Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:35]2[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]2)=[N:5][CH:6]=[C:7]([C:9](=[O:34])[NH:10][C:11]2[S:12][C:13]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][CH2:23]3)=[C:14]([C:16]3[S:17][CH:18]=[C:19]([Cl:21])[CH:20]=3)[N:15]=2)[CH:8]=1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N-]=C=O.C(O)C(N)(CO)CO>C1COCC1>[ClH:2].[Cl:2][C:3]1[C:4]([N:35]2[CH2:40][CH2:39][CH:38]([C:41]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:42])[CH2:37][CH2:36]2)=[N:5][CH:6]=[C:7]([CH:8]=1)[C:9]([NH:10][C:11]1[S:12][C:13]([N:22]2[CH2:23][CH2:24][N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:26][CH2:27]2)=[C:14]([C:16]2[S:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[N:15]=1)=[O:34]
Reactant: C1COCCN1
Reactant: O=C(Nc1nc(-c2cc(Cl)cs2)c(N2CCN(C3CCCCC3)CC2)s1)c1cnc(N2CCC(C(=O)O)CC2)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2cc(Cl)cs2)c(N2CCN(C3CCCCC3)CC2)s1)c1cnc(N2CCC(C(=O)N3CCOCC3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 16 in 1.8 ml of THF (0.0856 mM), 39 mg of morpholine, 342 mg of PS-DCC (1.35 mmol/g), and 0.2 ml of a solution of HOBt in THF (0.77 mM) were added, and the mixture was stirred at room temperature overnight. To the reaction solution, 2 ml of THF, 370 mg of PS-isocyanate (1.25 mmol/g), and 205 mg of PS-trisamine (3.75 mmol/g) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the obtained residue was purified by silica gel column chromatography (chloroform-MeOH=99:1˜97:3) and the obtained compound was dissolved in 2 ml of EtOAc. And, 1 ml of 4M HCl-EtOAc was added thereto at room temperature, and the mixture was stirred for 15 minutes. The thus-precipitated solid was collected by filtration to obtain 84 mg of 5-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-6-[4-(morpholinocarbonyl)piperidino]nicotinamide hydrochloride.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH3:35]>CS(C)=O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][C:14]2[CH:15]=[C:11]([NH:10][C:8]([C:5]3[CH:4]=[N:3][C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH:30]([CH3:35])[CH2:31]4)=[CH:7][N:6]=3)=[O:9])[NH:12][N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: CC1CNCCN1C
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)C(C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (388 mg, 1.00 mmol) was added in one portion to 1,2-dimethyl-piperazine (228 mg, 2.00 mmol) in anhydrous dimethylsulfoxide (2.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (375 mg, 81%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:24]([O-])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:23])[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:23])[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[NH2:24]
Reactant: Cc1ccc(C(=O)c2ccc(Cc3ccc([N+](=O)[O-])cc3Cl)n2C)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(C(=O)c2ccc(Cc3ccc(N)cc3Cl)n2C)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
3-Chloro-4-{5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-ylmethyl}nitrobenzene (14.38 g, 39.0 mmol) [prepared as in Example 4, Step (c)] was dissolved in ethanol (300 ml) and an aqueous solution of ammonium chloride (14.0 g in 150 ml) and iron powder (14.0 g) were added to the solution. The reaction mixture was refluxed for 30 min, then cooled to room temperature and filtered. The filtrate was concentrated, diluted with water, and extracted with ether and methylene chloride. The organic layer were combined, washed with brine and dried over sodium sulfate. Evaporation gave 3-chloro-4-{5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-ylmethyl}aniline (12.09 g, 92%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[Si:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([N:35]2[C:39](=[O:40])[C:38]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]3[C:36]2=[O:45])=[C:32]([CH:34]=1)[NH2:33])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CC=CC=1>C(Cl)Cl.C(Cl)Cl.CO>[Si:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([N:35]2[C:36](=[O:45])[C:37]3=[CH:44][CH:43]=[CH:42][CH:41]=[C:38]3[C:39]2=[O:40])=[C:32]([CH:34]=1)[NH:33][C:13]([CH:10]1[CH2:9][CH2:8][N:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH2:12][CH2:11]1)=[O:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c(N)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c(NC(=O)C2CCN(c3ccncc3)CC2)c1
Reaction time: 0.75 h
Yield: 76.1 %

