Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](O)=[O:19])=[CH:15][CH:16]=2)[N:11]([S:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.N1C(Cl)=NC(Cl)=NC=1Cl.[CH2:49]([O:51][C:52](=[O:60])[C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1)[CH3:50]>CC(C)=O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:19])[NH:59][C:56]3[CH:57]=[CH:58][C:53]([C:52]([O:51][CH2:49][CH3:50])=[O:60])=[CH:54][CH:55]=3)=[CH:15][CH:16]=2)[N:11]([S:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)O)cc21
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester (100 mg, 0.21 mmol) in acetone (30 mL) and tetrahydrofuran (10 mL) was treated with triethylamine (21 mg, 0.21 mmol) and stirred at room temperature 1 hour. A solution of cyanuric chloride (46 mg, 0.25 mmol) in tetrahydrofurane (2 mL) was added dropwise over a period of 1 hour. The reaction mixture was stirred at room temperature for 2 hours, then 4-amino-benzoic acid ethyl ester (51 mg, 0.31 mmol) and a further aliquot of triethylamine (42 mg, 0.42 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours, the solvents were then removed. The residue was purified by flash chromatography, to yield 4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester as a light yellow solid, 100 mg (77%), δH (300 MHz; CDCl3) 8.01-8.08 (4H, m), 7.94 (1H, d), 7.73-7.77 (3H, m), 7.48 (1H, dd), 6.82 (1H, d), 4.38 (2H, q), 3.89 (2H, m), 3.64 (2H, m), 3.47 (3H, s), 1.48 (9H, s), 1.40 (3H, t).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:16][CH3:17])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[CH2:23]([O+](CC)CC)[CH3:24]>C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[C:11]([O:15][CH2:23][CH3:24])=[N:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:16][CH3:17])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c2c1CCNC2=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NCCc2c(CC)nn(C3CCCC3)c21
Reaction time: 21 h

Procedure:
esterifying said lactam compound of Formula (9.0.0) using triethyloxonium tetrafluoroborate, (CH3CH2)2OBF4; wherein a reaction mixture is established by slowly adding a solution of triethyloxonium tetrafluoroborate, (CH3CH2)3OBF4 in methylene chloride to a suspension of said lactam compound of Formula (9.0.0) in methylene chloride over a period of 40 minutes; and thereafter, maintaining said reaction mixture at a temperature of from 18° to 22° C., for a period of 21 hours; whereby there is produced a corresponding imino ester (imidate) compound of Formula (10.0.0):
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Br:18]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:18][C:7]1[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:9][C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCO2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cc2c(cc1Br)OCC2
Temperature: 65 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a mixture of tert-butyl (2,3-dihydro-1-benzofuran-5-yl)carbamate (410 mg) and acetonitrile (9.00 mL) was added N-bromosuccinimide (341 mg), followed by stirring at 65° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 92:8) to obtain tert-butyl (6-bromo-2,3-dihydro-1-benzofuran-5-yl)carbamate (178 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:20])[C:3]=1[N+:21]([O-])=O>O1CCCC1.C(O)(=O)C.[Zn]>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=2)[N:5]=[C:4]([NH2:20])[C:3]=1[NH2:21]
Reactant: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(N)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(N)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
To a vigorously stirred solution of 6-methyl-5-nitro-N*2*-(4-trifluoromethylbenzyl)-pyrimidine-2,4-diamine (450 mg, 1.376 mmol) in tetrahydrofuran (20 ml) and acetic acid (5 ml) on cold water bath, zinc powder (particle size<10 micron, 5 g) was added by portions in 2 min. Water bath was removed and more zinc powder (2 g) were added. The suspension was stirred at ambient temperature for 60 min and quenched with 10% aqueous sodium carbonate to pH>8. The obtained suspension was extracted with ethyl acetate (10 times). The combined organic solution was filtered via plug of silica gel (10 g) and eluted with 20% in ethyl acetate to give 430 mg of pale yellow oil after evaporation. The product solidified after drying in vacuo. Yield 100%. It was used in the next step without further purification. LC-MS (m/z) 298.1 (MH+); tR=1.68. 1H NMR (500 MHz, DMSO-d6): 2.02 (s, 3H), 3.1-3.8 (br, NH2+H2O), 4.43 (d, 2H), 5.88 (br, 2H), 6.26 (t, 1H, NH), 7.48 (d, 2H), 7.62 (d, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][C:10](=[CH:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[C:8]3=2)[O:3][CH2:2]1.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.C(=O)([O-])O.[Na+]>[CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH:11]=[C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[C:8]3=2)[O:3][CH2:2]1
Reactant: CCC(=O)NCC=C1CCc2cnc3c(c21)CCO3
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCC(=O)NCCC1=CCc2cnc3c(c21)CCO3
Yield: 15.8 %

