Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH:51]2[CH2:56]O[CH:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[O:53][CH2:52]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:54]([O:53][C@H:52]1[CH2:51][C@H:56]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:21][CH:22]=2)[CH2:34]1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OC2COC(c3ccccc3)OC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O[C@H]2C[C@H](OCc3ccccc3)C2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To 349 mg (0.75 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxy-benzyl)-L-glutamate (Example 1 b) in 15 mL NA-dimethylformamide were added 138 mg (1.0 mmol) of potassium carbonate and 332 mg (1.0 mmol) of 2-phenyl-1,3-dioxan-5-yl 4-methylbenzenesulfonate (Studii si Cercetari de Chimie (1960), 8, 187-99.) and the resulting suspension was heated for 2 h at 100° C. in a microwave oven. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in DMSO. The crude product obtained in this manner was chromatographed on a PrepCon® C-18 reversed phase column using a water/acetonitrile gradient (35/65 to 0/100), and the appropriate fractions were combined and concentrated.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH3:12]>>[NH2:12][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Reactant: N
Product: Nc1ccnc(Cl)c1[N+](=O)[O-]
Yield: 71 %

Procedure:
A solution of 28.0 g (0.193 mol) of 2,4-dichloro-3-nitropyridine in 300 ml of ammonia-saturated ethanol was stirred for four days at ambient temperature, then evaporated to dryness and the crude product thus obtained was purified by column chromatography (silica gel, eluant:dichloromethane with 0–5% ethanol).
Reaction SMILES: C([Mg]Cl)C.Br[C:6]1[S:10][C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:8][C:7]=1[CH3:28].[CH2:29]([O:31][C:32](C#N)=[O:33])[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32]([C:6]1[S:10][C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:8][C:7]=1[CH3:28])=[O:33])[CH3:30]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1Br
Reactant: CCOC(=O)C#N
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Ethylmagnesium chloride (10.9 ml, 2M in THF) is added over 30 minutes to a solution of 3-(5-bromo-4-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (10.0 g, Example 2, step D) in THF (15 ml) at 0° C. After 1 hour at room temperature, a solution of ethylcyanoformate (2.81 g) in THF (15 ml) is added to the reaction mixture. After 40 minutes, the reaction is quenched with a saturated aqueous solution of NH4Cl in water. The mixture is extracted three times with MTBE. The organic phases are combined, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid ethyl ester (5.6 g) as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 120 °C
Yield: 11.2 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 1-propanesulfonyl chloride (22.5 mL, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was chromatographed on reverse phase HPLC eluting with 0.1% aqueous trifluoroacetic acid/methanol (90/10) to 0.1% aqueous trifluoroacetic acid/methanol (5/95) to give the title compound (3 mg, 11%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (m, 9 H) 1.57 (m, 2 H) 1.69 (m, 3 H) 3.17 (t, J=7.74 Hz, 2 H) 4.49 (t, J=7.74 Hz, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (dd, J=8.82, 2.57 Hz, 1 H) 7.64 (d, J=2.21 Hz, 1 H) 7.75 (d, J=8.82 Hz, 1 H) 8.56 (dd, J=7.72, 1.84 Hz, 1 H) 8.90 (dd, J=4.41, 1.84 Hz, 1 H) 10.35 (s, 1 H) 14.09 (s, 1 H). MS (ESI−) m/z 532 (M−H)−.