Procedure:
1-(4-Pyridyl)piperidine-4-carboxylic acid (176 mg, 0.85 mmol) and thionyl chloride (93 mL, 1.28 mmol) in 5 mL methylene chloride were heated under reflux for 2 h. The mixture was allowed to cool, concentrated in vacuo to a white foam and dried under vacuum. The foam was suspended in dry methylene chloride (5 mL) then added were 5-tert-butyldimethylsilyloxy-2-(phthalimido)aniline (314 mg, 0.85 mmol)(see Example 167, step C, above) as a solution in 5 mL methylene chloride and 1 mL pyridine in several portions. The cloudy mixture was stirred 45 min then passed through a 35×80 mm plug of silica gel eluting first with methylene chloride then with 9:1:0.1 methylene chloride/methanol/-ammonium hydroxide. Appropriate fractions were combined, concentrated in vacuo and dried under vacuum to yield 360 mg (76%) of the desired intermediate phthalimide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCOCC3)nc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 241.3, 290 mg, 0.87 mmol) in methanol (6 mL). Then a solution of sodium hydroxide (139 mg, 3.48 mmol) in water (3 mL) was added to the reaction. The reaction mixture was stirred for 1 h at 60° C., then concentrated under reduced pressure. The pH of the solution was adjusted to 1 with hydrogen chloride (2 M). The resulting mixture was concentrated under reduced pressure. Methanol (10 mL) was added to the residue. The salt was filtered off, and the filtrate was concentrated under reduced pressure to give 300 mg of the title compound as a brown solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:21]([O:23][CH3:24])=[O:22]>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:31]2[CH2:30][CH2:29][N:28]([C:27]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=3[CH3:17])[CH2:33][CH2:32]2)=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: COC(=O)c1ccc(N2CCNCC2)c(C)c1
Product: COC(=O)c1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 77.6 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (1.08 g) described in Preparation Example 16 and methyl 3-methyl-4-(piperazin-1-yl)benzoate (1.05 g) described in Preparation Example 97 and by the reaction and treatment in the same manner as in Example 87, the title compound (1.59 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].CC(C)=[O:12].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:12])=[O:9]
Reactant: COCCCCCCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COCCCCCC(=O)O

Procedure:
6-Methoxy-hexanol (8.16 g) was oxidized with Jones reagent (2.67-M, 53 ml) in acetone (100 ml) at -10° C. to give 6.17 g of 6-methoxy-caproic acid.
Reaction SMILES: CS([Cl:5])(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[C:9]([CH3:15])[CH:8]=1.C(N(CC)CC)C.O>ClCCl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:5])=[C:9]([CH3:15])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Br)ccc1CO
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
Methanesulfonyl chloride (6.83 mL, 88.3 mmol) is added slowly to a solution of (4-bromo-2-methyl-phenyl)methanol (16.14 g, 80.27 mmol) and triethylamine (16.78 mL; 120.4 mmol) in dichloromethane (80.7 mL) cooled in ice/water. The mixture is allowed to slowly warm to ambient temperature and is stirred for 16 hours. Further methanesulfonyl chloride (1.24 mL; 16.1 mmol) is added and the mixture is stirred at ambient temperature for 2 hours. Water (80 mL) is added and the phases are separated. The organic layer is washed with hydrochloric acid (1N; 80 mL) then saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2SO4. Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane) to give the title compound (14.2 g; 80.5% yield). 1H NMR (300.11 MHz, CDCl3): δ 7.36-7.30 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.ClCC(OC(=O)CCl)=O.ClCC(NCCCCCCC(OCC)=O)=O.C([O:36][CH:37]([CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:38][CH2:39][CH2:40][N:41]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([O:54]CC)=[O:53])[C:42](=[O:45])[CH:43]=C)(=O)C.OC(CCCCC)CCCN(CCCCCCC(O)=O)C(=O)C=C>>[OH:36][CH:37]([CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:38][CH2:39][CH2:40][N:41]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([OH:54])=[O:53])[C:42](=[O:45])[CH2:43][OH:3]
Reactant: C=CC(=O)N(CCCCCCC(=O)OCC)CCCC(CCCCC)OC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: C=CC(=O)N(CCCCCCC(=O)O)CCCC(O)CCCCC
Agent: CCOC(=O)CCCCCCNC(=O)CCl
Agent: O=C(CCl)OC(=O)CCl
Product: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(=O)CO