Procedure:
To a solution of N-[2-(1,2,6,7-tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridin-8-ylidene)ethyl]propanamide (612 mg, 2.37 mmol) in xylene (20 mL) was added sulfuric acid (693 μL, 12.9 mmol), and the mixture was heated under reflux for 22 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and recrystallization (ethyl acetate) to give the title compound (97.0 mg, yield 16%).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([CH2:18][CH2:19]O)=[C:16]([CH3:21])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:28])CC)C.O>ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([CH2:18][CH2:19][F:28])=[C:16]([CH3:21])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1CCO
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1CCF
Reaction time: 4 h

Procedure:
2.0 g (6.5 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-methyl-5-(2-hydroxyethyl)pyrimidine (Example 33) were dissolved in 30 ml of dichloromethane, and 1.16 g (7.2 mmol) of diethylaminosulfur trifluoride (DAST) were added at -50° C. The mixture was allowed to rise to room temperature, and was subsequently stirred for 4 hours. It was poured into water, the dichloromethane phase was extracted by stirring with sodium hydrogen carbonate solution and the organic extracts were dried and concentrated. Chromatography on silica gel gave 1.55 g (77.6% of theory) of product as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:36])=[C:25]([CH:27]=[N:28][C:29]([O:31][Si](C)(C)C)=[CH2:30])[CH:26]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C:6]3([CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=4)[CH2:31][C:29](=[O:30])[NH:28][CH:27]3[C:25]3[CH:26]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=3[CH3:36])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(N=Cc1cc(Cl)ccc1C)O[Si](C)(C)C
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12

Procedure:
In a manner similar to the method described in example 157b, E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 157a was reacted with 1-(5-chloro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 160a, in toluene to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2,3-dihydro-2′-(5-chloro-2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine] as a white solid. (Yield 0.3 g, 51%).
Reaction SMILES: [CH:1]([S:4]([O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[OH:38]>>[CH:1]([S:4]([O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[C:23]2[OH:38])=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Oc1ccc(OCC2CO2)cc1
Reactant: NCCn1c(O)nc2cc(C3=NNC(=O)CC3)ccc21
Product: CC(C)S(=O)(=O)Oc1ccc(OCC(O)CNCCn2c(O)nc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-(4-isopropylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].CCN=C=NCCCN(C)C.[ClH:19].C1C=CC2N(O)N=NC=2C=1.[C:30]1([C@H:40]([N:42]([CH2:50][CH:51]2[CH:55]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH2:54][NH:53][CH2:52]2)C(=O)OC(C)(C)C)[CH3:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>O.C(#N)C>[ClH:19].[CH3:6][C:2]([OH:1])([CH3:7])[C:3]([N:53]1[CH2:54][CH:55]([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:51]([CH2:50][NH:42][C@@H:40]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)[CH3:41])[CH2:52]1)=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC#N
Product: C[C@@H](NCC1CN(C(=O)C(C)(C)O)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 60 °C
Reaction time: 12 h
Yield: 10.2 %