Reaction SMILES: O1CCCC1.C(O)C.[Cl:9][C:10]1[C:11]([NH:35]C(C2CC2)=O)=[N:12][CH:13]=[N:14][C:15]=1[NH:16][C:17]1[C:22](=[O:23])[N:21]2[C:24]3([NH:31][C:32](=[O:33])[C:20]2=[C:19]([CH3:34])[CH:18]=1)[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3.[OH-].[Na+]>O>[NH2:35][C:11]1[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]2[C:22](=[O:23])[N:21]3[C:24]4([NH:31][C:32](=[O:33])[C:20]3=[C:19]([CH3:34])[CH:18]=2)[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[C:10]=1[Cl:9]
Reactant: Cc1cc(Nc2ncnc(NC(=O)C3CC3)c2Cl)c(=O)n2c1C(=O)NC21CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2ncnc(N)c2Cl)c(=O)n2c1C(=O)NC21CCN(C)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A flask containing tetrahydrofuran, ethanol and water (1:1:1, 5 mL each) was charged with 6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione (3, 0.17 g, 0.371 mmol) and sodium hydroxide (75 mg, 1.85 mmol). The reaction was stirred at 50° C. for 16 h. After completion, the reaction mass was extracted with 10% methanol in dichloromethane. Combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate concentrated under vacuum obtained solid was washed with ether and dried under vacuum to afford 6-((6-amino-5-chloropyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione as light yellow solid. Yield: 88 mg, 31%; MS (ESI) m/z 390.14 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.52 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.10 (brs, 2H), 3.30-3.20 (m, 2H), 2.90-2.82 (brs, 2H), 2.49-2.40 (m, 2H), 2.46 (s, 3H), 2.30 (s, 3H), 1.46-1.40 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[ClH:21].[OH:8][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])[CH2:11][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCCCCl)c1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cl
Product: O=C(CCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccccc1

Procedure:
A mixture of 27.6 g (0.1 mole) of α,α-diphenyl-4-piperidinemethanol, 21.6 g (0.11 mole) of 5-chlorovalerophenone, 20 g of potassium bicarbonate, and 0.1 g of potassium iodide in 300 ml of toluene and 25 ml of water is stirred and refluxed for 136 hours then worked up by the procedure described in Examples 2 and 3 to give 5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone hydrochloride, M.P. 162°-164°C.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][N:24]([C:48](=[O:53])[CH2:49][N:50]([CH3:52])[CH3:51])[CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:54][CH2:55][CH2:56][OH:57]>C(#N)C>[Br-:54].[C:1]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:48](=[O:53])[CH2:49][N+:50]([CH2:55][CH2:56][OH:57])([CH3:52])[CH3:51])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCN(CCCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CN(C)C
Reactant: OCCBr
Solvent: CC#N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCN(CCCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)C[N+](C)(C)CCO
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In a sealed system, (Z)-((2-(dimethylamino)acetyl)azanediyl)bis(propane-3,1-diyl) dioleate (269 mg, 0.360 mmol) was dissolved in ACN (10 mL) and 2-Bromoethanol (200 uL) was added. The reaction vessel was flushed with inert gas and then sealed. Reaction was heated to 80° C. and allowed to stir overnight. The reaction mixture was cooled and concentrated. Purification by silica gel chromatography with a DCM/MeOH gradient yielded 2-(bis(3-(oleoyloxy)propyl)amino)-N-(2-hydroxyethyl)-N,N-dimethyl-2-oxoethanaminium bromide (129 mg). QTOF MS ESI+: m/z 791.7 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.[C:34]([CH:39]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl>[C:11]([N:18]1[CH2:19][CH2:20][CH:21]([CH2:24]/[CH:25]=[CH:39]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:22][CH2:23]1)([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 54.8 %

Procedure:
To a stirred solution of oxalyl chloride (0.43 mL, 5.0 mmol) in CH2Cl2 (20 mL) at -78° C. was added DMSO (0.52 ml, 7.0 mmol) dropwise. After gas evolution subsided (~5 minutes) the alcohol 17 (0.8 g, 3.5 mmol) in CH2Cl2 (20 mL) was added in a stream. After 20 minutes triethylamine (1.7 mL, 12 mmol) was added dropwise and then the cooling bath removed. After 20 minutes (carbethoxymethylene) triphenylphosphorane (1.4 g, 4.0 mmol) was added. After 2.0 hours the reaction mixture was diluted with petroleum ether and then washed sequentially with H2O, 5% KHSO4, and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 15% ethyl acetate/hexanes) gave the ester 18 (0.57 g) as a colorless oil.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[NH4+:5].[NH4+].[O:7]=O>>[S:1]([O-:7])([O-:4])(=[O:3])=[O:2].[NH4+:5].[NH4+:5].[S:1]([O-:4])([O-:3])=[O:2].[NH4+:5].[NH4+:5]