Procedure:
The synthesis of this compound is carried out as described in Example 2 except that, in Step A, the acetic anhydride is replaced by an equimolar amount of chloroacetic anhydride. The product of Step A is ethyl 7-(2-chloroacetamido)heptanoate. Subsequent steps yield: ethyl 7-[N-(4-acetoxynonyl)-2-chloroacetamido] heptanoate (B); and 7-[N-(4-hydroxynonyl-2-hydroxyacetamido]-heptanoic acid (C); (the basic hydrolytic conditions cause the replacement of the chlorine atom by hydroxy in this step).
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH2:3][O:4][NH2:5].[C:12]([N:16]=[C:17]=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([NH:16][C:17]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N=C=O
Reactant: CCN(CC)CC(O)CON
Solvent: ClC(Cl)Cl
Product: CCN(CC)CC(O)CONC(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
O-(2-hydroxy-3-diethylamino-propyl)-hydroxylamine was dissolved in 40 ml abs chloroform and 3,08 ml (0,027 mol) tert-butyl isocyanate was added thereto dropwise. The mixture was stirred at room temperature for 15 hours and evaporated. The product thus obtained was purified by column chromatography. The material thus obtained is in oily form which crystallizes when storing in refrigerator. The crystals were filtered after trituration with petroleum ether. Yield: 1,44 g (20%). Mp.: 58-61° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH2:28])=[CH:23][CH:22]=2>CCO>[CH3:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:23][CH:22]=2
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Solvent: CCO
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCCC5)sc34)ccc2[nH]1
Temperature: 25 °C
Yield: 112.4 %

Procedure:
A solution of (7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone (0.359 g, 1.34 mmol) and 2-methyl-1H-indol-5-ylamine (0.19 g, 1.3 mmol) in EtOH (10 mL) was heated to reflux for 48 h. The reaction mixture was cooled to room temperature and concentrated onto silica gel (5 mL). Purification by flash chromatography on silica gel eluting with CH2Cl2/NEt3 (99.5/0.5) afforded the title compound as a yellow solid (550 mg) MS: 377.2 (MH+); HPLC Rf: 4.45 min; HPLC purity: 97%.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(=O)([O-])[O-].[Na+].[Na+].CO.Br[CH2:20][CH:21]=[C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:21][CH2:20][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCC=C(c1ccccc1)c1ccccc1
Reactant: O=S([O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(=O)(CC=C(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
15.5 gm of sodium phenyl sulfinate and 1.5 gm of sodium carbonate were introduced into 80 cc of methanol. Then 25.6 gm of 1-bromo-3,3-diphenyl-2-propene were added to the reaction mixture under an atmosphere of nitrogen and at room temperature which was then agitated for 1 hour and 30 minutes. Next, the reaction mixture was poured into cold water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with water, dried and concentrated to dryness. The residue was partly crystallized. The precipitate formed was isolated by vacuum filtering and dried to obtain 25.48 gm of (3,3-diphenyl-2-propenyl)-phenyl sulfone having a melting point of 104° C. A sample of this product, recrystallized from isopropyl ether, had a melting point of 106° C.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]#[C:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][CH2:12]1)C)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:6][NH:8][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]#[C:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:16]1
Reactant: CN(C[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Reaction time: 0.25 h