Procedure:
An 8 ml acetonitrile solution of 192 mg of 2-hydroxy-2-methylpropanoic acid was mixed with 392 mg of WSC hydrochloride, 62 mg of HOBt and 400 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[4-phenylpyrrolidin-3-yl]methyl}carbamate and stirred at 60° C. for 12 hours. After completion of the reaction, 30 ml of water was added thereto, and acetonitrile was evaporated. This was extracted with ethylamine, the organic layer was concentrated, and then the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate). This was further mixed with 2 ml of ethyl acetate and 0.5 ml of 4 M hydrogen chloride/ethyl acetate and stirred at 60° C. for 4 hours. After completion of the reaction, this was neutralized with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate and concentrated, and then the thus obtained residue was again purified by a silica gel column chromatography (chloroform-ethyl acetate), treated with 4 M hydrogen chloride/ethyl acetate and crystallized (ethyl acetate-hexane) to obtain 43 mg of 2-methyl-1-[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-1-oxopropan-2-ol hydrochloride as a colorless solid
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][CH:13]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[N:25]12[CH2:32][CH2:31][CH:28]([CH2:29][CH2:30]1)[C@@H:27](O)[CH2:26]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:24][O:23][C:20]1[N:19]=[CH:18][C:17]([CH:13]([NH:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14](=[O:16])[O:15][C@@H:27]2[CH:28]3[CH2:31][CH2:32][N:25]([CH2:30][CH2:29]3)[CH2:26]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cccc(NC(C(=O)O)c2ccc(OC)nc2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A mixture of 2-(3-(ethoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I64) (951 mg, 2.51 mmol), (R)-quinuclidin-3-ol (694 mg, 5.47 mmol), HOBT (837 mg, 5.47 mmol), and DCC (1.13 g, 5.47 mmol) in dry THF (35 ml) was stirred at room temperature overnight. The solvent was evaporated, and the crude product was partitioned between DCM and 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DMC/MeOH=97/3 to 95/5) to obtain ethyl 3-(1-(6-methoxypyridin-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (348 mg, 27.5% yield).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12](O)=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([Cl:22])=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1
Reactant: O=S(Cl)Cl
Reactant: CCCCCC(CC(=O)O)c1cccc2c1OCO2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCC(CC(=O)Cl)c1cccc2c1OCO2

Procedure:
To a solution of 2.64 g (10 mmol) of 3-(2, 3-methylenedioxyphenyl)octanoic acid in 25 ml of methylene chloride were added 1.46 ml (20 mmol) of thionyl chloride and 0.1 ml of N, N-dimethylformamide, and the resultant mixture was stirred at room temperature for 4 hours and concentrated in vacuo to give 3-(2, 3-methylenedioxyphenyl)octanoic acid chloride as a crude oil. A solution of this acid chloride in 15 ml of methylene chloride was dropwise added to a solution of 1.95 g (11 mmol) of 2, 6-diisopropylaniline and 1.67 ml (12 mmol) of triethylamine in 40 ml of methylene chloride chilled with water under stirring. Stirring was continued for 2 hours, and the reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/6) and crystallized from hexane to give 3.60 g (Yield, 85%) of N-(2, 6-diisopropylphenyl)-3-(2, 3-methylenedioxyphenyl)octanamide as white crystals,
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22](O)=[O:23])=[O:18]>>[CH3:28][C:26]1[N:27]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:20]=[C:21]([C:22](=[O:23])[NH:12][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=2)[CH3:11])[CH:25]=1
Reactant: COC(=O)c1cc(C(=O)O)cc(C)n1
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Product: COC(=O)c1cc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)cc(C)n1

Procedure:
The title compound is prepared from (+)-1-(3-(trifluoromethoxy)phenyl)ethanamine (Amine-9) and 2-(methoxycarbonyl)-6-methylisonicotinic acid by the similar manner in Step-1 of Example 8.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[C:11]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH3:21])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>ClCCl>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[C:11]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=2)[CH3:21])[N:10]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Yield: 102.4 %