Reactant: O=O
Agent: O=S([O-])[O-]
Agent: [NH4+]
Product: O=S(=O)([O-])[O-]

Procedure:
In an embodiment, the present invention provides for a process for reducing nitrogen oxides and halogenated organic compounds in an incineration plant having at least one combustion chamber. The process comprises separating out fly ash using a dust collector. Water is added to and hydrochloric acid separated out in a first acid-operated scrubber. Water and ammonia are added so as to separate out sulphur dioxide in a second neutral or slightly acid-operated scrubber so as to form ammonium sulphite, a portion of the ammonium sulphite being reacted with oxygen so as to form an aqueous ammonium sulphate/ammonium sulphite solution. The aqueous ammonium sulphate/ammonium sulphite solution is introduced into an oxygen-containing smoke gas downstream of a secondary gas introduction area so as to decompose the ammonium sulphate and ammonium sulphite so as to form ammonia and sulphur dioxide. Ammonia, oxygen and nitrogen oxides are reduced in the smoke gas by selective non-catalytic reduction so as to produce nitrogen and water, the chloride-containing fly ash in the smoke gas reacting with sulphur dioxide, water and oxygen so as to produce sulphates and hydrochloric acid.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13]([N:17]=[C:18]=[O:19])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:13]([NH:17][C:18]([NH:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN=C=O
Reactant: CC1(C)CC(N)CC(C)(C)N1O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Reaction time: 16 h

Procedure:
To a stirred solution of 1.0 g of 1-oxyl-4-amino-2,2,6,6-tetramethylpiperidine in 75 mL of dry toluene is added dropwise 0.65 mL of butyl isocyanate. The reaction mixture is stirred for 16 hours. The solution is then concentrated to yield the title compound as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: Oc1ccccc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccccc3F)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluorophenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 535.1 (M+H)+.
Reaction SMILES: [NH3:1].Cl[CH2:3][C:4]([N:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11](/[CH:15]=[CH:16]/[S:17]([N:20]2[CH2:41][CH2:40][C:23]3([N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=4)[NH:25][C:24]3=[O:39])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[C:10]([CH3:42])[CH:9]=1)[CH3:7])=[O:5]>C(O)C>[NH2:1][CH2:3][C:4]([N:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11](/[CH:15]=[CH:16]/[S:17]([N:20]2[CH2:41][CH2:40][C:23]3([N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=4)[NH:25][C:24]3=[O:39])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[C:10]([CH3:42])[CH:9]=1)[CH3:7])=[O:5]
Reactant: N
Reactant: Cc1cc(N(C)C(=O)CCl)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Solvent: CCO
Product: Cc1cc(N(C)C(=O)CN)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Temperature: 55 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
Ammonia (6 N solution in ethanol, 0.3 ml) was added to a solution of 2-chloro-N-(3,5-dimethyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-N-methyl-acetamide (38 mg, 0.06 mmol) in anhydrous ethanol (0.5 ml), and the mixture was stirred at 50 to 60° C. for five hours. The mixed solution was concentrated under reduced pressure, and the resulting residue was then purified by silica gel column chromatography (dichloromethane) to give 2-amino-N-(3,5-dimethyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-N-methyl-acetamide (11 mg, 31%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:37])[N:12]([CH:28]1[CH2:32][CH2:31][CH:30]([C:33]([O:35]C)=[O:34])[CH2:29]1)[CH2:13][CH2:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[OH-].[Li+]>CO.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:37])[N:12]([CH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1)[CH2:13][CH2:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc3ccccc3s2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc3ccccc3s2)C1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)cyclopentanecarboxylate 35 (308 mg, 600 μmol) in 10:1 MeOH/H2O (5.5 ml) was added lithium hydroxide hydrate (50.3 mg, 1199 μmol). The reaction mixture was stirred for overnight at 55° C. Volatiles were removed by concentration under reduced pressure. The leftover residue was solubilized with 60 mL of a 1:1 mixture of Water and Ethyl Acetate. An additional 2 mL of 2M KOH was added. The organic phase was separated and the aqueous phase was extracted further with ethyl acetate (2×20 mL). The organic extracts were discarded and the aqueous layer was acidified with 10 mL of 10% aqueous HCl and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica using 10->45% EtOAc/Hexanes as eluant to afford 36 as a white solid. LCMS (ES) calcd for C29H29N3O3S 499.2 found 500.2 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:12][CH3:13])C#N)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[CH2:14]([C:16]1[CH:17]=[C:18]([NH:22][C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1)[CH3:15].