. % in water), followed by sodium borohydride (0.039 g, 1 mmol). After stirring for 1 hour, the reaction was quenched with water and diluted with methylene chloride. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The title compound was isolated as a yellow amorphous solid by preparative HPLC. MS (ES+): 369.2 (M+H)+; (ES−): 367.1 (M−H)−.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:53][CH:54]1[CH2:59][CH2:58][CH2:57][N:56]([C:60]2[CH:65]=[C:64]([N:66]3[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]3)[CH:63]=[CH:62][C:61]=2[NH2:73])[CH2:55]1>C(Cl)Cl>[F:53][CH:54]1[CH2:59][CH2:58][CH2:57][N:56]([C:60]2[CH:65]=[C:64]([N:66]3[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]3)[CH:63]=[CH:62][C:61]=2[NH:73][C:17]([C:6]2[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=2)=[O:19])[CH2:55]1
Reactant: CN1CCN(c2ccc(N)c(N3CCCC(F)C3)c2)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(N3CCCC(F)C3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A suspension of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 3, step (d), 48 mg, 0.16 mmol) in CH2Cl2 (5 mL) was treated with DIEA (68 μL, 0.39 mmol) and PyBroP (0.11 g, 0.24 mmol). The reaction stirred at room temperature for 10 min. A solution of 2-(3-fluoro-piperidin-1-yl)-4-(4-methyl-piperazin-1-yl)-phenylamine (as prepared in the previous step, 46 mg, 0.16 mmol) in CH2Cl2 (4 mL) was added, and the reaction was stirred at room temperature for 19.5 h. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (62 mg, 70%) as an off-white solid, which was used directly in the next reaction. LC-MS (ESI, m/z): Calcd. for C27H40FN7O2Si, 542.3 (M+H), found 542.4.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O-])(O)=O.[Na+].[NH2:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>CO>[CH2:1]([NH:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCBr
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCNc1cccc(O)c1
Yield: 62 %

Procedure:
0.11 mol of n-heptyl bromide and 0.1 mol of NaHCO3 are added to 0.1 mol of m-aminophenol in 150 ml of methanol, and the mixture is refluxed for 5 h. After cooling, it is filtered and the solvent is removed in vacuo. The oil which remains is fractionated in vacuo, to give 3-(n-heptyl-amino)phenol.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:31](=[O:33])[CH3:32])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:10]2[CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=[CH:37][C:9]1=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:26][C:23]([F:24])([F:25])[C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([C:27]([F:29])([F:30])[F:28])[CH:20]=1)[CH2:16][N:15]([CH:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][C:10]1=2)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2ccc(C(F)(F)F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2ccc(C(F)(F)F)cc21

Procedure:
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.118 g, 0.197 mmol) was treated with 1:1 TFA/DCM (2.00 ml) at room temperature. Evaporation of solvents provided the titled compound, which was used directly for the next step without further purification. MS (ES+): 499 (M+H).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][CH:18]3[N:23]([S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[C:26]([F:37])[CH:25]=2)=[C:9]([CH3:50])[CH:8]=1)[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][CH:18]3[N:23]([S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([F:37])[CH:25]=2)=[C:9]([CH3:50])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(OCCSCC)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCSCCOc1cc(C)c(-c2cccc3c2CCC3N(c2ccc(CCC(=O)O)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
To a mixture of ethyl 3-(4-{(4-{4-[2-(ethylthio)ethoxy]-2,6-dimethylphenyl}-2,3-dihydro-1H-inden-1-yl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate (1.06 g, 1.47 mmol), ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1 N aqueous sodium hydroxide solution (2.94 mL, 2.94 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and concentrated under reduced pressure to evaporate the organic solvent. The residue was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20%-100% ethyl acetate/hexane) to give the title compound (0.804 g, yield 79%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1)#[N:18].[OH-].[Na+].O>C1(C)C(C)=CC=CC=1>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]3=[N:26]2)=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: N#Cc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 25 °C

Procedure:
38.5 ml of a 0.17 M solution of ethyl 4-chloroquinoline-3-carboxylate in xylene, and 0.96 g of p-cyanophenylhydrazine in 30 ml of xylene are mixed and heated at 115° to 120° for 3 hours. The mixture is then cooled to room temperature, and stirred with 20 ml of 1 N aqueous sodium hydroxide and sufficient water to dissolve all solids. The aqueous layer is separated, washed twice with diethyl ether, then treated with an aqueous solution of 1.07 g ammonium chloride, and the resulting precipitate is collected, washed with water and dried to yield the 2-(p-cyanophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing peaks in the IR-spectrum at 885, 830, 780, 755 and 730 cm-1.
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[C:8](Cl)[C:7]=1[N+:17]([O-:19])=[O:18])([CH2:3][CH3:4])[CH3:2].[NH3:20]>>[CH:1]([NH:5][C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]([NH2:20])[C:9]([CH3:15])=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(Cl)c1[N+](=O)[O-]
Reactant: N
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]

Procedure:
This compound was prepared in a similar manner by reaction of N-sec-butyl-3-chloro-2,6-dinitro-4-methylaniline with ammonia. The crystalline product melts at 151.5°-152.5°C.