Procedure:
A solution of 12.5 g (corresponds to 28.9 mmol) of crude trans-methanesulfonic acid 3-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexyl}-prop-2-ynyl ester in 160 ml methylenechloride was treated at 0° C. with 78 ml of trifluoroacetic acid (for 30 minutes). After 15 minutes at this temperature, the reaction was evaporated, redissolved in toluene and evaporated (4×) to give 23.12 g of crude trans-methanesulfonic acid 3-(4-methylaminomethyl-cyclohexyl)-prop-2-ynyl ester trifluoro-acetate as dark brown viscous oil, MS: 260 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(OC([N:20]1[CH2:25][CH2:24][C:23]2([CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1)=O)(C)(C)C>>[CH2:22]1[C:23]2([CH2:30][CH2:29][CH:28]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)[CH2:27][CH2:26]2)[CH2:24][CH2:25][NH:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Reactant: O=c1ccc2ccc(O)cc2o1
Product: O=c1ccc2ccc(OC3CCC4(CCNCC4)CC3)cc2o1

Procedure:
Was prepared according to method A from 7-hydroxycoumarin and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>O1CCCC1>[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:8][CH:9]=[CH:10][N:11]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.642 g, 2.56 mmol) in tetrahydrofuran (9.39 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (2.68 ml, 2.68 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see Example 73, Step 1; 1.0 g, 2.441 mmol) in THF (5 mL) was added drop wise, and the reaction was stirred for 30 minutes. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on an 80-g with 0 to 50% EtOAc/Heptane to afford 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE OOO) as a white solid. (ESI) 498.2 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:10]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([I:9])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(I)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(I)ccc1CBr
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of 3-chloro-4-methyliodobenzene (9.0 g), N-bromosuccinimide (8.5 g), benzoyl peroxide (0.3 g) and carbon tetrachloride (80 ml) was stirred and heated to reflux for 3 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated to give 4-bromomethyl-3-chloroiodobenzene (11 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:23]([C:22]([O:29][CH3:30])=[O:28])[C:24]([O:26][CH3:27])=[O:25])[CH2:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(=O)OC
Product: COC(=O)C(C(=O)OC)C(CC(=O)c1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 3-(4-chlorophenyl)-1-(4-(trifluoromethyl)-phenyl)prop-2-en-1-one and dimethyl malonate, dimethyl 2-(1-(4-chlorophenyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)-propyl)malonate was obtained as colourless solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[CH:30][CH:29]=3)=[CH:24][C:19]=2[C:18](=[O:38])[N:17]([CH3:39])[C:16]2[CH:40]=[CH:41][C:42]([C:44]([F:47])([F:46])[F:45])=[N:43][C:15]1=2)[CH3:13]>C(Cl)Cl>[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N+:31]([O-:9])=[CH:30][CH:29]=3)=[CH:24][C:19]=2[C:18](=[O:38])[N:17]([CH3:39])[C:16]2[CH:40]=[CH:41][C:42]([C:44]([F:46])([F:45])[F:47])=[N:43][C:15]1=2)[CH3:13]
Reactant: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(C(F)(F)F)nc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCN1c2ncc(CCOc3cc[n+]([O-])c4ccccc34)cc2C(=O)N(C)c2ccc(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54 %

Procedure:
Solid mCPBA (80-85%, m-chloroperbenzoic acid) (16 mg, 0.08 mmol) was added to a solution of 5,11-dihydro-11-ethyl-5-methyl-8-{2-(4-quinolinyloxy)ethyl}-2-(trifluoromethyl)-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (22 mg, 0.04 mmol) in CH2Cl2 (0.5 mL) at room temperature. The mixture was stirred at room temperature for 2.5 h then diluted with CH2Cl2. The resulting solution was successively washed with aqueous 10% Na2S2O3, aqueous saturated NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH:CHCl3, 5% to 10%) to give the title compound (11 mg, 52% yield) as a white solid: MS (ESI) m/z 511 (MH)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[OH-].[Na+].O>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=3)[N:11]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C(N)=O)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of methyl 2-(4-carbamoylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (103 mg, 0.27 mmol) in MeOH (20 mL) was added sodium hydroxide (68 mg, 1.69 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (2 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(4-carbamoylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a brown solid (57.9 mg, 58%).