[H-].[Na+].[CH2:27](Br)[CH3:28]>C1COCC1.O.CO>[C:18]1([NH:22][C:23]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH2:12][CH3:13])=[NH:24])[C:17]2[C:16](=[CH:14][CH:15]=[CH:27][CH:28]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCBr
Reactant: CCc1cccc(NC#N)c1
Reactant: CCc1cccc(N(C#N)CC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1cccc(N(CC)C(=N)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
N-(m-Ethylphenyl)-N-ethylcyanamide: A suspension of m-ethylphenylcyanamide (2.26 g, 15.45 mmol) and sodium hydride (820 mg, 34.2 mmol, pre-washed thrice with hexane) in anhydrous THF (20 ml) was heated at 80°-85° C. for 2.5 hours. After it was allowed to cool to room temperature ethyl bromide (4.66 g, 42.76 mmol) was added and continued stirring at room temperature for 6 hours. Methanol (20 ml) followed by water (40 ml) were added and then extracted with dichloromethane (3×25 ml). Concentration of the organic layer followed by quick flash chromatography afforded the title compound (2.36 mg, 88%) as a light yellow liquid:
Reaction SMILES: [Na].Cl[CH:3]=[C:4]([Cl:8])[C:5](=[O:7])[CH3:6].[C:9]([OH:12])(=O)[CH3:10].[CH2:13]([OH:15])[CH3:14]>>[Cl:8][CH:4]([C:5](=[O:7])[CH3:6])[CH:3]([O:12][CH2:9][CH3:10])[O:15][CH2:13][CH3:14]
Reactant: CCO
Reactant: CC(=O)C(Cl)=CCl
Reactant: CC(=O)O
Agent: [Na]
Product: CCOC(OCC)C(Cl)C(C)=O
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 2.30 g of sodium metal in 180 ml ethanol, cooled in an ice-bath is added dropwise a solution of 13.90 g (0.10 mole) 1,2-dichloro-1-buten-3-one in 20 ml ethanol. The mixture is stirred for 2 hours, acidified with glacial acetic acid (4 ml) and the precipitated salt removed by filtration, washing with ethanol. The filtrate is concentrated in vacuo, the residue slurried in ethyl ether and filtered to remove salt. The ether is evaporated in vacuo and the residual oil is distilled to yield 12.49 g (64%) of the title compound, B.P. 52° C. at 1.5 torr. 1H-NMR (CDCl3) ppm (delta): 1.17 (t, 3H), 1.22 (t, 3H), 2.30 (s, 3H), 3.63 (m, 4H), 4.18 (d, 1H), 4.68 (d, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1)(=O)=O>CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nccc2ccccc12
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CO
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nccc3ccccc23)c1
Yield: 18.2 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.04 g) and 1-methylsulphonylisoquinoline (1.70 g) were fused at 135° C. for 51/4 hours. The cooled reaction mixture was taken up in methanol, filtered, evaporated and subjected to medium pressure column chromatography on silica (chloroform:methanol 1:19-second column using chloroform) to give the title compound (0.56 g) as an oil. This was treated with maleic acid (0.35 g) in warm ethanol to yield, on cooling, 1-[3-[3-(piperidinomethyl)phenoxy]propylamino]isoquinoline dimaleate (0.15 g), m.p. 103°-105° C. (recrystallised from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Temperature: 120 °C

Procedure:
5-Chloro-6-(quinolin-3-yloxy)-pyridin-3-yl amine (1 mmol) (obtained as per procedure described in preparation 1) was dissolved in toluene under heating. To the clear solution was added succinic anhydride (1 mmol) and refluxed at 120° C. for 6 hours. The solvent the evaporated and the crude obtained was purified by column chromatography to provide the title compound.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:19])([F:18])[C:4]1[CH:5]=[C:6]([S:14](Cl)(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1>>[F:2][C:3]([F:19])([F:18])[C:4]1[CH:5]=[C:6]([S:14]([NH2:1])(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
An aqueous solution of NH3 (32%) is added at RT to a solution of 3,5-bis(trifluoromethyl)-benzene-sulfonylchloride in EtAc. The mixture obtained is stirred and two phases are obtained and are separated. The organic layer obtained is washed with 1 N HCl and H2O, and dried. Solvent of the organic solution obtained is evaporated. 3,5-Bis-trifluoromethyl-benzene sulfonamide is obtained.