Procedure:
A mixture of ethyl 2-bromoacetate (0.23 g), 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (0.40 g), anhydrous potassium carbonate (0.19 g) and methyl ethyl ketone was heated under reflux for 12 hrs. The mixture was cooled, diluted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give an oil, which was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}acetate (0.52 g) as a yellow crystalline solid, mp 99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]2[C:14]3[C:3]=1[CH2:4][CH2:5][C:6]=3[CH:7]=[CH:8][C:9]=2[Cl:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([NH:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]2[C:14]3[C:3]=1[CH2:4][CH2:5][C:6]=3[CH:7]=[CH:8][C:9]=2[Cl:15])(=[O:18])[CH3:17]
Reactant: Nc1cc(Cl)c2c(Cl)ccc3c2c1CC3
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c2c(Cl)ccc3c2c1CC3
Temperature: 10 °C

Procedure:
A suspension of 3-amino-5,6-dichloroacenaphthene (3.3 g, 13.8 mmol, from Example D4) in 10 mL of acetic acid was treated with 10 mL of acetic anhydride and heated on a steam bath for 1 hour. The reaction was cooled to 10° C., and the solid was removed by filtration, washed with petroleum ether, and dried in vacuo to give 3.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Cl)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(CBr)c1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
40.4 g of methyl 4-chloro-3-methylbenzoate, 39 g of N-bromosuccinimide and 1 g of azobisisobutyronitrile were added to 300 ml of carbon tetrachloride, followed by reflux under heating for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, insoluble matters were collected by filtration and the filtrate was concentrated. The obtained crude crystals were washed with hexane to obtain 34.3 g of methyl 3-bromomethyl-4-chlorobenzoate as white crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:7]3[C:8]=2[C:4]=1[CH:5]=[C:6]3[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23]([O-:26])(=[O:25])[CH3:24].[K+].[Cl-].[Na+]>CN(C)C=O>[C:23]([O:26][CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:7]3[C:8]=2[C:4]=1[CH:5]=[C:6]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:25])[CH3:24]
Reactant: CCOC(=O)c1cc2c(CBr)ccc3c2n1CCCCC3=O
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(COC(C)=O)ccc3c2n1CCCCC3=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-bromomethyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (2.92 g, 8.02 mmol), potassium acetate (1.18 g, 12.0 mmol) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was poured into 10% aqueous sodium chloride solution and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified with silica gel column chromatography (eluated with ethyl acetate/n-hexane=1/5) to give 2.33 g of ethyl 5,6,7,8-tetrahydro-11-acetoxymethyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[F:7][C:8]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([F:18])[C:11]([F:19])=[C:10]([F:20])[C:9]=1[F:21]>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:6]2[CH2:5][CH2:4][CH2:3][N:2]([S:14]([C:13]3[C:8]([F:7])=[C:9]([F:21])[C:10]([F:20])=[C:11]([F:19])[C:12]=3[F:18])(=[O:16])=[O:15])[N:1]=2)=[CH:10][CH:9]=1
Reactant: c1ccnnc1
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Product: O=S(=O)(c1c(F)c(F)c(F)c(F)c1F)N1CCCC(c2ccc(F)cc2)=N1

Procedure:
The title compound was prepared as described in Example 3 starting with pyridazine (1C) (R1 =4-F) and pentafluorobenzenesulfonyl chloride to give a solid: mp 140°-141° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:7]=1
Reactant: Cc1ccc(NCc2cccnc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(N(Cc2cccnc2)S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
A 3.5 g. portion of 3-(4-methylphenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.7 g. of potassium carbonate and 2 ml. of methanesulfonyl chloride were added. The mixture was stirred overnight under reflux, and was then extracted with 20 ml. of water and evaporated under vacuum. The residue was triturated with diethyl ether and dried to obtain 4.5 g. of the desired product, m.p. 143°-146°.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:9][NH:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.O>ClCCl>[Si:5]([O:13][CH2:12][CH2:11][NH:10][CH3:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CNCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of tert-butyldimethylchlorosilane (4.2 g, 27.9 mmol) in dichloromethane (10 mL) was added dropwise over 3 min to a stirred solution of 2-(methylamino)ethanol (2.0 g, 26.6 mmol) and imidazole in dichloromethane (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water (20 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane then the combined organic phases were passed through a phase separation cartridge and the solvent removed under reduced pressure to afford a colorless oil (5.10 g, 95%). This was taken through to the next step with no further purification.